Published studies focusing the antigenotoxic evaluation of several types of chemicals, nanoparticles and plants/seaweeds/seeds/oils using somatic mutation and recombination tests (SMARTs).
Abstract
Genotoxicological studies are emerging as fundamental for knowing the hazards to our genome, to our health. Drosophila melanogaster is one of the preferable organisms for toxicological research considering its metabolic similarities (viz. on dietary input, xenobiotic metabolizing system, antioxidant enzymes and DNA repair systems) to mammals. Accordingly, somatic mutation and recombination tests (SMARTs) of D. melanogaster are fast and low-cost in vivo assays that have shown solid results evaluating genotoxicity. The w/w + SMART uses the white (w) gene as a recessive marker to monitor the presence of mutant ommatidia (eye units), indicating the occurrence of point mutations, deletions, mitotic recombination or/and nondisjunction. Additionally, several studies used SMARTs to assess antigenotoxicity, with some using the w/w + SMART. We reviewed the state of the art of the w/w + SMART used for antigenotoxicity analysis, focusing on published results, aiming to contribute to the conception of a reliable protocol in antigenotoxicity. As such, genotoxic agents with known action mechanisms, as streptonigrin (oxidative stress inducer), were used as a genotoxic insult for proving the antigenotoxic effects of natural substances (e.g. seaweeds), demonstrating the presence of antimutagens in their composition. These antigenotoxicity studies are crucial for promoting preventive measures against environmental genotoxics that affect humans daily.
Keywords
- genotoxicity test
- w/w+ SMART
- eye-spot test
- Drosophila melanogaster
- streptonigrin
- genotoxic agent
- oxidative stress
- DNA damage
- ROS inhibition
- antigenotoxicity
- antimutagens
- dietary antioxidants
1. Introduction
The environmental emergency is largely related to environmental toxicology. Each day, new molecules are synthesized, or natural molecules are intensively produced that enter in ecosystems and affect them at all levels. Nowadays there are circulating in living organisms thousands of substances that did not exist 100 years ago, with somewhat unpredictable consequences. As such, more than 159 million chemical substances are registered in the Chemical Abstracts Service (CAS), with approximately 4000 new substances being registered daily [1]. As a controlling measure, the EU Commission created, in 2004, a network (NORMAN network) of laboratories, research centres and organizations for monitoring the emerging environmental substances [1].
Environmental toxicology encompasses exposure to toxic substances whether through the air we breathe, the food we eat, the water we drink and the clothes we wear or through the skin, cosmetics, etc. There is also radiation exposure, which also has harmful effects, and is much more problematic today than some years ago. The planet is poisoned, affecting the air, the water, the soil and the food we produce, which causes serious problems to human health and ecosystems. It is hoped that worldwide awareness of this reality will be achieved, and the focus of humanity’s greatest concerns will be on the cleansing of the planet by eliminating or at least greatly reducing the produced toxic agents.
This whole problem greatly affects DNA, causing DNA damage (genotoxicity), affecting DNA repair mechanisms and causing mutations when damage is not properly repaired. In the short term, this genome instability leads to diseases such as cancer, degenerative diseases, fertility decrease and other problems. In the long term, we may see the emergence of new diseases due to new mutations in the germ line, which, if recessive, may take several generations until there is a chance of homozygosis, where rare diseases may arise. All combined may affect the life expectancy of several species, causing an environmental collapse. Preventive strategies are indispensable to reduce the heavy burden on national healthcare systems and families. The most effective is a healthy lifestyle including diet, as an antigenotoxic diet reduces DNA damage and all the associated diseases. Antigenotoxic activities include inactivation of genotoxic compounds, by several mechanisms and increasing repair capacity, decreasing the effectiveness of a genotoxic. While DNA damage is clearly implicated as the initiating event in most cancers, the link is not a simple one. Most damage is removed by repair enzymes before it can interfere with the process of DNA replication and introduce mutations. Given a carcinogenic exposure, the individual variation in the capacity for DNA repair is therefore likely to be an important factor in determining cancer risk.
Over the years, many investigations in DNA damage and DNA repair mechanisms were made, in vitro and in vivo, aiming to know our environment and thus identifying the harmful compounds to our genome, to our health, leading to preventive actions such as prohibiting the commercialization of certain drugs, construction materials, foods and drinks. Genotoxicological studies using cell cultures and animals are essential for increasing human’s wellbeing, since they display solid results in showing the genotoxicity of compounds and should be standardized (with optimal test conditions) for increasing their reproducibility and precision.
2. Drosophila melanogaster in toxicological research
2.1 Somatic mutation and recombination tests of D. melanogaster
The somatic mutation and recombination tests of
Briefly, in the late embryogenesis, larval structures are set, and groups of diploid cells of undifferentiated epithelium, imaginal discs, are formed in the embryo [12]. Then, upon the ending of the larval stages, pupa emerges, and metamorphosis takes place upon systemic hormonal regulation, with the histolysis of the larval organs and differentiation of the imaginal discs into adult structures [13, 14]. Accordingly, the exposure of imaginal discs to genotoxic agents may lead to genetic alterations (the product of DNA damage) capable of being transmitted to daughter cells upon mitosis. These genetic alterations can be phenotypically manifested in the adults in structures such as the wings and the eyes, which can be assessed according to the wing-spot test and the eye-spot test, respectively. The loss of heterozygosity (LOH) for specific genetic markers in heterozygous individuals allows the quantification of DNA damage/level of genotoxicity in the adult tissues by visual scoring [9, 15].
Between the two types of SMART currently used, from the practical point of view, the
Reference | SMART type | Genotoxic agent | Substance tested as antigenotoxic | Response |
---|---|---|---|---|
Abraham [18] | Wing-spot | Cyclophosphamide (CPH) Diethylnitrosamine (DEN) Mitomycin C (MMC) Procarbazine (PRO) Urethane (URE) |
Coffee | + + + − + |
Alaraby et al. [19] | Wing-spot | Potassium dichromate (PD) | CeO2 NPs Cerium sulphate |
+ |
Alaraby et al. [20] | Wing-spot | Potassium dichromate (PD) Ethyl methanesulfonate (EMS) Potassium dichromate (PD) Ethyl methanesulfonate (EMS) |
CuO NPs Copper oxide |
+ + |
Amkiss et al. [21] | Eye-spot | Methyl methanesulfonate (MMS) | Fennel plant fruit extracts | + |
Anter et al. [22] | Wing-spot | Hydrogen peroxide | Virgin Olive oil Triolein Tyrosol Squalene |
+ + + + |
Anter et al. [23] | Wing-spot | Hydrogen peroxide | Red table grapes | + |
Anter et al. [24] | Wing-spot | Hydrogen peroxide | Phenols: apigenin, bisabolol, protocatechuic acid |
+ + + |
Aydemir et al. [25] | Wing-spot | Fotemustine | Amifostine | + |
Cápiro et al. [26] | Eye-spot | Methyl methanesulfonate (MMS) Ethylnitrosourea (ENU) Juglone (JG) Dimethylbenz(a)anthracene (DMBA) |
|
+ + + + |
Demir and Marcos [27] | Wing-spot | Potassium dichromate | Boron nitride nanotubes | + |
De Rezende et al. [28] | Wing-spot | Doxorubicin (DXR) | Grape seed proanthocyanidins | + |
De Rezende et al. [29] | Wing-spot | Doxorubicin (DXR) | Dibenzylbutyrolactolic lignan(−)-cubebin | +/− |
Drosopoulou et al. [30] | Wing-spot | Mitomycin C (MMC) | Chios mastic products: verbenone α-terpineol linalool trans-pinocarveol |
+ + + − |
El Hamss et al. [31] | Wing-spot | Urethane (URE) | Turmeric | + |
Fernandes et al. [32] | Wing-spot | Doxorubicin (DXR) Benzo(a)pyrene (B(a)P) |
Vitexin | + + |
Fernandez-Bedmar and Alonso-Moraga [33] | Wing-spot | Hydrogen peroxide | Green sweet pepper Red sweet pepper Green hot pepper Red hot pepper Capsaicin Capsanthin Lutein |
+ + − + + + + |
Fernández-Bedmar et al. [34] | Wing-spot | Hydrogen peroxide | Citrus juices Hesperidin Limonene |
+ + + |
Fernandez-Bedmar et al. [35] | Wing-spot | Hydrogen peroxide | Tomato Lycopene |
+ + |
Fernández-Bedmar et al. [36] | Wing-spot | Hydrogen peroxide | Garlic Onion Diallyl disulphide Dipropyl disulphide |
+ + + + |
Ferreira et al. [3] | Eye-spot | Streptonigrin (SN) |
|
+ + |
Graf et al. [37] | Wing-spot | Urethane (URE) Methyl urea + sodium nitrite |
Instant coffee Ascorbic acid Catechin |
+ + + |
Guterres et al. [38] | Wing-spot | Doxorubicin (DXR) |
Fruit |
− + |
Idaomar et al. [39] | Wing-spot | Urethane (URE) | Essential oils from: |
+ + + |
Kylyc and Yesilada [40] | Wing-spot | Mitomycin C (MMC) | Dried mycelia from: |
+ + |
Laohavechvanich et al. [41] | Wing-spot | Urethane (URE) | Bird pepper Red chili spur pepper Green bell pepper Green sweet pepper |
+ + + + |
Lozano-Baena et al. [42] | Wing-spot | Hydrogen peroxide |
Sinigrin |
+ + |
Marques et al. [43] | Eye-spot | Streptonigrin (SN) |
|
+ + + |
Martinez-Valdivieso et al. [44] | Wing-spot | Hydrogen peroxide | Lutein β-Carotene Zeaxanthin Dehydroascorbic acid Yellow zucchini Light green zucchini |
+ + + + + + |
Mateo-Fernandez et al. [45] | Wing-spot | Hydrogen peroxide | Caramel color class IV | + |
Merinas-Amo et al. [46] | Wing-spot | Hydrogen peroxide | Choline | + |
Mezzoug et al. [47] | Wing-spot | Urethane (URE) |
|
+ |
Niikawa et al. [48] | Wing-spot | Mitomycin C (MMC) | Salicylic acid Salicyluric acid Gentisic acid Gentisuric acid 2,3-Dihydroxybenzoic acid |
− + + + + |
Niikawa et al. [49] | Wing-spot | Mitomycin C (MMC) | Salicylic acid Salicyluric acid Gentisic acid Gentisuric acid 2,3-Dihydroxybenzoic acid |
− + + + + |
Oliveira et al. [50] | Wing-spot | Doxorubicin (DXR) | Metformin | + |
Orsolin et al. [51] | Wing-spot | Doxorubicin (DXR) | Simvastatin | + |
Pádua et al. [52] | Wing-spot | Mitomycin C (MMC) Ethyl methanesulfonate (EMS) |
extracts |
+ + |
Patenkovic et al. [53] | Wing-spot | Methyl methanesulfonate (MMS) | Sage tea | + |
Patenkovic et al. [54] | Wing-spot | Methyl methanesulfonate (MMS) | Gentian tea | − |
Prakash et al. [55] | Wing-spot | Ethyl methanesulfonate (EMS) | Caffeine | + |
Prakash et al. [56] | Wing-spot | Methyl methanesulfonate (MMS) |
|
+ |
Rizki et al. [57] | Wing-spot | Potassium dichromate (PD) | Sodium selenite | + |
Romero-Jiménez et al. [58] | Wing-spot | Hydrogen peroxide |
|
+ + + + + + |
Sarıkaya et al. [59] | Wing-spot | Ethyl methanesulfonate (EMS) | Boron | + |
Savić et al. [60] | Wing-spot | Methyl methanesulfonate (MMS) | Royal Sun Agaricus extract | − |
Sukprasansap et al. [61] | Wing-spot | Urethane (URE) | Eggplants | + |
Taira et al. [62] | Wing-spot | 2-AAF Aflatoxin B1 DMBA IQ MeIQx MNU NDMA 4NQO 2-AAF Aflatoxin B1 DMBA IQ MeIQx MNU NDMA 4NQO 2-AAF Aflatoxin B1 DMBA IQ MeIQx MNU NDMA 4NQO |
|
+ + + + + + + + - + − − − + + + + + + + + + + + |
Tasset-Cuevas et al. [63] | Wing-spot | Hydrogen peroxide | Borage seed oil Gamma linolenic acid |
+ + |
Toyoshima et al. [64] | Wing-spot | Sun and UV light | Sunscreens: SPF 20 SPF 40 SPF 60 |
+ + + |
Valadares et al. [65] | Wing-spot | Doxorubicin (DXR) | Propolis (water extracts) | + |
Valente et al. [66] | Eye-spot | Streptonigrin (SN) | Thalassotherapy products | + |
3. w /w
+ SMART (eye-spot test)
The basis of the
Moreover, Vogel and Nivard [69, 70] designed a more refined, as well as time-consuming, version of the
3.1 Antigenotoxicity with w /w
+ SMART
Among the processes related to genotoxicity, with an increased relevance in the last years, the analysis of antigenotoxicity is probably the most important one. The search for antigenotoxic agents that could prevent or counteract the harmful consequences of the exposure to DNA damaging agents has increased exponentially lately [78, 79, 80]. Since most of the possible antigenotoxic agents are components of natural products that could be included in the diet, the analysis of their properties should be performed in in vivo experiments. As so,
Ferreira and Marques [3] and Marques and Ferreira [43] studied the exposure of
MMS (at 1 mM) was used as a genotoxic insult against a fennel plant fruit aqueous extract [21]. The positive control showed a great number of induced mutant ommatidia, proving the results from Vogel and Nivard [72], and the fennel extract showed antigenotoxic activity against MMS. According to the authors, and considering the mutagenic activity of MMS, an alkylating agent, consisting of direct interactions with DNA bases that induce mutagenic events, fennel may possess antimutagens that interact directly with the methyl radical groups of MMS and inactivate them in such a manner that they cannot bind to DNA as effectively to induce their mutagenic activity. The antimutagenic properties displayed by fennel may be related to components of its essential oil [21]. In a similar way, Cápiro and Sánchez-Lamar [26] demonstrated the antigenotoxic potential of lemongrass decoction extracts against different genotoxics, MMS, ENU, juglone (JG) and dimethylbenz(a)anthracene (DMBA), that exhibit different mechanisms of action. According to the authors, the lemongrass extract modulated the genotoxic action of the alkylating agents MMS and ENU by interacting with them directly or/and with their mutagenic derivatives. Regarding JG, a naphthoquinone that induces ROS production in an analogous way to SN, damages were reduced upon exposure to the decoction extract by probably inhibiting ROS production, by sequestrating/inhibiting ROS activity or/and activating intracellular defence mechanisms. For DMBA, as it needs metabolic activation by microsomal enzymes, the extract may have interfered with the microsomal enzymatic system for avoiding DMBA activation. Overall, lemongrass extract acted as an antimutagen in the protection of DNA.
In fact, SMART can be assayed using different test conditions, including the
4. Conclusions
In vitro and especially in vivo genotoxicity testing of substances such as foods, drinks, drugs and herbicides is fundamental for increasing humans’ knowledge on the hazards that we may be exposed to. In this way, upon the identification of a substance/compound as genotoxic, priorities should be focused on avoiding this genotoxic or, at least, when the exposure is unavoidable, preventing our metabolism from damages to DNA that can culminate in mutagenic events and, in a later stage, on carcinogenesis. Upon in vitro testing, in vivo genotoxicological assays, such as
Acknowledgments
This work was supported by the project UIDB/CVT/00772/2020, which was supported by the Portuguese Science and Technology Foundation (FCT), and by the Gobierno del Principado de Asturias (Oviedo, Spain) through Plan de Ciencia, Tecnología e Innovación (PCTI), co-financed by FEDER funds (Ref. FC-GRUPIN-IDI/2018/000242) and by the Ministerio de Economia y Competitividad (MINECO) of Spain under the Project CTQ2016-80060-C2-1R.
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