\r\n\t \r\n\tRecently in 2019, International Council on Systems Engineering (INCOSE) has released the latest version of the “Guidelines for the Utilization of ISO/IEC/IEEE 15288 in the Context of System of Systems (SoS) Engineering” to industry for review and comments. The document was developed under the Partner Standards Development Organization cooperation agreement between ISO and IEEE, as it was approved by Council Resolution 49/2007. This document provides guidance for the utilization of ISO/IEC/IEEE 15288 in the context of SoS in many domains, including healthcare, transportation, energy, defense, corporations, cities, and governments. This document treats an SoS as a system whose elements are managerially and/or operationally independent systems, and which together usually produce results that cannot be achieved by the individual systems alone. This INCOSE guide book perceives that SoS engineering demands a balance between linear procedural procedures for systematic activity and holistic nonlinear procedures due to additional complexity from SoS perspectives. \r\n\tThe objective of this book is to provide a comprehensive reference on Systems-of-Systems Engineering, Modeling, Simulation and Analysis (MS&A) for engineers and researchers in both system engineering and advanced mathematical modeling fields. \r\n\tThe book is organized in two parts, namely Part I and Part II. Part I presents an overview of SOS, SOS Engineering, SOS Enterprise Architecture (SOSEA) and SOS Enterprise (SOSE) Concept of Operations (CONOPS). Part II discusses SOSE MS&A approaches for assessing SOS Enterprise CONOPS (SOSE-CONOPS) and characterizing SOSE performance behavior. Part II focuses on advanced mathematical application concepts to address future complex space SOS challenges that require interdisciplinary research involving game theory, probability and statistics, non-linear programming and mathematical modeling components.
\r\n
\r\n\tPart I should include topics related to the following areas: \r\n\t- SOS and SOS Engineering Introduction \r\n\t- Taxonomy of SOS \r\n\t- SOS Enterprise (SOSE), SOSE CONOPS, Architecture Frameworks and Decision Support Tools
\r\n
\r\n\tPart II should address the following research areas: \r\n\t- SOS Modeling, Simulation & Analysis (SOS M&SA) Methods \r\n\t- SOS Enterprise Architecture Design Frameworks and Decision Support Tools \r\n\t- SOS Enterprise CONOPS Assessment Frameworks and Decision Support Tools.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"677fbbd5fc2550e8be540f40c0969a62",bookSignature:"Dr. Tien Manh Nguyen",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7772.jpg",keywords:"Autonomy of Constituents, Operational Independence, Taxonomy, Acquisition Classification, SOS Enterprise Architecture Design, Decision Support Tools, State Modeling, SOS Simulation Methods, DOD Architecture Framework, Enterprise System Engineering, SOS Enterprise CONOPS, Satellite Operations (SATOPS)",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 31st 2019",dateEndSecondStepPublish:"November 21st 2019",dateEndThirdStepPublish:"January 20th 2020",dateEndFourthStepPublish:"April 9th 2020",dateEndFifthStepPublish:"June 8th 2020",remainingDaysToSecondStep:"21 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,editors:[{id:"210657",title:"Dr.",name:"Tien",middleName:"Manh",surname:"Nguyen",slug:"tien-nguyen",fullName:"Tien Nguyen",profilePictureURL:"https://mts.intechopen.com/storage/users/210657/images/system/210657.jpg",biography:"Dr. Tien M. Nguyen received his M.A. in Mathematics, and his Ph.D. in Applied Mathematics from the Claremont Graduate University; M.S.E.E. in Communication Systems Theory from University of California San Diego; and B.S.E. in Electronics and M.S.E. in Electromagnetic Field Theory from California State University Fullerton (CSUF). He also completed all course requirements and passed the comprehensive exam for his M.S.E.E. in Digital Signal Processing from California State University Long Beach. Dr. Nguyen is an expert in Satellite Operations (SATOPS), Satellite Communications (SATCOMs), advanced mathematical modeling for complex systems-of-systems, sensing and communication networks.\nCurrently, he serves as Adjunct Research Professor at CSUF, Mathematics Dept. Concurrently, he is also with the Aerospace Corporation, serving as a Sr. P.E. in Space System Group Program Office, Space System Architect Division, Global Partnerships Subdivision. He has more than 13-years of service at Aerospace, and prior to his current position; he has served as Sr. Engineering Specialist, Sr. Project Lead, Section Manager, Associate Director, Interim Director, and Principal Technical Staff (the highest technical level at the corporation). At Aerospace, he invented HPA linearizer, GMSK synchronizers and developed advanced optimization techniques using game theory for achieving affordable and low-risk acquisition strategy. Prior to CSUF, he had also held a Research Assistant Professor at the Catholic University of America in concurrent with The Aerospace Corporation positions. \nHe was a Engineering Fellow from Raytheon, where he had 10-year of services at Raytheon, serving as Program Area Chief Engineer, Program Chief Engineer, PI, Technical Director, Program Manager, Lead Architect and Lead System Engineer for many advanced programs and pursuits related to sensing and communication networks. At Raytheon, he invented radar-communication technology and gun barrel detector using millimeter-wave. Previous to Raytheon and Aerospace Corporation, Dr. Nguyen was with NASA/JPL for more than 11-years, where he served as the NASA delegate to the international Consultative Committee for Space Data System (CCSDS). Many of his works on RF and Modulation were adopted as the CCSDS standards for USB waveforms and space RF systems. At JPL he invented QPSK phase ambiguity resolver and developed innovative optimization technique for simultaneous range-command-telemetry operation. He built the first laser lab and automated manufacturing lab when he was with ITT Technical Services in the early ’80s. \nHe has published more than 250 technical reports and papers. His work has appeared in NASA TechBrief, textbook, Open Access Book, SIAM Publication, CCSDS Blue Book, and Wiley & Sons Encyclopedia of Electrical and Electronics Engineering. He was selected as a Vietnamese-American Role Model by KCSI-TV, Channel 18 in 2002, and Recognition Honoree at 50-Year Celebration of CSUF in 2007. He received numerous Raytheon, Aerospace and NASA awards, and Air Force commendations. He holds 16 patents. 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\n
1. Introduction
\n
The objective of this study is to analyze the institutional and organizational structure of public service companies in Italy. This structure was the subject of a profound reform generated by reasons of public finance protection. After analyzing the concept of the public sector and the object of this study, the theoretical framework of the analysis will be addressed, which will be carried out from a historical-temporal perspective, with an interpretation of a company nature on observation phenomena.
\n
In this sense, recalling what is reported in national and international literature, we analyzed the different strands of research that characterized the various reforms of the public administration. Research areas have shifted the objectives of the studies toward conditions of greater efficiency and value of public performance while allowing to identify and analyze the evolution of the various systems of planning and control of public administration. In consideration of the pathological phenomena that have occurred with increasing frequency in recent years, research has focused on the crisis and the insolvency of publicly owned companies, as, for the first time and recently the legislator has organically regulated the consequences of the insolvency of the same, affirming their general submission to bankruptcy and insolvency proceedings. Still the norm also outlined the procedure for the adoption of preventive plans should aim to avoid insolvency in financial hardship cases and to remedy the crisis of the investee companies. After having dealt with the issue of historical evolution and territorial distribution of the phenomenon of public enterprises in Italy, aspects of the legal framework of the object of study will be addressed. This last topic is very controversial in doctrine; in fact, far from being a mere academic exercise, the qualification of the legal nature of such enterprises involves significant practical consequences on the disciplinary level. The next section analyzes the contents of the reform of public companies, recalling the reference standards and the important news concerning the coverage of losses of companies. The new discipline produces important repercussions on public budgets and therefore on the community: for this reason the conclusions of the study will deal with this aspect.
\n
\n
\n
2. What constitutes the public sector and the public entities: defining boundaries
\n
The public sector is traditionally constituted by all organizations owned and controlled by government, which provide utilities and services to the community [1].
\n
Especially public complex and difficult to define, inputs are not being easily measured, and as a consequence, it is difficult to value the public sector efficiency [2].
\n
Public entities differ from private sector organizations, but rather the delivery of outcomes to stakeholders [3].
\n
Bossi et al. [4] have identified specific characteristics that define the public sector in relation to the private sector:
Less incentive to adopt new management approaches, due to a non-competitive environment.
Intangible objectives are less linked with the market value and financial profit.
More importance is given to social and environmental responsibility.
Most public organizations provide services (education, health, etc.), that is, intangibles.
Intangibles—knowledge and human resources.
Inflexible management procedures and rigid structures—the bureaucratic model does not facilitate new approaches.
Less necessity to quantify.
Increase in external demand for accountability and transparency in the use of public funds.
\n
In general terms, we can point out that the public sector has experienced great processes of intense transformation which have been caused mainly by two factors: (1) financial and tax burdens, and as a result, the increasing importance of an efficient public sector management and (2) society’s new demands to improve services [5].
\n
The modern public sector management boasts public attention and service quality, which justifies the need to establish a series of initiatives to help efficiency and effectiveness in the public function.
\n
The concepts related to innovation in the public sector can be included in new managerial view (or framework) of governmental administration called new public management (NPM) [6] since public service quality improves.
\n
According to the paradigm of NPM, the role of public entities is changed to the name of decentralization, increase in autonomy of public managers, competition, quality strategies, economy, efficiency and efficacy, citizen guidance, emphasis on private sector management techniques, and performance indicators.
\n
Since the new vision of public administration is the result of a process for the introduction of the principles of NPM [7, 8, 9].
\n
NPM has brought about transformations in managing entities in public entities, whose main characteristics—defined by Hood [10], Olsen and Peters [11], and Hodges and Mellet [8]—include a wide variety of changes such as deregulation, decentralization, subcontracting, substitution of input control systems, management of results, responsibility assignment, and the introduction of different management techniques. The ultimate objective of these reforms is to improve the efficacy and effectiveness of public entities, surpassing bureaucratic problems and guaranteeing transparency in entities and accounts renderings.
\n
As a result of NPM, public entities better response to the needs of service users, emphasis on performance and result management, introduction of performance standards, better communication of results, decentralization and competence of financial and personal management, interest in market forces and the creation of internal markets, privatization of public companies, and application of private sector management methods [12].
\n
These characteristics all justify the need to draw together in an easily understandable system to those elements that are differentiating the sources of competition and that will generate value for the administration, such as the focus on the citizen, social responsibility, and professionalism.
\n
In order to achieve this task, we consider public funding, ownership and operation of services. These organizations may be part of two areas of activity: the other is those monopolies which supply services and utilities and which also charge their customers for their services. In the 1990, the policy of privatization has made it more difficult the identification of public sector, given the less direct links which now exist between organizations and government.
\n
The provision of public services may be organized in a variety of ways and controls through different organizational and regulatory mechanisms. Public services might have some element of government funding, ownership, public direction, or regulation, in different combinations, but there is no longer a need for direct government ownership for the provision of these public services. This study includes some hybrid organizations, in which private sectors were used by the public sector and public service organizations were urgent to be “commercial.”
\n
Public services are those activities that are enshrined within the public service rather than the private provision through market. It is assumed these “public services” should be available for all members of the society provided in an equitable fashion [1].
\n
Regime around it is a complex of domains of public services that relies on the perceived nature of the services. This is for several reasons. The main issue concerns the nature of public services and is widely used by the public services to be provided, that is, the boundary of public services is not fixed but varies from country to country. Thus, we use only the public services business (PBE) but not public institutional systems (PIS).
\n
In light of this premise, the research field identifies which universe of companies on which the investigation is to be carried out partially or totally held directly or indirectly by public administrations, with the following legal form:
Srl and SpA
Srl and SpA in cooperative form
Consortium companies in the form of Srl or SpA
\n
\n
\n
3. Public companies in Italy: evolutionary profiles
\n
The reasons behind the latest reform of publicly owned companies are the need to simplify and rationalize an impressive number of public companies in Italy.
\n
For the purposes of the analysis of the regulations contained in Legislative Decree 175/2016 laying down “Consolidated Law on the subject of companies owned by the public administration,” it is necessary to define a public entity, and therefore, it is necessary to start from the models of public bodies that have become known over time.
\n
The administrative organization of the liberal state was simple and was characterized by few territorial entities: state, provinces, and municipalities. There were, also, very few other government-owned businesses by local authorities, who mostly were characterized by a structure-associated ativa.
\n
This state was essentially concerned with controlling the internal public order and the defense of the territory from external enemies, leaving the market free to seek its equilibrium.
\n
Toward the end of the nineteenth century and the beginning of the twentieth century, the state was strengthened, with the relative growth of the ministries and agencies that began to take care of public services.
\n
This historical moment marks the start of the process of expansion of the original organizational structures of the state, with the creation, at the state level, of autonomous companies(entities included in the ministerial area with management autonomy and a different financial, accounting and controls), while at the local level, municipalized companies (as branches of the territorial bodies that carried out, at the levels closest to the citizen, the same functions of the autonomous companies), as well as with the multiplication of functional public bodies, which has led to a progressive differentiation and multiplication of public bodies. We pass, in this way, from one State controller to an “interventionist.”
\n
Following the crisis of 1929, as well as in the post-war period, there was a strong state intervention in the economy due to the consequential economic difficulties of these historical events.
\n
In particular, the state started to take stock of private companies in difficulty in order to avoid bankruptcy (e.g., the purchase of shareholdings by IRI, an institute for industrial reconstruction).
\n
We have thus moved on to a model of State entrepreneur and lender.
\n
With the entry into force of the Constitution, the panorama of public bodies has been enriched by another body: the region (public body endowed with legislative and statutory power in certain matters listed in Article 117 of the Constitution) and with the reform of the Title V administrative functions has been redistributed with a view to subsidiarity, differentiation, and adequacy.
\n
In the same perspective of the evolution of the group of public subjects, the law on parastato (L.70/1975) continued the work of transformation through an uncontrolled proliferation of necessary public bodies, qualified as parastatals. This framework has made it difficult to give a single definition of public administration, or we speak, in fact, of pluralism of public administrations or public administrations with variable geometry.
\n
This organizational pluralism is presented as:
Pluralism of public authority (state, regions, and local authorities)
Pluralism of the state organization (plurality of ministries)
Plurality of public bodies (i.e., organizations differentiated by public authorities in the strict sense and endowed with their own legal personality but linked to them by more or less intense organizational ties)
\n
Uniformity has given way to the diversification of models, envisaging a system of administration no longer revolving around the State-apparatus, but inspired by the principle of institutional pluralism, by virtue of which alongside the State, the public body par excellence and other subjects operate and are endowed, as well as of private juridical capacity, also of public juridical capacity, which pursue aims of public interest.
\n
The penetrating intervention of the State in the economy has led to an uncontrollable increase in public debt, imposing a peculiar process of liberalization and privatization in order to reduce it. Figures 1 and 2 show a quantitative analysis of the public investee companies in Italy, illustrating the public companies currently controlled by the Ministry of the Economy and Finance and the number of public companies established between 1990 and 2015.
\n
Figure 1.
Public companies currently controlled by the Ministry of the Economy and Finance.
\n
Figure 2.
Number of public enterprises by year of establishment from 1990 to 2015.
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\n
\n
4. Legal profiles and disciplinary aspects of public enterprises
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With the privatization process, there have arisen problems of formal classification of the discipline; in fact, within the syntagma “public companies” can be, in practice, surrounded by deeply heterogeneous figures. It is for this reason that it cannot be further supported by a static concept of a public body, indeed, must give notice of the fact that recently the Stato Council (judgment no. 2660/20151) is oriented toward a “functional and iridescent notion of public body: the same subject may have the nature of public body for certain purposes and with respect to certain institutions and may, however, not have it for other purposes, preserving, respect to other institutions, and regulatory regimes of a private nature.”
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Far from being a merely classificatory matter, the public qualification of an institution involves significant practical consequences on the disciplinary level.
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A first limit is found in the controls, of various kinds (on the deeds, on the management bodies, internal or external, accounting), which are the object of all public bodies, aimed at assessing the legitimacy of the institution’s activity and compliance in the public interest.
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A strong limitation is, moreover, by the absence of a complete and perfect negotiating freedom, characterized by a number of constraints, rules, and publicistic limits, aimed at transparent proceduralisation of a contractual choice, with regard to an, the content of the contract and the choice of the negotiating partner. It is therefore an activity that is always functional and not free, characterized, that is, by a teleological constraint susceptible of control and syndication in the jurisdictional seat.
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With regard to the configurability of public bodies to a corporate structure, the debate has polarized around the question of whether the public finalization of the corporate body and the alteration of the typical corporate model can lead to affirming the attraction of the so-called investee companies to the public sphere.
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This assimilation took place fundamentally for reasons of public finance protection, given that often the private module constitutes an elusive means of provisions that are undoubtedly binding on the (public) participating bodies but not also for the private entities constituted or participated by them. In general, it should be noted that nowadays there is a tendency to identify between public bodies and institutions included in the consolidated account of the public administration.
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The growing attention on the system of public investments, at central and territorial level, is a consequence of the previous use of the corporate instrument as a way of avoiding the constraints of public finance. In compliance with the new rules on budget balances, the legislator has set up a coherent system of measures, directed toward the common objective of restoring efficiency to companies in public participation, including through the strengthening of corporate governance and to consider the “public administration group” (GAP) in a unified manner, with particular reference to the effects on institutions of the results of the exercise of the investee organizations.
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The lack of homogeneity of the financial statements, determined by the phenomenon of outsourcing, involved an incomplete and not representative representation of the financial, economic, and equity situation of the GAP and the overall functions performed by the entity through its organizational structures, its instrumental entities, and its investee companies.
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With a view to greater transparency and accountability of the various levels of government, Legislative Decree June 23, 2011, n. 118, in harmonizing the accounting systems and financial statements of the regions, provinces, and local authorities, establishes the consolidation of the accounts between the institutions and their participated bodies.
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The “centrality of the consolidated financial statements” is functional to compliance with the public finance constraints, since it allows to achieve the objective of “neutrality” of the budget with respect to the phenomenon of outsourcing and is approved by 30 September of the year following the reference year (accounting principle applied consolidated financial statements). The scope of consolidation extends to cases in which the dominant influence is exercised by virtue of particular contractual restrictions, even in the absence of participation. The obligation of consolidation, long postponed, from September 30, 2017, is mandatory for all institutions with a population of more than 5000 inhabitants. In force since 2018, the financial statements that present, for each of the three parameters (total assets, net assets, and total revenues), are less than 3% compared to the parent company’s economic and financial position.
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The valuation of irrelevance must be formulated both with reference to the single entity or company and to the set of entities and companies considered to be scarcely significant, as the consideration of more modest situations could be of interest for consolidation purposes. It must be avoided that the exclusion of so many autonomously insignificant realities subtracts important information from the group budget. Consider, for example, the limit case of a corporate group consisting of a considerable number of institutions and companies, all of a small size such as to allow exclusion if considered individually.
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Therefore, for the purposes of exclusion for irrelevance, starting from the financial year 2018, the sum of the percentages of the financial statements considered as irrelevant must present, for each of the parameters indicated above, an incidence of less than 10% compared to the equity, economic, and financial management of the parent company. If these sums have a value equal to or greater than 10%, the parent company identifies the financial statements of the individually irrelevant entities to be included in the consolidated financial statements, until the sum of the percentages of the accounts excluded for irrelevance is reduced to less than 10%.
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On the other hand, the entities and companies wholly owned by the parent company and the in-house companies and the investee entities holding direct assignment by the members of the group, irrespective of the shareholding, are considered significant.
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In the case of direct assignment, the shareholdings of less than 1% of the investee company’s capital are considered irrelevant and not subject to consolidation.
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The amplitude of the scope of consolidation makes it possible to achieve a unitary economic result of the “public administration group,” which takes into account both the result of the institution’s exercise and the profits and losses of the investee organizations.
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The proliferation of participating companies is now a phenomenon subject to attention by the Court of Auditors, which has identified the critical profiles of the use of the corporate instrument for the pursuit of the institutional goals of public bodies. The Autonomous Section of the Court of Auditors2 in resolution no. 24/2015 highlighted the fact that only 35.72% of the participated bodies operate in the local public services sector, with a clear predominance of in-house assignments with respect to assignments through public tenders. From the point of view of financial management, the Court of Auditors highlighted the strong prevalence of debts on loans in the relations between local authorities and investee companies.
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The regulatory framework, in the field of public companies, presented a strong regulatory disorder that negatively characterized the regulation of corporate holdings held by public administrations.
\n
In consideration of this, it was necessary to introduce a unitary discipline aimed at resolving the classification problems and legal regime of these subjects.
\n
It is for this reason that the Parliament, with the law of August 7, 2015, has delegated the government to adopt a decree reforming the public administration as a whole.
\n
The purpose of the reform, as stated by the Council of State in its opinion no. 968/20163, is to “simplify and rationalize the rules in force in this area, through the reorganization of national provisions and the creation of an organic general discipline.”
\n
\n
\n
5. The reform of public enterprises as an instrument for rationalizing public spending in Italy
\n
These are the essential points of the intervention delegated by the Madia reform:
Firstly, limit the establishment of new public companies, make the financial statements of companies in public control transparent, reduce the number of public companies, and prevent the proliferation of unnecessary societies.
Secondly, reduce the areas of intervention of public companies, eliminate or limit public companies that are not in economic equilibrium, redefine the personnel management system of publicly controlled companies, and ensure that the activities of publicly owned companies are more efficient.
Finally, improve the services provided to citizens and businesses, giving greater credibility and transparency to the public administration and favoring the best use of public resources, through the efficient allocation of resources and the removal of waste sources.
\n
This is the framework in which the Legislative Decree 175/2016 laying down “Consolidated Law on the subject of companies owned by the public administration,” then amended by Legislative Decree, 100/2017.
\n
The Consolidation Act is essentially divided into four types of intervention:
Introductory provisions containing the indication of the object and scope of the TU, the formulation of definitions, and the identification of the types of companies in which public participation is admitted
Provisions aimed at establishing the conditions and limits of public shareholdings, as well as redefining the rules for the incorporation of companies or for the taking up or maintenance of shareholdings by public authorities and for the sale of public holdings
Provisions concerning the administrative and control bodies of publicly controlled companies
Provisions aimed at encouraging economic efficiency and efficiency through the introduction of procedures for periodic rationalization and extraordinary auditing, personnel management, specific financial rules for the local authorities’ subsidiaries and the promotion of transparency
\n
The Consolidation Act draws the “perimeter” within which a public administration can decide to set up a company (in the forms, governed by the Civil Code, of joint-stock companies or limited liability companies), specifying in Art. 4, paragraph 1, that “le Public administrations cannot directly or indirectly constitute companies having as their object activities of production of goods and services not strictly necessary for the pursuit of its institutional purposes or acquire or to maintain holdings, including minorities, in these companies.”
\n
This is the so-called restriction of purpose, drawn up by the jurisprudence and implemented by the delegated legislator, which places a limit on the participation of the public administration in companies, so that they pursue a purpose compatible with the institutional purpose of the participating administration.
\n
Paragraph 2, of the Art. 4, also introduces an activity constraint: companies in which public administrations can participate and perform “exclusively” certain activities, strictly listed (e.g., production of a service of general interest, design and construction of a work published on the basis of a program agreement, self-production of goods or services instrumental to the participating institution or public bodies, etc.).
\n
The most important aspects of Legislative Decree 175/2016 then amended by the Legislative Decree, 100/2017, are essentially concern with:
Art 20–24 rationalization plans
Art 14 recapitalization
Art 21 financial rules
\n
The main instrument through which the need to reduce public spending has been pursued is the obligation to periodically rationalize public holdings, to which the administrations are held annually.
\n
The rationalization plans concern all public administrations and are designed to highlight the following situations:
Company shareholdings that are not included among those “indispensables” for the purposes of pursuing institutional goals.
Companies that do not have employees or have more directors than employees.
Investments in companies that perform similar activities to those carried out by other investee companies or by instrumental public bodies (the so-called dual company).
Investments in companies which, in the previous 3 years, have achieved an average turnover not exceeding 1 million euro4.
Investments in companies other than those established for the management of a service of general interest that has produced a negative result for four of the previous 5 years.
Investments in companies with a need to contain operating costs.
Investments in companies that need to be aggregated regarding the activities permitted pursuant to Art. 4 (see Article 20, paragraph 2).
\n
The real novelty of the Consolidated Law consists in the provision of a periodic revision alongside the extraordinary one, providing that the public administrations carry out, annually (from 2018, by December 31) and the analysis of the investments held and prepare rationalization plans, according to the criteria enunciated by the aforementioned Art. 20.
\n
To complete the reorganization procedure, the Art. 24 of the disciplinary decree regulates the procedure for the extraordinary compulsory review of investments held, directly or indirectly, by public administrations, for the disposal or rationalization of certain types of companies.
\n
The section of the autonomies, with resolution n. 19/SEZAUT/2017/INPR5 issued guidelines aimed at favoring the correct fulfillment of the provisions, underlining the obligatory nature of the recognition of the investments held, so that the recognition is always necessary and also to certify the absence of shareholdings.
\n
The rationalization plan includes:
The recognition of holdings held.
Decision of those not necessary for the pursuit of the corporate purpose.
\n
The results of the survey are left to the discretion of the participating administrations, which are required to expressly motivate the choice made that may consist of a reorganization measure (alienation /rationalization/merger) and the maintenance of participation without intervention. In any case, a motivation is required, both for dismissing and for maintaining the company.
\n
In summary, the aforementioned regulation provides two dismissal obligations:
The prohibition of maintaining companies that are not consistent with their institutional aims (principle of functionalization);
The prohibition to maintain companies, which are consistent with the institutional aims of the institution, are not indispensable for their prosecution (see Corte conti Lombardia Section control, resolution of May 13, 2015, No. 195; Corte conti-Basilicata Sez control, resolution of 14 June 2017, No. 40; Corte conti-Piemonte Control Section, Resolution No. 28 of January 28, 2016; and Court of Auditors-Emilia Romagna Control Section, Resolution 12 January 2016, No. 4).
\n
\n
\n
6. The accounting tools for covering losses of public companies
\n
Among the fundamental principles that characterize the accounting harmonization reform, there is the recourse to adequate allocations to specific provisions for risks and charges (in the past often hidden among the residual liabilities) destined to safeguard the present and future balance of the financial statements. With this in mind, the provision for the investee loss provision is envisaged, in addition to the tied multiyear fund and the doubtful loan fund.
\n
First envisaged by Art. 1, cc. 550 et seq of Law 147/20 13 (2014 Stability Law) and, currently, governed by Art. 21, Legislative Decree no. 175/2016, the obligation is foreseen (which will come into force at full capacity from 2018 but provides for a transitional regime of first application already in the 3-year period 2015–2017) for local public administrations to set up a fixed fund to cover the losses of participated bodies not immediately cleared up.
\n
The establishment of the captive fund to cover the losses of investee organizations will make it possible to include in the financial statements of local authorities the effects of losses incurred by these entities, and not immediately repaid. As emphasized by the Court6, the fund:
Avoids, in the forecast budget, that the failure to take into account any losses reported by the body could have a negative impact on future budget balances.
Favors the progressive managerial accountability of the member bodies, through a stringent correlation between the economic-financial dynamics of the investee organizations and those of the entrusting members.
\n
The obligation to create the fixed fund for the losses of the participated bodies concerns all local public administrations included in the ISTAT list referred to in Article 1, paragraph 3 of Law 196/09. Therefore, in addition to regions, provinces, and municipalities, the provision calls into question, among others, mountain communities, unions of municipalities, consortia between local authorities, chambers of commerce, and local health authorities.
\n
The “participatory bodies” that the Art. 1, c. 5507 considers for the purpose of determining the provision to the fund are special companies, institutions, and investee companies. The financial intermediaries referred to Art. 106 of Legislative Decree 385/93 (Consolidated Law on Banking and Credit Law), as well as companies issuing financial instruments listed on regulated markets and their subsidiaries. It should also be noted that the provision is made if the investee organizations present, in the last available financial year, a financial result or a negative financial balance, not immediately paid by the participating entity (Article 1, paragraph 551).
\n
Article 21 d. Legislative Decree 175/2016, as amended by Legislative Decree 100/2017, establishes that in the event that companies in which local public administrations have a negative operating result, the participating local public administrations, which adopt financial accounting, set aside subsequent year in an appropriate restricted fund an amount equal to the negative result, in proportion to the shareholding.
\n
It should be noted that the Art. 21 of Legislative Decree. 175/2016 is also concerned with standardizing the cases in which the entities holding the loss-making interest are not in financial accounting but adopt a civil accounting system. In such cases, they adjust the value of the investment, during the following year, to the amount corresponding to the fraction of the equity of the investee company where the negative result is not immediately settled and constitutes a lasting loss in value.
\n
For companies that prepare consolidated financial statements, the operating result to be considered is that relating to these financial statements.
\n
The amount set aside returns to availability to the public administration budget, always in proportion to the participation fee, in the following cases:
The participant body stores the loss or retires the participation.
The participant is placed in liquidation.
The investee companies, with their own resources, pay in full or in part the losses achieved in previous years.
\n
Apart from these cases, the provision allocated to the budget is included in the statement of the share of the administrative result and therefore remains essentially unavailable for purposes of expenditure other than those for which it was established.
\n
In the first application, for the years 2015, 2016, and 2017, the legislator has provided a transitional period in which the provision is gradually increasing, with an important distinction between the participation in bodies that, despite having reported a loss in last available budget, the accounts worsened and those that improved them compared to the average of the previous 3 years.
\n
The first situation includes the hypotheses of the bodies that recorded a loss after previous financial statements in profit or which reported a negative result above the average of the previous 3-year period. In these cases, the portion to be allocated in the 2015 financial statements of the participating entity is equal to 25% of the negative result achieved in the previous year by the body. The provisions will be set at 50% for 2016 and at 75% for 2017, again with reference to the losses reported by the investee in the previous year.
\n
If, on the other hand, the loss in the last available balance sheet is lower than the average of the previous 3 years (showing an improvement in the accounts), the provision in the 2015 estimated budget must be made equal to the difference between the result achieved in previous year and the 2011–2013 average result improved by 25% for 2014. In the following financial years, the amount should be calculated as a slide considering that the average result must be improved by 50% for 2015 and by 75% for 2016.
\n
The Autonomy Section of the Court of Auditors, which with Resolution no. 4 of 17 February 2015,8 highlights that provisions to the fund must be coordinated with the provisions of the Italian Civil Code on the automatic dissolution of the company whose capital has fallen below the legal limit, which entitles the entity to decide, based on a prognostic judgment on the future profitability of the company, whether to provide for the reintegration of the share capital or to take note of the automatic liquidation of the body (Articles 2484, paragraph 1, No. 4 and 2447 CC).
\n
To be specific, the Art. 14 d. Decree 175/2016 establishes the prohibition for public authorities to carry out capital increases, extraordinary transfers, credit facilities, or issue guarantees in favor of subsidiaries, with the exception of listed companies and banks, who have registered for three consecutive financial statements and losses for the year or that have used reserves available for the settlement of losses also during the year.
\n
The local partner institution can intervene in the area of losses:
Only within the limits of its participation in the share capital and cannot provide additional resources.
Only if the financial intervention is compatible with the provisions of the Community law on state aid.
\n
Local administrations will be able to intervene for losses only against companies responsible for the performance of the service of general economic interest.
\n
Therefore, the local public administration can make the losses of an investee company with the resources set aside in the restricted fund, within the limits of its shareholding and only after the compatibility with the state aid legislation has been assessed.
\n
It should, however, be kept in mind that the provision for losses is a prudential budget rule, so that the entities that have set aside resources cannot, however, freely repay the losses of the investee companies and must instead comply with the requirements indicated in the same paragraph 5 of the aforementioned article 14 of the single text, so any intervention in this sense can only take place within a restructuring plan that guarantees the future balance of the subsidiary’s accounts.
\n
Legislative Decree n. 100/2017, conforming to the indications given by the Council of State in its opinion, has also added a paragraph 3-bis to the aforementioned article 21 of d. lgs. n. 175/2016, under which the participating local public administrations can proceed to the level of the losses suffered by the investee company with the sum set aside, within the limits of their shareholding and in compliance with the principles and legislation of the European Union in terms of state aid. This means that, on the one hand, the local partner body (beyond the amount of amounts entrusted to an investee for the performance of certain services) can intervene in the level of losses only within the limits of its participation in the share capital and cannot provide additional resources and, on the other hand, that a local public administration can proceed only if the financial intervention is compatible with the provisions of the Community law on state aid: this compatibility is defined by the decision of the EU Commission of December 20, 2011, which codifies the principles established by the ruling judgment on the Altmark case to exclude that a public intervention is an improper aid, conflicting with Article 107 of the EU Treaty.
\n
Consequently, local administrations will be able to intervene for losses only against companies responsible for the performance of the service of general economic interest (e.g., transport companies), to offset the service obligations imposed on them and only to condition that the four principles of the Altmark judgment are respected:
The recipient undertaking must have been effectively entrusted with the fulfillment of public service obligations, and those obligations must be clearly defined.
The parameters on the basis of which the compensation is calculated must be established in advance in an objective and transparent manner.
The compensation cannot exceed what is necessary to cover all or part of the costs arising from the fulfillment of the public service obligations, taking into account the relevant revenue and a reasonable profit.
The choice of the company to be entrusted with the fulfillment of public service obligations must be made in the context of a public procedure that allows to select the candidate able to provide these services at the lowest cost for the community. If the choice of the company, in a specific case, takes place outside of such a procedure, the compensation must be determined on the basis of a cost analysis that should be borne by a medium-sized company, efficiently managed and adequately equipped with means to carry out the service.
\n
With regard to the methods for hedging the financial resources allocated to recapitalization and/or loss coverage of investee companies: Art. 3 paragraph 18 of the Budget Law 2004 stipulates that the bodies No on can borrow to finance contributions aimed at the recapitalization of companies or companies aimed at covering of losses.
\n
The Court of Auditors9 (Regional section Abruzzo, sent. No. 1/08) stated that the costs of covering of losses and recapitalizations of participatory bodies should be considered current expenditure, and, as such, be taken into account in the calculation of the fund balances.
\n
\n
\n
7. Conclusions
\n
The use of corporations by local administrations has been consolidated since the beginning of the nineties of the last century. Since the beginning of the twentieth century, the phenomenon of public intervention in the country’s economy had spread, as the corporate phenomenon developed in public administrations, in the absence of specific rules, the belief that the joint-stock company as an organism governed by the civil code was exempted from the application of accounting rules and public finance of public bodies.
\n
The results of the deductive phase have shown that the public investee companies are called to identify new methodologies to direct and control the action of their actions in order to prevent company crises and reorganization.
\n
The provisions of Legislative Decree 175/2016 urge the governance bodies of the public investee companies to use the best and most adequate instruments for monitoring and evaluation with a view to promptly emerge the business crisis. From an economic-business point of view, it can be seen that insolvency can be ascertained mainly ex-post also from outside and through accounting and/or final data 91; on the contrary, the crisis, which has not yet crystallized, giving rise to insolvency, presupposes a vision that is no longer historical but prospective, aimed at identifying the incapacity in the future of fulfilling not only the obligations already assumed but also those foreseeable in the normal course of business.
\n
This suggests considering the possibility of using accounting and/or historical data but with a view to their ability to signal future imbalances, since the accounting indicators examined individually are not very significant for this purpose, that is, without adequate spatial comparison, time and a joint analysis with ratios, and operating results in the multiple economic-financial-equity aspects of the investee company.
\n
Consistently with what is outlined by the economic-business doctrine on the uncertainty that distinguishes the identification of an actual state of crisis, there is a need to always combine qualitative information with the most immediate accounting quantitative data and to accompany simple historical analysis, results with a thorough examination of the future action plans, and the related forecast financial and economic flows.
\n
The analysis shows that the legislator has provided a fairly adequate instrumentation (fund for investee losses) only after the losses have been produced. Here it is considered that preference should be given to a prospective and planning perspective. Basically, only a medium-term planning can effectively detect a state of crisis, confirming its finality or anticipating the outcomes; therefore, the introduction of such an approach would give rise to an extremely useful planning logic for the public investee companies.
\n
\n\n',keywords:"public service companies, default, budget, Italy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/69327.pdf",chapterXML:"https://mts.intechopen.com/source/xml/69327.xml",downloadPdfUrl:"/chapter/pdf-download/69327",previewPdfUrl:"/chapter/pdf-preview/69327",totalDownloads:41,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"April 27th 2018",dateReviewed:"August 3rd 2018",datePrePublished:"December 31st 2018",datePublished:"October 23rd 2019",readingETA:"0",abstract:"The objective of this study is to analyze the institutional and organizational structure of public service companies in Italy. After analyzing the various reforms of the Public Administration, research has focused on the crisis and the insolvency of publicly owned companies, as, for the first time and recently the legislator has organically regulated the consequences of the insolvency of the same, affirming their general submission to bankruptcy and insolvency proceedings. Still the norm also outlined the procedure for the adoption of preventive plans should aim to avoid insolvency in financial hardship cases, and to remedy the crisis of the investee companies. After having dealt with the issue of historical evolution and territorial distribution of the phenomenon of public enterprises in Italy, aspects of the legal framework of the object of study will be addressed. The next section analyzes the contents of the reform of public companies, recalling the reference standards and the important news concerning the coverage of losses of companies. The new discipline produces important repercussions on public budgets and therefore on the community: for this reason, the conclusions of the study will deal with this aspect.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/69327",risUrl:"/chapter/ris/69327",book:{slug:"public-economics-and-finance"},signatures:"Pina Puntillo",authors:[{id:"256533",title:"Dr.",name:"Pina",middleName:null,surname:"Puntillo",fullName:"Pina Puntillo",slug:"pina-puntillo",email:"pina.puntillo@unical.it",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. What constitutes the public sector and the public entities: defining boundaries",level:"1"},{id:"sec_3",title:"3. Public companies in Italy: evolutionary profiles",level:"1"},{id:"sec_4",title:"4. Legal profiles and disciplinary aspects of public enterprises",level:"1"},{id:"sec_5",title:"5. The reform of public enterprises as an instrument for rationalizing public spending in Italy",level:"1"},{id:"sec_6",title:"6. The accounting tools for covering losses of public companies",level:"1"},{id:"sec_7",title:"7. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Broadbent J, Guthrie J. Changes in the public sector: A review of recent ‘alternative’ accounting research. Accounting, Auditing & Accountability Journal. 1992;5(2):3-31\n'},{id:"B2",body:'Puntillo P. Inter-municipal cooperation in service delivery and governance: Insights from Italy. International Journal of Business Governance and Ethics. 2017;12(3):197-217\n'},{id:"B3",body:'Del Bello A. Intangibles and sustainability in local government reports: An analysis into an uneasy relationship. Journal of Intellectual Capital. 2006;7(4):440-456\n'},{id:"B4",body:'Bossi A, Fuentes Y, Serrano C. Reflexiones en torno a la aplicacion del capital intelectual en el sector publico. Revista Espanola de Financiacion y Contabilidad. 2005;XXXIV(124):211-245\n'},{id:"B5",body:'Joyce P. Strategic Management for the Public Services. UK: McGraw-Hill Education; 1999\n'},{id:"B6",body:'Bossi A. La medicion del capital intelectual en el sector publico [doctoral dissertation]. Zaragoza: University of Zaragoza; 2003 (summary in Revista Espanola de Financiacion y Contabilidad, Vol XXXII No. 118, pp. 921-5)\n'},{id:"B7",body:'Carlin TM. Debating the impact of accrual accounting and reporting in the public sector. Financial Accountability & Management. 2005;21(3):309-336\n'},{id:"B8",body:'Hodges R, Mellet H. Testing the new public management: Accounting regulation and due process. Paper for presentation at The European Accounting Association Congress; 2002\n'},{id:"B9",body:'Mouritsen J et al. Intellectual capital and new public management: Reintroducing enterprise. The Learning Organization. 2004;11(4-5):380-392\n'},{id:"B10",body:'Hood C. The new public management’ in the 1980s: Variation on a theme. Accounting Organizations and Society. 1995;20(2-3):93-109\n'},{id:"B11",body:'Olsen JP, Guy Peters B, editors. Lessons from Experience: Experiential Learning in Administrative Reforms in Eight Democracies. Oslo: Scandinavian University Press; 1996\n'},{id:"B12",body:'EFQM. Common interest day workshops—Management of innovation. Quality Link. 1997;9(51):7-11\n'}],footnotes:[{id:"fn1",explanation:"https://www.giustizia-amministrativa.it/cdsintra/cdsintra/AmministrazionePortale/DocumentViewer/index.html?ddocname=7CQIJE5IDUT64IMHJ4XI75AXDE&q."},{id:"fn2",explanation:"http://www.corteconti.it/export/sites/portalecdc/_documenti/controllo/sez_autonomie/2015/20150720_20150722_Deln024_FRG_Organismi_Partecipati_Linkrelto.pdf."},{id:"fn3",explanation:"https://www.giustizia-amministrativa.it/cdsintra/cdsintra/Notiziasingola/Ilcodicedeicontrattipubblici/PareriresidalConsigliodiStato/Parere21aprile2016968/index.html."},{id:"fn4",explanation:'With the modification provided by the Art. 17, co. 1, lett. (f), Legislative Decree no. 100/2017, the turnover threshold, during the transition period, has been reduced to 500,000.00 euros. See Art. 26, co. 12-quinquies, Legislative Decree no. 175/2016: "For the purposes of applying the criterion referred to in Article 20, paragraph 2, letter (d), the first 3-year period is the 3-year period 2017–2019. Pending the first application of the aforementioned criterion for the 3-year period 2017–2019, the average turnover threshold not exceeding 500,000 euro applies for the 3 years preceding the entry into force of this decree for the purpose of adopting the extraordinary audit plans in Article 24 and for the 3-year periods 2015–2017 and 2016–2018 for the purposes of the adoption of the rationalization plans referred to in Article 20."'},{id:"fn5",explanation:"http://www.corteconti.it/export/sites/portalecdc/_documenti/controllo/sez_autonomie/2017/delibera_19_sezaut_inpr_2017_e_linee_guida.pdf."},{id:"fn6",explanation:"http://www.corteconti.it/export/sites/portalecdc/_documenti/controllo/campania/pareri/2016/delibera_333_2016.pdf."},{id:"fn7",explanation:"Art. 1 c. 550 applies to special companies, institutions, and companies owned by local public administrations indicated in the list referred to in Art. 1, of Law 196/2009. Financial intermediaries pursuant to Art. 106 of the consolidated text referred to in d. lgs n. 385/1993, as well as companies issuing financial instruments listed on regulated markets and their subsidiaries."},{id:"fn8",explanation:"http://www.quotidianoentilocali.ilsole24ore.com/pa24.php?idDoc=16742623&idDocType=3."},{id:"fn9",explanation:"http://www.corteconti.it/export/sites/portalecdc/_documenti/controllo/abruzzo/pronunce/2017/delibera_115_2017_e_relazione.pdf."}],contributors:[{corresp:"yes",contributorFullName:"Pina Puntillo",address:"pina.puntillo@unical.it",affiliation:'
Department of Business Administration and Law, University of Calabria, Cosenza, Italy
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Maxwell, Pavel Klang, Werner Schrenk and Gottfried Strasser",authors:[{id:"4537",title:"DI",name:"Alexander",middleName:null,surname:"Benz",fullName:"Alexander Benz",slug:"alexander-benz"},{id:"135394",title:"Prof.",name:"Christoph",middleName:null,surname:"Deutsch",fullName:"Christoph Deutsch",slug:"christoph-deutsch"},{id:"135395",title:"Prof.",name:"Gernot",middleName:null,surname:"Fasching",fullName:"Gernot Fasching",slug:"gernot-fasching"},{id:"135396",title:"Prof.",name:"Karl",middleName:null,surname:"Unterrainer",fullName:"Karl Unterrainer",slug:"karl-unterrainer"},{id:"135397",title:"Prof.",name:"Aaron",middleName:null,surname:"Maxwell",fullName:"Aaron Maxwell",slug:"aaron-maxwell"},{id:"135398",title:"Prof.",name:"Pavel",middleName:null,surname:"Klang",fullName:"Pavel Klang",slug:"pavel-klang"},{id:"135399",title:"Prof.",name:"Werner",middleName:null,surname:"Schrenk",fullName:"Werner Schrenk",slug:"werner-schrenk"},{id:"135400",title:"Prof.",name:"Gottfried",middleName:null,surname:"Strasser",fullName:"Gottfried Strasser",slug:"gottfried-strasser"}]},{id:"8448",title:"High-Power and High Efficiency Yb:YAG Ceramic Laser at Room Temperature",slug:"high-power-and-high-efficiency-yb-yag-ceramic-laser-at-room-temperature",signatures:"Shinki Nakamura",authors:[{id:"4143",title:"Dr.",name:"Shinki",middleName:null,surname:"Nakamura",fullName:"Shinki Nakamura",slug:"shinki-nakamura"}]},{id:"8449",title:"Polarization Properties of Laser-Diode-Pumped Microchip Nd:YAG Ceramic Lasers",slug:"polarization-properties-of-laser-diode-pumped-microchip-nd-yag-ceramic-lasers",signatures:"Kenju Otsuka",authors:[{id:"4259",title:"Professor",name:"Kenju",middleName:null,surname:"Otsuka",fullName:"Kenju Otsuka",slug:"kenju-otsuka"}]},{id:"8450",title:"Surface-Emitting Circular Bragg Lasers – A Promising Next-Generation On-Chip Light Source for Optical Communications",slug:"surface-emitting-circular-bragg-lasers-a-promising-next-generation-on-chip-light-source-for-optical-",signatures:"Xiankai Sun and Amnon Yariv",authors:[{id:"4201",title:"Prof.",name:"Xiankai",middleName:null,surname:"Sun",fullName:"Xiankai Sun",slug:"xiankai-sun"},{id:"122981",title:"Dr.",name:"Amnon",middleName:null,surname:"Yariv",fullName:"Amnon Yariv",slug:"amnon-yariv"}]},{id:"8451",title:"Novel Enabling Technologies for Convergence of Optical and Wireless Access Networks",slug:"novel-enabling-technologies-for-convergence-of-optical-and-wireless-access-networks",signatures:"Jianjun Yu, Gee-Kung Chang, Zhensheng Jia and Lin Chen",authors:[{id:"8503",title:"Dr.",name:"Jianjun",middleName:null,surname:"Yu",fullName:"Jianjun Yu",slug:"jianjun-yu"},{id:"133376",title:"Prof.",name:"Gee-Kung",middleName:null,surname:"Chang",fullName:"Gee-Kung Chang",slug:"gee-kung-chang"},{id:"133378",title:"Prof.",name:"Zhensheng",middleName:null,surname:"Jia",fullName:"Zhensheng Jia",slug:"zhensheng-jia"},{id:"139599",title:"Prof.",name:"Lin",middleName:null,surname:"Chen",fullName:"Lin Chen",slug:"lin-chen"}]},{id:"8452",title:"Photonic Crystal Multiplexer/Demultiplexer Device for Optical Communications",slug:"photonic-crystal-multiplexer-demultiplexer-device-for-optical-communications",signatures:"Sahbuddin Shaari and Azliza J. M. Adnan",authors:[{id:"19951",title:"Dr.",name:"Sahbudin",middleName:null,surname:"Shaari",fullName:"Sahbudin Shaari",slug:"sahbudin-shaari"}]},{id:"8453",title:"Improvement Scheme for Directly Modulated Fiber Optical CATV System Performances",slug:"improvement-scheme-for-directly-modulated-fiber-optical-catv-system-performances",signatures:"Hai-Han Lu, Ching-Hung Chang and Peng-Chun Peng",authors:[{id:"4684",title:"Professor",name:"Hai-Han",middleName:null,surname:"Lu",fullName:"Hai-Han Lu",slug:"hai-han-lu"},{id:"62688",title:"Prof.",name:"Peng-Chun",middleName:null,surname:"Peng",fullName:"Peng-Chun Peng",slug:"peng-chun-peng"}]},{id:"8454",title:"Optical Beam Steering Using a 2D MEMS Scanner",slug:"optical-beam-steering-using-a-2d-mems-scanner",signatures:"Yves Pétremand, Pierre-André Clerc, Marc Epitaux, Ralf Hauffe, Wilfried Noell and N.F. de Rooij",authors:[{id:"5054",title:"Dr.",name:"Yves",middleName:null,surname:"Petremand",fullName:"Yves Petremand",slug:"yves-petremand"},{id:"135512",title:"Prof.",name:"Pierre-Andre",middleName:null,surname:"Clerc",fullName:"Pierre-Andre Clerc",slug:"pierre-andre-clerc"},{id:"135514",title:"Prof.",name:"Marc",middleName:null,surname:"Epitaux",fullName:"Marc Epitaux",slug:"marc-epitaux"},{id:"135516",title:"Prof.",name:"Ralf",middleName:null,surname:"Hauffe",fullName:"Ralf Hauffe",slug:"ralf-hauffe"},{id:"135518",title:"Prof.",name:"Wilfried",middleName:null,surname:"Noell",fullName:"Wilfried Noell",slug:"wilfried-noell"},{id:"135519",title:"Prof.",name:"N.F.",middleName:null,surname:"De Rooij",fullName:"N.F. De Rooij",slug:"n.f.-de-rooij"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"62389",title:"Polymorphism of Xenobiotic Detoxification Genes and Male Infertility",doi:"10.5772/intechopen.79233",slug:"polymorphism-of-xenobiotic-detoxification-genes-and-male-infertility",body:'
1. Introduction
Deterioration of male reproductive health has become a serious problem in most countries [1]. Contributing factors for male infertility comprise genital infections, ejaculatory duct obstruction (EDO), hypogonadism, varicoceles, or exposure to environmental factors (e.g., xenobiotics, ionizing radiation), lifestyle factors (e.g., alcohol, smoking and obesity), genetic causes, systemic diseases, and abnormal ejaculation [2]. However, in approximately 30–45% of male infertility cases, the etiology remains undetermined and is called the idiopathic infertility [3]. Genetic factors make a significant contribution to the development of idiopathic male infertility. For example, oligozoospermia and azoospermia have been recently determined to be tied with such genetic deviations as translocations, microdeletions and mutations [4] in genes that play a role in testicular development, gametogenesis and metabolism of xenobiotics associated with reproductive system disorders. Xenobiotic metabolism causes the main damage to the organism by creating covalent bounds with cellular macromolecules (DNA or protein). This indicates that the expression regulation and activity of xenobiotic-metabolizing enzymes may play the crucial role in determination of male reproductive system susceptibility to chemically induced damages. Thus, xenobiotic-mediated adverse effects of male reproductive system are associated with the polymorphisms in xenobiotic detoxification genes. Different variants of one gene are categorized as polymorphism if their frequency in the population exceeds 1% [5]. In contrast to mutations, polymorphisms have indirect connections with particular seminal fluid abnormalities but may be indispensable during the investigation of multifactorial diseases. Polymorphic variants may change the expression or function of encoded protein, leading to its conformational changes that would result in different pharmacokinetics, chemical reaction capacities and efficiency of the xenobiotic-detoxifying enzymes. In this chapter, we discuss polymorphisms in the main enzymes capable of maintaining the oxidants/antioxidants balance in reproductive tissues, focusing mainly on phase I cytochrome P4501A1 (CYP1A1) and phase II (GSTM1, GSTT1, GSTP1 and arylamine N-acetyltransferase 2 (NAT2)) detoxifying enzymes.
2. Xenobiotic metabolism
The foreign environmental chemicals are known as xenobiotics (Gk. xenos—“stranger”) and include drugs, drug metabolites and environmental pollutants (such as synthetic pesticides, herbicides and industrial pollutants). Xenobiotics may cause damages in the innate state (alkyl iodides, acyl halides and nitrogen mustards) or after activation in the metabolizing process.
Xenobiotic metabolism is performed in three stages (Figure 1):
Phase I enzymes initiate the detoxification process, during which the lipophilic xenobiotics become more polar and acquire sites for subsequent conjugation reactions. Phase I enzymes comprise mainly the cytochrome P450 (CYP) superfamily of microsomal enzymes, which include the 36 gene families. It is considered that CYP1, CYP2, CYP3, CYP4 and CYP7 families play the key roles in hepatic and extra-hepatic metabolism and in the elimination of xenobiotics and drugs in human [6].
Phase II enzymes catalyze the conjugation process. These enzymes can interact with xenobiotics either directly or, more generally, interact with the metabolites produced by phase I enzymes. Phase II enzymes include a lot of superfamilies, namely, the sulfotransferases (SULT), UDP-glucuronosyltransferases (UGT), DT-diaphorase or NAD(P)H quinone oxidoreductase (NQO) or NAD(P)H menadione reductase (NMO), glutathione S-transferases (GST) and N-acetyltransferases (NAT). Each superfamily consists of families and subfamilies of genes encoding the various isoforms with different substrate and tissue specificities [7].
Phase III elimination via transporters or passive transport. Phase III transporters involve P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), which belongs to the subfamily of the ATP binding cassette (ABC) transporters and organic anion transporting polypeptide 2 (OATP2).
Figure 1.
The three-step detoxification of xenobiotics. Lipophilic substances subjected to metabolic activation by phase I enzyme cytochrome P450 (CYP) acquire reactive center for phase II conjugation reactions that lead to formation of hydrophilic compounds, following elimination by phase III transporters or passive transport. Most of the noxious effects are caused by reactive electrophiles after phase I activation, but some xenobiotics pose a threat before metabolic activation. CYP—cytochrome P450; NATs—N-acetyltransferases; GSTs—glutathione S-transferases; SULT—sulfotransferase; UGT—UDP-glucuronosyltransferase; NQO—NAD(P)H quinone oxidoreductase; OATP2—organic anion transporting polypeptide 2; P-gp— P-glycoprotein; MRP—multidrug resistance-associated protein.
3. Potential mechanisms for idiopathic male infertility
Male infertility is a complex, multifactorial disorder and often its etiology remains poorly understood. Increasing volume of data suggests that oxidative stress is the most probable cause of idiopathic male infertility. Oxidative stress is mediated by reactive oxygen species (ROS), if their level exceeds antioxidant capacity of the organism. An increased ROS level is observed in 40–80% of infertile men and in 11–78.5% of infertile men with normal sperm count [8]. Elevated ROS levels can be explained by several reasons such as increased leukocytes’ activity due to inflammation in the genital tract, varicocele or presence of immature spermatozoa as well as external causes like exposure to noxious chemical compounds, radiation and lifestyle factors [9]. A small amount of ROS is necessary in some physiological processes such as capacitation [10], while excessive ROS may damage sperms. Spermatozoa have restricted volume of cytoplasm, therefore the quantity of ROS-metabolizing enzymes is also limited and make them more vulnerable to ROS compared to other cells [9]. ROS cause sperm damages in several ways: first, ROS are capable of interacting with the sperm plasma membrane, which is rich in polyunsaturated fatty acids, promoting the decrease of its flexibility and, hence, tail motility [11]. Second, ROS may lead to the sperm’s acrosome membrane peroxidation and decline in acrosin activity, thus making fertilization less probable [12]. Lastly, an increased ROS level is associated with the increase in sperm DNA fragmentation (that is used as an assessment tool for unexplained male infertility) and diminished sperm motility [13]. Moreover, considering that ROS are intensively produced in the mitochondria of stressed spermatozoids, they may cause mutations of mitochondrial DNA of different cells which participate in spermatogenesis. As a result, sperm maturation and functioning could be violated. Thus, the development of effective antioxidant treatment and antistress strategies has become one of the paramount tasks for the scientific society [10].
Mutations (that include both chromosomal and single-gene alterations) in several hundred genes are the other important and significant factor that potentially may lead to male infertility. For instance, Y-chromosome microdeletions (YCM), which influence genes responsible for spermatogenesis, are one of the best-studied types of mutations that may cause male infertility. Thus, recent meta-analysis has shown that oligospermic men with sperm concentration > 1 million/mL had significantly higher rates of YCM compared to normospermic men [14]. Among the other examples of mutations, there are the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations, which lead to the absence of vas deferens; deletions of the autosomal Doublesex and Mab-3 Related Transcription factor 1 (DMRT1) gene in the azoospermic men (which is critical for germ cells development), ranging in size from 54 kb to over 2 Mb; and alterations in autosomal PLEC1 (plectin) and microRNA 661 (MIR661) genes in an azoospermic and oligozoospermic men and various single-nucleotide polymorphisms (SNPs) [15]. The latter is one of the most promising candidates for the elucidation of “hidden” genetic factors responsible for idiopathic male infertility. For example, rs1801133 (677C > T) variant in the methylenetetrahydrof>olate reductase (MTHFR) (NAD (P) H) gene found in males with impaired spermatogenesis [16], rs4986938 (1406 + 1872G > A) polymorphism of estrogen receptor 2 (ESR2) gene, rs2070744 (786C > T in the promoter region) and rs61722009 (27 bp Variable Number Tandem Repeat (VNTR) polymorphisms in the intron 4, also known as 4a4b polymorphisms) variants of NOS3 (nitric oxide synthase 3) are the potential predisposal factors of male infertility [15].
Still, male infertility depends not only on mutations alone but also on the complex system of gene–environmental interactions and epigenetic factors. A bright example of environmental factors, which may cause seminal fluid abnormalities in the corresponding genetic background, is xenobiotics, which is discussed in the following sections.
4. Association of xenobiotics with male infertility
Xenobiotics may interact with macromolecules in reversible (forming noncovalent bindings, for example, ion pairing, hydrogen bonding, hydrophobic interactions, etc.) or irreversible ways through covalent bond formation between electrophilic xenobiotics or their active metabolites and endogenous molecules. The first variant may lead to the alteration in enzyme and transporter activity, ion channels blockade, activation of specific receptors and violation in DNA transcription, if the specific structure of the xenobiotic fits to macromolecule-binding sites. Irreversible covalent interaction does not demand such fitness of structures and leads to the formation of endogenous adducts of nucleophiles (such as nucleophilic amino acid or nucleic acids). As a result, such reactions may cause genetic mutations, carcinogenesis (if the violated gene participates in regulation of cell reproduction and differentiation) and protein malfunctions, which consequently may promote cell death and tissue toxicity.
It is worth mentioning that xenobiotics injure the male reproductive system not only by themselves and their metabolites but also via defensive reactions of the organism, such as innate and specific acquired immune responses. Thus, locally available reactive metabolites may cause disruption of testis immunoprivilege through the immunocompetent cells activation. This would lead to organ-specific immunopathology. Xenobiotics may have a toxic effect due to the malfunction of both the first and the second phase enzymes because of their hyperactive or inhibited functioning. In the case of increased phase I enzyme activity, or decreased phase II enzyme activity, electrophilic intermediates of the xenobiotic metabolism are accumulated in the cells and mediate the abovementioned damages. At the same time, the reduced activity of the first phase enzymes leads to metabolism retardation and accumulation of noxious chemical compounds in different tissues of the organism, including in those of the reproductive system. For example, decreased activity of GST (phase II enzyme that transfers glutathione (GSH) to activated environmental chemicals) will probably lead to the formation of reactive intermediates that will mediate cell damage mechanisms. On the other hand, phase I enzyme CYP1A1 is able to metabolize the polycyclic aromatic hydrocarbons (PAHs) to intermediate substances, which prompt genotoxic and mutagenic effects before they are further detoxified by phase II enzymes. This indicates that the increased activity of CYP1A1 may contribute to the accumulation of these compounds in the organism and to the elevation of the PAH-DNA adducts level. Although the liver performs the main functions of detoxification, reactive metabolites can also be generated in a particular organ, mediating organ specific toxicity. For example, experiments on laboratory animals such as rats and mice showed the presence of both phase I and phase II enzymes in their testicles. [17, 18]. The possibility of PAHs (benzo(a)pyrene) detoxification was also shown on the rats’ Leydig cells [19]. The xenobiotic-detoxification enzymes are much needed in the reproductive system, since some endocrine-deteriorating agents (phthalates, dioxins, polychlorinated biphenyls (PCBs) and pesticides) have been shown to exert a negative influence on the reproductive tissues [20]. Thus, stable and lipophilic chlorinated hydrocarbons are capable of penetrating into the male reproductive tract, promoting idiopathic sterility and other reproductive impairments. One of the well-studied examples of male testicular toxins is occupational xenobiotic nematocide 1,2-dibromo 3-chloropropane (DBCP) that causes a partially reversible damage to the seminiferous epithelium, leading to diminished sperm counts and sterility [21]. Another occupational and environmental toxin dichlorodiphenyldichloroethylene also reduces sperm count and mediates male infertility [22].
5. Polymorphism of genes that affect spermatogenesis
Except xenobiotic detoxification gene polymorphisms, another target group of genes that are most probably involved in development of male infertility is genes take part in spermatogenesis. This group includes genes with different functions such as endocrine regulation of spermatogenesis (i.e., androgen receptor (AR), follicle-stimulating hormone receptor (FSHR) and Estrogen receptor α and β), specific spermatogenic functions (i.e., deleted azoospermia-like (DAZL), Ubiquitin carboxyl-terminal hydrolase 26 (USP26), protamine-1 (PRM1) and gonadotrophin-regulated testicular helicase (GRTH)), regulation of cell functions such as metabolism, cell cycle and mutation repair (i.e., mtDNA polymerase γ (POLG) and Methylene tetrahydrofolate reductase (MTHFR)) and Y-chromosome haplogroups. Y-chromosome abnormalities are the best studied, while data about association of male infertility with the other spermatogenesis regulation genes remain contradictory. For example, the spermatogenesis locus azoospermia factor c (AZFc) region partial deletion (gr/gr deletions, which include DAZ (Deleted in azoospermia) genes) is regarded as classical Y-chromosome mutation. Its role in male infertility was proven by several studies, although it is present in normospermic men as well [16, 23]. Here are some examples of the other probable risk factors obtained by meta-analysis [23]. One of gene candidates, which is regarded as the most probable risk factor of male infertility, is MTHFR, which encodes methylenetetrahydrofolate reductase—one of the key enzymes in folate metabolism. The C → T substitution in the position 667 changes an alanine to a valine (Ala222Val) and decreases activity of enzyme, thus leading to the decrement of spermatogenesis. FSHR SNP showed a significant association with seminal fluid abnormalities only in the case when both the exon 10 SNPs and SNP of promoter at position 29 are present. G197 T SNP in PRM1 gene, which encodes DNA-binding protein, responsible for packing of DNA into the sperm head, may by a novel risk factor for patients with a normal sperm count but elevated levels of sperm DNA fragmentation and/or teratozoospermia. Studying of the genes affecting spermatogenesis also demonstrated significant influence of ethnicity on the association of polymorphisms and the risk of male infertility. Thus, AR repeat length polymorphism with repeat number more than 23 is a risk factor for Asiatic but not the European population. T54A mutation in exon 3 of DAZL gene was significantly associated with oligospermia or azoospermia in the Chinese population, while in Japanese or Caucasian populations, such an association was not established. The POLG gene, which encodes mtDNA polymerase γ and thus important for mitochondria functioning, has common 10-fold repeated CAG motif in the first exon. It is known that mitochondria are one of the main determinants of sperm motility, and their altered regulation may be connected with asthenozoospermia (which is characterized by reduced sperm motility). Nevertheless, only one study [24] among four considered [24, 25, 26, 27] established that the absence of this allele was significantly associated with male infertility. These results may not be relevant enough, as far as the sample size was not sufficiently big, (verum group included 99 infertile men, while control, 98 fertile men). In spite of the increased interest in the genetic causes of male infertility, there are no clear predictive and diagnostic criteria, except few polymorphisms such as AZF gr/gr deletions (OR 1.81, 1.46–2.24 CI, P < 0.00001) and MTHFR 677C → T (OR 1.39, 1.15–2.69 95% CI, P = 0.0006) [16]. The only way to build an adequate picture of reasons standing behind idiopathic male infertility is application of methods based on whole genome analysis, taking into account environmental factors.
6. Polymorphism of xenobiotic detoxification genes
The reasons behind the idiopathic cases of male infertility can probably be explained by the existence of unidentified genetic abnormalities involving several hundred genes, environmental interaction and epigenetics. Each of these genes is accountable for only a small part of the cases. In the late 1990s, the polymorphisms-based approach to searching for genetic factors in patients with idiopathic infertility was reinforced because of the findings of other investigations related to multifactorial impairments. Potential polymorphic genes that participate in male infertility development were determined from the increasing data on model organisms, expression analyses (transcriptome and proteome analyses) associated with poor germ cells quality and from data available from the Genome-Wide Association Studies (GWAS). In total, 2000 genes (housekeeping and germ cell specific genes) are engaged in spermatogenesis [28], but 314 single-nucleotide polymorphisms (SNPs) have been reported only in 123 genes for the year 2015 [15]. Nearly 70% of these SNPs are responsible for general cell functions (regulation of apoptosis, DNA repair, xenobiotic metabolism and detoxification of reactive oxygen species), while the rest are involved in specific processes associated with spermatogenesis, meiosis and endocrine regulation of the reproductive system. However, available data are often contradictory and only a small amount of genetic polymorphisms are well studied. Meta-analyses were conducted for such genes as AR, CYP1A1, GSTP1, GSTM1, GSTT1, DAZL, ESR1, ESR2, MTHFR, NOS3, POLG, TP53 and USP26, among which CYP1A1, GSTP1, GSTM1 and GSTT1 detoxify the environmental chemicals and are of great interest. In addition to the abovementioned genes, NAT2 will also be regarded as an important candidate carrying SNPs that alter xenobiotic detoxification phenotypes. Readers considering the represented data should always bear in mind that determination of connections between xenobiotic detoxification genes polymorphisms and male infertility is significantly complicated by the existence of intricate interactions among phase I and phase II metabolizing enzymes, as well as among the phase III transporters and their nuclear receptors (aryl hydrocarbon receptor (AhR), orphan nuclear receptors, nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), constitutive androstane receptor (CAR) and pregnane X receptor (PXR)). These receptors can act as transcriptional factors for some xenobiotic metabolizing enzymes. For instance, CYP1 genes can be induced by AhR in response to PAHs, while CYP2B and CYP3A genes are activated by CAR and PXR in response to phenobarbital-like compounds and dexamethasone and rifampin-type of agents, respectively. It was also assumed that Nrf2 is the most likely transcriptional factor for phase II detoxification enzymes (such as GST) [29]. Thus, mutations or polymorphisms of these genes may contribute to alteration of xenobiotic metabolism indirectly that can also lead to a damage of the male reproductive system.
6.1. Cytochrome P4501A1 polymorphism
Cytochrome P4501A1 (CYP1A1) is a heme-thiolate containing monooxygenase that plays a central role in phase I extra-hepatic metabolism of lipophilic xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs) that are produced during the combustion of fossil fuels, protein pyrolysis in well-fried meat, as well as from aromatic amines, which are present in cigarette smoke, pesticides, dyes, drugs and industrial products. CYP1A1 is expressed in male reproductive organs. Thus, its polymorphisms may define susceptibility to male infertility [30]. In addition to PAHs metabolism, CYP1A1 participates in the synthesis of cholesterol, steroids and other lipids, as well as in steroid hormone metabolism. Thus, its polymorphic variants can intervene in the endocrine and paracrine regulation of testicular function [31]. Cytochrome P4501A1 gene is located on 15q22-q24 chromosome. It is 5987-bp long and encodes a 512 amino acid protein. Benzo(a)pyrene, 3-methylcholanthrene, PCBs or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activate its expression. Although the CYP1A1 is a polymorphic gene, only two common SNPs have been found to be functionally significant, namely, CYP1A1*2A (3801 T > C in the 3′-flanking region, rs4646903) and CYP1A1*2C (Ile462Val, 2455A > G (exon 7), rs1048943) [32]. The T > C substitution in CYP1A1*2A promotes the creation of a new MspI restriction site in the noncoding 3′-flanking region that causes elevation of transcript half-life and consequently enzyme activity, leading to increased levels of reactive metabolites [33]. The A > G substitution prompts an isoleucine-valine exchange in the heme-binding region of the enzyme, and according to some studies, it changes the enzyme’s kinetics during the generation of diol metabolites of benzo[a]pyrene or causes a -threefold increase in transcripts quantity and microsomal enzyme activity in Asians [34]. Such data can be explained by the fact that the CYP1A1*2A and CYP1A1*2C allelic variants appear much more frequently in Asians compared with other ethnic groups, namely, Caucasians and African Americans [35]. However, these data are contradictory. A recent meta-analysis of 1060 cases and 1225 controls from 7 published case–control studies revealed that the homozygous CYP1A1*2A genotype was significantly associated with the susceptibility to idiopathic male infertility in Asians (CC vs. TT: OR = 2.88, 95% CI: 1.20–6.89, TC vs. TT: OR = 1.42, 95% CI: 1.03–1.98, recessive model: OR = 1.63, 95% CI: 1.08–2.45.) but not in Caucasians, while no association with male infertility risk was found in the case of CYP1A1*2C genotype (GG vs. AA: OR = 1.03, 95% CI: 0.53–1.99, GA vs. AA: OR = 1.51, 95% CI: 0.51–4.43, dominant model: OR = 0.81, 95% CI: 0.42–1.54, recessive model: OR = 1.57, 95% CI: 0.55–4.47) [36]. Still, these results seem to be preliminary, since such individual characteristics as age, body mass index, smoking status and environmental factors, as well as the sperm concentration, motility and other semen parameters were not taken into account during the data analysis. Another meta-analysis of 6 studies including 1060 cases and 1225 controls also confirmed a valid association between CYP1A1*2A genotype and the male infertility risk with the highest figures for the homozygous variant (OR = 2.18, 95% CI: 1.15–4.12) [37]. Subgroup analysis based on ethnicity, sample size and quality assessment score failed to expose any significant level probably due to limited studies and population numbers discussed in the meta-analysis. Moreover, these conclusions may be irrelevant and need to be confirmed, as only two of six considered studies showed significant correlation and the abovementioned meta-analysis did not account the differences in exposure to environmental factors. The latter factor is of prime importance in the case of xenobiotic detoxification genes. Thus, Yarosh et al. [38] revealed a significant association between CYP1A1*2C and idiopathic male infertility risk only among smokers but not among nonsmokers. Finally, CYP1A1 may participate in male infertility through induction of the oxidative imbalance in cells as far as together with ligand-dependent transcription factor—Aryl hydrocarbon receptor (AhR)—it is capable of generating local reactive oxygen species (ROS) [39]. Considering that morphologically abnormal semen has reduced antioxidant capacity and increased ROS production [40], CYP1A1 may play a crucial role in male infertility development.
6.2. GSTM1, GSTT1 and GSTP1 polymorphisms
Human semen is rich in Glutathione S-transferases (GSTs) [41], which belongs to phase II superfamily of antioxidant enzymes involved in the cellular detoxification of various physiological substances (e.g., excessive ROS) or exogenous electrophiles. Detoxification process depends on the gene family class. At least seven gene classes of GSTs can be allocated: alpha (α), mu (μ), pi (π), sigma (ς), theta (θ), kappa (k) and zeta (ζ). They are coding GSTA, GSTM, GSTP, GSTS, GSTT, GSTK and GSTZ enzymes, respectively. Polymorphisms are encountered most frequently in GSTM1, GSTT1 and GSTP1 subfamilies. According to the available data, GSTM1 and GSTT1 null polymorphic variants are the most studied GST SNPs and are associated with the increased susceptibility to several diseases and hypersensitivity to toxic xenobiotics [42]. For instance, GSTM1 was shown to have homozygous deletion in nearly half of the people from various ethnicities. Such deletion results in decreased enzyme function [43]. In general, inhibited GST activity leads to diminished semen motility via membrane damage. Considering that unmetabolized toxic substances, which accumulate in the cellular matrix of the testis, cause spermatogenesis deterioration, another probable reason for sperm impairment in subjects with GSTM1 or GSTT1 null genotypes may be considered to be the insufficient functioning of seminiferous tubules and fibrosis developed in the testicular tissue [44].
GSTM1 is located on 1p13.3 chromosome; three alleles have been identified at its locus: GSTM1*A, GSTM1*B (causing the lysine 172 replacement by aspartic acid (534C > G) and not exhibiting alterations in enzyme activity) and GSTM1 null genotype (gene deletion) [45].
GSTT1 is located on 22q11 chromosome and has one polymorphism (GSTT1 null genotype) that leads to the inhibition of enzyme production in homozygote [46].
Several studies have suggested that GSTM1, as well as GSTT1, might be crucial isozymes in the metabolism of ROS [47, 48]; meanwhile, diminished antioxidant capacity of seminal plasma turned out to promote subfertility.
Numerous studies reported the connection between the polymorphisms of GST genes and the DNA fragmentation increased due to the impaired defense against oxidative stress [49], which may result in some kinds of cancers. Considering that surplus of reactive oxygen species is a damaging factor for spermatozoa, GST SNPs most likely contribute to idiopathic male infertility. A possible explanation for the spermatogenesis impairment in GSTT1 and GSTM1 null allele carriers was proposed by Wu et al. [50]. Considering that null genotypes eliminate the binding site for some transcription factors, such as nuclear factor 1 (NF-1) (may act as transcriptional repressor or activator, determined by target gene expression), specificity protein 1 (SP1) (involved in cell differentiation, cell growth, apoptosis, immune responses, response to DNA damage and chromatin remodeling) and serum response factor (SRF) (participates in transforming extracellular signals into specific nuclear responses), GSTT1 and GSTM1 null variants may cause changes in gene expression through the removal of transcription factors. Such alterations in gene expression may entail deterioration of sperm maturation and impaired fertility.
Another polymorphic gene (GSTP1) is approximately 4 kb in length and is located on 11q13.2 chromosome. It includes 7 exons and encodes a 210 amino acid protein. Two polymorphisms of GSTP1 rs1138272 (341C > T (exon 6) leading to the alanine 114 replacement by valine) and rs1695 (313A > G (exon 5) encoding the amino acid exchange (replacement of isoleucine in the position 105 by valine) were associated with a decreased heat stability and the detoxification ability of this enzyme [51].
Most of the current data on the polymorphisms of xenobiotic detoxification gene are devoted to GST SNPs. A pooled analysis of 11 studies (7 involve Asians and 4 involve Caucasians), which included 1323 cases and 1054 controls, revealed that GSTM1 (OR = 2.75, 95%; CI: 1.72–3.84, P = 0.003) and GSTT1 null (OR = 1.54, 95%; CI: 1.43–3.47, P = 0.02) genotypes showed significant association with strong/moderate risk of impaired male fertility, respectively. At the same time, GSTP1 Ile/Val genotype was proved to mediate the protective effect on male reproductive system (OR = 0.48, 95%; CI: 0.27–0.77) [52]. These results are reliable enough, as far as researchers took into account the age, ethnicity and the smoking status. Interestingly, that in contrast to CYP1A1 polymorphism, there was no difference between smokers and nonsmokers (P = 0.26). At the same time, GSTM1 null genotype, considered in the research on Indian subjects, showed 8.6 times increment of infertility risk if the subject was a smoker. Going back to the pooled analysis, synergistic effects of GSTM1 null allele, GSTT1 null allele and GSTP1 Ile/Ile polymorphism on male infertility was recognized as a valuable feature of this research [53]. However, further analysis showed that GSTM1 null genotype was associated with male infertility only at a borderline level of significance [53]. Such inconsistency may be explained by more rigid selection criteria in the latter meta-analysis. Since 161 of 168 studies were excluded, only 6 case-control studies concerning the GSTM1 genotype and 5 studies concerning the GSTT1 were eligible. Moreover, most studies referred to Caucasian subjects (except one, concerning the GSTM1 polymorphism, and two, concerning the GSTT1 polymorphism). On this basis, no ethnic variations were analyzed. Another doubtful issue touches upon the possibility of association between GSTP1 Ile/Ile polymorphism and the susceptibility to idiopathic male infertility. The fact is that in human population, Ile allele is encountered more frequently than the Val allele is. Thus, its positioning as a risk factor for male infertility contradicts the principles of evolutionary genetics, as Ile allele should have disappeared from the population. Furthermore, recent meta-analysis, devoted to the association between GSTP1 polymorphism and cancer susceptibility, revealed that Val allele was a risk factor for carcinogenesis, and no accumulation effect of Ile/Ile genotype was revealed [54]. All this indicates the necessity of additional researches that would comprise GSTP1 Ile/Ile polymorphism.
Another GSTP1 polymorphism—Ala/Val (rs1138272) substitution—was studied even less extensively than the Ile/Val polymorphism. Recently, this SNP was shown to be associated with the increased risks of infertility in Vietnam male subjects (OR = 7.42, 95%; CI: 3.86–14.30) [55], while previously, another work, devoted to the oxidative damage in infertile men with varicoceles, revealed no significant differences between the indices recorded in the patient and control groups [56]. Further meta-analysis that focused on the relationship between the prostate cancer and the GSTP1 Ala/Val polymorphism revealed no significant associations [57]. Although Aydemir et al. did not report such a correlation, they revealed a connection between the GSTM1 null polymorphic variant with markers of oxidative stress in patients and the idiopathic male infertility [58]. Thus, most investigations, including five meta-analyses, confirmed the GSTM1 association with the risk of male infertility [52, 59, 60, 61].
A meta-analysis of 15 researches (8 involve Asian people, 6—European people, and 1 comprises a mixed population) that included 1897 cases and 1785 controls showed that GSTM1 null genotype was significantly associated with susceptibility to idiopathic male infertility, but not with sperm concentration. In the case of GSTT1 null genotype, no association with oligoasthenoteratozoospermia and sperm concentration was revealed. Subgroup analysis on ethnicity did not show any reliable association between the idiopathic male infertility and the GSTM1 null or GSTT1 null genotype [59].
Contradicting data were obtained via the case-control study of Han people from East China, which included 1476 infertile men with normozoospermia, oligozoospermia and nonobstructive azoospermia and 895 healthy controls, matched by age, drinking and smoking status, body mass index and semen volume [50]. The research revealed that GSTT1 null genotype is a predisposing factor for idiopathic male infertility (OR = 1.26; 95%; CI: 1.07–1.50; P = 0.007), while GSTM1 null genotype showed no significant association with the idiopathic male infertility risk (OR = 1.15; 95%; CI: 0.97–1.36; P = 0.116). At the same time, GSTM1 null variant was prevalent in oligozoospermic patients (OR = 1.55; 95%; CI: 1.15–2.08; P = 0.004), while the GSTT1 null polymorphism was associated with normozoospermia (OR = 1.23; 95%; CI: 1.03–1.48; P = 0.025) and azoospermia (OR = 1.58; 95%; CI: 1.18–2.11; P = 0.002). Interestingly, no differences were found in GSTM1 expression between the present and deleted genotypes, but such were found in the GSTT1 null polymorphism, which expression was significantly decreased in comparison with the present variant.
The authors also conducted a meta-analysis of 19 case-control studies in 2002–2013. The meta-analysis included 3981 cases and 2953 controls involving the Asian and Caucasian ethnic groups [50]. As a result, GSTM1 null allele carriers were subjected to the risk of male infertility (OR = 1.39; 95%; CI: 1.14–1.70; P = 0.001) and to oligoasthenoteratozoospermia (OR = 1.53; 95%; CI: 1.25–1.89; P < 0.001). This association persisted in the case of subgroup analyses that involved Asians (OR = 1.51; 95%; CI: 1.13–2.10; P = 0.005) and Caucasians (OR = 1.24; 95%; CI: 1.00–1.52; P = 0.046). The GSTT1 null variant, however, was significantly associated with male infertility only among Asian people (OR = 1.44; 95%; CI: 1.10–1.90; P = 0.009). Such results may be explained by the fact that the GSTT1 null genotype is most frequently encountered in individuals of Asian origin than in other populations [62]. On the whole, differences from the previous meta-analysis [59] may be explained by the fact that they have added some recent studies.
Data of numerous studies revealing the GST polymorphism effect on the male infertility development remain contradictory. The list of the most probable underlying causes includes the relatively small number of participants, ignoring some gene-environment and gene–gene interactions and the possible small influence of the GST SNPs on the risk of idiopathic male infertility.
6.3. Arylamine N-acetyltransferase 2 polymorphism
Arylamine N-acetyltransferase 2 (NAT2) is a phase II xenobiotic detoxification enzyme metabolizing such chemicals as arylamines, aromatic and heterocyclic amines and hydrazines via N-acetylation and O-acetylation. In other words, it transfers the acetyl group from acetyl-coenzyme A to the nitrogen or oxygen of the substrate. It takes part in the metabolism of such drugs as sulfadimidine, sulfamethazine, isoniazid, nitrazepam, dapsone or caffeine [63]. Therefore, it determines human susceptibility to cancer and the side effects of drugs [64].
Biological significance of NAT2 could be demonstrated through the association between its polymorphisms with susceptibility and different types of cancer—lung, colon or bladder cancer [65, 66].
NAT2 is expressed in the male reproductive organs (genital ducts, testicular tissues, exocrine and prostate glands), promoting protective effect against the environmental chemicals that may lead to male urogenital diseases [67].
NAT2 is a 290 amino acid protein, encoded by intronless 9.9 kb gene, located on the 8p22 chromosome and consists of 3 exons. Scientists identified the acetylation polymorphism more than 60 years ago in tuberculosis patients, who reacted to isoniazid toxicity in different ways [68]. NAT2 is characterized by a high number of polymorphic genes, comprising more than 66 alleles [69]. Most of these polymorphisms are synonymous and do not always cause variations in enzyme activity [70]. The most common and important variants of SNPs are rs1799929 (481C > T that does not cause leucine alteration at amino acid 161, L161 L) marked as NAT2*11A and rs1799930 (590G > A that leads to the charged arginine replacement by polar glutamine at the codon 197 (R197Q)) marked as NAT2*6 [71]. NAT2*6 corresponds to a slow acetylator phenotype, while the NAT2*11A to a rapid one that may differ from the NAT2*6 by a threefold incensement in the metabolic rate [72]. These two extreme acetylator phenotypes are considered as risk factors for disease development after the subjection to arylamines and other NAT2 targets. For instance, NAT1 and NAT2 slow acetylator phenotypes were shown to be predisposing factors for prostate cancer [73], while the rapid NAT2 phenotypes had higher frequencies in contact-allergic patients [74]. It is considered that the existence of canonical isoniazid slow acetylator phenotype is caused by the reduction in NAT2 protein [75]. Among the other reasons, there are low levels of expression, instability or reduced catalytic activities [76].
There are substantial interethnic variations of the slow acetylator phenotype. Thus, it can be found in 40–70% of Caucasian and African people. At the same time, its frequency ranges from 10 to 30% in Japanese, Chinese, Korean and Thai people [77].
There is a lack of evidence to confirm the role of NAT2 polymorphism in the development of male infertility. However, recently it was proved that gene-environment interactions play a very important role in the case of NAT2 polymorphism and determine whether it will predispose male infertility. Thus, several data have showed that rs1799929 and rs1799929 SNPs themselves were not associated with the increased risks of idiopathic male infertility [78]. However, if the subject was exposed to cigarette smoking (OR = 1.71, 95% CI: 1.02–2.87, P = 0.042), alcohol abuse (OR = 2.14, 95% CI: 1.08–4.27, P = 0.029) and low fruit/vegetable intake (OR = 1.68, 95% CI: 1.01–2.79, P = 0.04), the risk of male infertility significantly increased in the case of slow acetylator phenotype rs1799930.
Contrariwise, rapid acetylator phenotype was found to cause higher DNA-fragmentation levels after 2 days of meat diet [79]. Considering that the level of DNA fragmentation is significantly higher in infertile men [80], this study also proves that NAT2 polymorphism is involved in the process of impaired reproductive development in men.
The latest study, conducted on Vietnam males, revealed that idiopathic male infertility is associated with both the rs1799930 (OR = 3.10, 95%; CI: 1.92–5.01) and the rs1799929 (OR = 3.74, 95%; CI: 2.26–6.18) alleles. The current research also shows that GSTP1 and NAT2 have a synergetic effect—they cause the biggest risk of infertility only when both polymorphisms are present. Namely, the 481C > T rs1799929 (NAT2) and the 341C > T or 341 T > T rs1138272 (GSTP1) cause the 17-fold increase in the risk of idiopathic male infertility (OR = 17.24, 95%; CI: 7.30–40.74, P = 0.0001) [55].
Thereby, the NAT2 involvement in the process of male infertility development is highly probable, but more data are needed to confirm its role in mediating the impaired male reproduction.
7. Conclusions
Male infertility is a worldwide health problem with multifactorial etiology, showing an upward trend during the last decade. One of the most significant reasons behind this trend is the exposure to environmental factors—xenobiotics, hypo/hyperthermia, stress or harmful radiations (such as X-rays). All this phenomena may lead to oxidative stress, treated as one of the most common trigger of male infertility and found in nearly half of all the infertile men [81]. It causes impairment of sperm maturation, testis injury, sperm motility reduction and DNA damages. Research on the polymorphisms of xenobiotic detoxification genes may be helpful for determining the interethnic and interindividual peculiarities of noxious chemicals metabolism (including possible risks of male infertility development) based on gene-environment interactions. Overall, knowledge about the SNPs of xenobiotic metabolizing genes associated with male infertility is rather inconsistent or even contradictory. Thus, more comprehensive analysis is required that would be stratified according to the age, body mass index, ethnic background, diet, smoking and drinking status, environmental exposures and other lifestyle factors. Moreover, many studies were carried out on small samples. This factor increases the probability of overestimating the association. Numerous studies indicated that such polymorphisms as CYP1A1, GSTM1, GSTT1, GSTP1 and NAT2 are most likely to be involved in male infertility development. Their polymorphic transcripts were shown to change the xenobiotic metabolism. In some cases, they failed to provide sufficient antioxidant defense. Knowledge of the role that the polymorphisms of xenobiotic detoxification genes have in male infertility development could be useful for providing sufficient diagnostic methods, as well as for providing reliable recommendations for infertile men on disease prevention and treatment.
Acknowledgments
The authors would like to take this opportunity to extend their sincere thanks to the Ministry of Health for providing financial support for this study. We are also grateful for the technical support of the Hanoi Medical University Hospital. We thank Dr. Shkurat TP for a critical reading of the chapter.
Conflict of interest
The authors declare that they have no conflict of interest.
\n',keywords:"male infertility, xenobiotics, arylamine N-acetyltransferase 2, GSTM1, GSTT1, GSTP1, cytochrome P4501A1, genetic polymorphism, oxidative stress, DNA fragmentation, detoxification",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/62389.pdf",chapterXML:"https://mts.intechopen.com/source/xml/62389.xml",downloadPdfUrl:"/chapter/pdf-download/62389",previewPdfUrl:"/chapter/pdf-preview/62389",totalDownloads:233,totalViews:0,totalCrossrefCites:0,dateSubmitted:"March 26th 2018",dateReviewed:"June 1st 2018",datePrePublished:"November 5th 2018",datePublished:null,readingETA:"0",abstract:"Infertility is a multifactorial disease caused by both genetic and environmental factors. It is observed in 10–15% of couples, among which male infertility contributes for half the cases. Thus, identifying underlying causes of male infertility and for proper methods for treating and/or preventing sperm damage is of paramount importance. It is found that one of the factors that has been recently implicated in male infertility is oxidative stress, mediated by reactive oxygen species (ROS) that are produced during the metabolic process, as well as during the exposure to environmental chemical agents and their interaction with tissue-specific enzymes. Several studies have identified genetic variations at different loci, connected with male infertility, that may shed light on some idiopathic cases of seminal fluid abnormalities. In this chapter, we make an effort to decipher the contribution of polymorphisms in xenobiotic detoxification genes in the male infertility development.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/62389",risUrl:"/chapter/ris/62389",signatures:"Nguyen Thi Trang and Vu Thi Huyen",book:{id:"7931",title:"Male Reproductive Health",subtitle:null,fullTitle:"Male Reproductive Health",slug:null,publishedDate:null,bookSignature:"Dr. Wei Wu, Dr. Francesco Ziglioli and Dr. Umberto Maestroni",coverURL:"https://cdn.intechopen.com/books/images_new/7931.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"178661",title:"Dr.",name:"Wei",middleName:null,surname:"Wu",slug:"wei-wu",fullName:"Wei Wu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Xenobiotic metabolism",level:"1"},{id:"sec_3",title:"3. Potential mechanisms for idiopathic male infertility",level:"1"},{id:"sec_4",title:"4. Association of xenobiotics with male infertility",level:"1"},{id:"sec_5",title:"5. Polymorphism of genes that affect spermatogenesis",level:"1"},{id:"sec_6",title:"6. Polymorphism of xenobiotic detoxification genes",level:"1"},{id:"sec_6_2",title:"6.1. Cytochrome P4501A1 polymorphism",level:"2"},{id:"sec_7_2",title:"6.2. GSTM1, GSTT1 and GSTP1 polymorphisms",level:"2"},{id:"sec_8_2",title:"6.3. Arylamine N-acetyltransferase 2 polymorphism",level:"2"},{id:"sec_10",title:"7. Conclusions",level:"1"},{id:"sec_11",title:"Acknowledgments",level:"1"},{id:"sec_14",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Lassen TH, Iwamoto T, Jensen TK, Skakkebæk NE. Trends in male reproductive health and decreasing fertility: Possible influence of endocrine disrupters. Low fertility and reproductive health in East Asia. 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