General characteristics of the iodothyronine deiodinases.
\r\n\t
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His previous appointment was as researcher in School of Civil & Environmental Engineering of Nanyang Technological University of Singapore where he studied for his PhD during 2008-2011. His research is predominantly focused on hydrological modeling and flood forecasting using artificial intelligence techniques. Most recently, he has been also involved in research projects dealing with sustainable urban water management. To date, he has published over 50 articles in reputable journals and international conference proceedings. He has supervised several PhD and Master students and won the Supervisor of the Year Award in Monash University Malaysia in 2017. 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On account of TH action can be controlled in individual cells through selective TH uptake and intracellular TH metabolism, the placenta is an important link in the maternal-fetal communication network for THs which are essential for the normal development and differentiation of the fetus [1-3]. Generally, intracellular activation or inactivation of L-thyroxine (T4) and 3,5,3\'-triiodothyronine (T3) in turn is determined by three types of iodothyronine deiodinases (Ds), namely DI, DII, and DIII [4-7]. The placenta transports and metabolizes maternal THs, and mainly expresses DIII, which inactivates T4 and other iodothyronines and thus limits the transfer of maternal active THs to the fetus in the late pregnancy [8]. DII is also active in the placenta and locally provides active T3 from the maternal prohormone T4 for placental metabolic functions [1,2]. The placental expression of DI, which also activates T4 to T3, is still controversial. Because of the lipophilic nature of THs, it was thought that they traversed the plasma membrane by simple diffusion [9,10]. The transport of T4 and T3 in and out of cells is controlled by several classes of transmembrane TH-transporters (THTs) [11], including members of the organic anion transporter family (OATP), L-type amino acid transporters (LATs), Na+/Taurocholate cotransporting polypeptide (NTCP), and monocarboxylate transporters (MCTs) [10,12]. Particularly, monocarboxylate transporter 8 (MCT8) has recently been identified as an active and specific TH transporter. Also, placental membranes are also involved in 4\'-OH-sulfation reactions of iodothyronines [8]. Sulfation (S) plays a role in TH metabolism by interacting between the deiodination and sulfation pathways of TH [13]. Interestingly, placental cells express high affinity, stereo-specific, energy-dependent uptake systems for T4 and T3. On the other hand, the cellular activity of THs is usually classified as genomic (nuclear) and non-genomic (initiated either at cytoplasm or at membrane TH receptors) [14-21]. Binding of T3 to its nuclear thyroid receptors (TRs) directly affects transcription of many genes that are important in development [22].
In general, pregnancy is accompanied by profound alterations in the thyroidal economy (hypo- or hyper-thyroidism), resulting from a complex combination of factors specific to the pregnant state, which together concur to stimulate the maternal thyroid machinery [1,23]. Also, clinical studies showed that maternal TH deficiency during the first trimester of pregnancy can affect the outcome of human neurodevelopment [24,25]. Experiments in rats showed that early maternal TH deficiency affects neuronal migration in the cortex [26], while maternal hyperthyroidism too can disturb fetal brain development [27]. Experimental data on the mechanisms regulating intracellular TH availability and action prior to the onset of fetal TH secretion, however, remain scarce. Thus, in this chapter will be aware about the significant roles of THs, their metabolism by Ds and sulfotransferases, their transport by THTs and their binding to TRs from the mother via the placenta to the fetal compartment especially during the gestation period in both human and animals.
The synthesis of THs is regulated through the hypothalamus–pituitary–thyroid (HPT) axis [28] and the follicular cells of the thyroid gland synthesize and secrete T4 and T3 [1,2,21]. This process is under the control of the circulating TH levels through negative feedback loops of this axis [28]. The availability of the active ligand T3 within tissues is locally determined by the action of the iodothyronine deiodinases (Ds) [29]. There are three selenocysteine monodeiodinase subtypes (DI, DII and DIII) [30]. Whilst T3 is generated by the activity of DI and DII, via 5\'- reductive or outer ring deiodination (ORD) of the T4 [31], DIII activity (and to a lesser extent that of DI) convert T4 to 3,3\',5\'-tri-iodothyronine (reverse T3; rT3) and T3 into 3,3\'-T2 via inner ring deiodination (IRD), in effect acting as a deactivating enzyme for THs [13,32].
Activities of all three iodothyronine deiodinase subtypes have been demonstrated in most rat placenta [33]. However, in contrast to man, rodent total serum T3 and T4 increase with gestation [34] and the predominant subtype expressed appears to be DIII [35], although DII is also present with significant activity [36]. Placental DIII activity is much greater (approx. 200 times) than DII activity; however, the activity and expression of both DII and DIII fall as gestation progresses [37-40]. Placental DII provides T3 for ‘housekeeping’ processes, and as indicated above, its activity is much less than that of D3 [40]. DII has been localized to the villous cytotrophoblasts in the first trimester and syncytiotrophoblasts in the third trimester, whereas DIII has been localized to the villous syncytiotrophoblasts in both the first and third trimesters of pregnancy [39]. Both DIII mRNA and activity are present at the implantation site in rodents, as early as gestational day 9 (GD 9), being expressed in mesometrial and antimesometrial decidual tissue [41]. Also, in rabbit [42] and pig [43], the placenta appears to express DIII activity predominantly. The positioning of the deiodinases, particularly DIII, suggests that they might regulate the amount of maternal TH reaching fetal circulation [40]. Interestingly, however, fetuses with total thyroid agenesis but with evidence of circulating maternal TH have normal placental DIII activity, suggesting that there might be other factors modulating T4 access to the deiodinases, such as intracellular protection of TH by TH-binding protein (THBP) [40,44]. Collectively, express placental Ds (II, III) may play a critical role in delivery of TH to the fetus as summarized in figure1 [2,45-47] and table 1 [1,2,31,48].
Summary about the interactions of maternal, placental and fetal thyroid metabolism. I, II and III denote deiodinases type 1 (DI), type two (DII) and type three (DIII). SO4 is a sulfation pathway and –SO4 is a desulfation pathway. CNS is central nervous system, TRH is thyroid releasing hormone, M-TRH is maternal thyroid releasing hormone, TSH is thyrotrophin, T2 is diiodothyronine, T3 is triiodothyronine, rT3 is reverse triiodothyronine, T4 is thyroxine, T2S is diiodothyronine sulfate, T3S is triiodothyronine sulfate, T4S is thyroxine sulfate, rT3S is reverse triiodothyronine sulfate, MCT8 is monocarboxylate transporter 8, OATP4A1 is organic anion transporter 4A1, TBG is thyroxin binding globulin, TTR is transthyretin, ACTH is adrenocorticotrophin and hCG is human chorionic gonadotrophin.
Characteristic | DI | DII | DIII | ||
Reaction kinetics | Ping-pong | Sequential | |||
Reaction catalyzed (Deiodination) | 5 or 5\' (ORD+IRD) | 5\' (ORD) | 5 (IRD) | ||
Main form | T4-T3, rT3- T2 | - T4- rT3, T3- T2 | - T4- rT3- T2 | ||
Substrate preference | 5: T4S"/>T3S"/>"/>T3, T4 5\': rT3, rT3S"/>T2S"/>"/>T4 | T4"/>rT3 | T3"/>T4 | ||
Sulfation of substrates | Stimulation | Inhibition | |||
Substrate limiting KM | 0.5 mM | 1–2 nM | 5–20 mM | ||
In vitro cofactor limiting KM | 1–10 Mm DTT | "/>10 mM DTT | =70 mM DTT | ||
Molecular mass (kDa) | 29 | 30 | 32 | ||
Selenocysteine | present | ||||
Homodimer | Yes | ||||
Location | - Liver, kidney, thyroid and pituitary. | - Pituitary, brain, BAT, thyroida, hearta and skeletal musclea. | - Brain, skin, uterus, placenta, fetus and in other sites of the maternal- fetal interface, such as the umbilical arteries and veins. | ||
Subcellular location | - Liver: endoplasmic reticulum. - kidney: basolateral plasma membrane | - Microsomal membranes | |||
Functions | - Production serum T3 and the clearance of serum rT3. | - Catalyzes the outer ring deiodination of T4 to T3 and is thus important for the local production of T3. | - Catalyzes the inner ring deiodination of T4 to rT3 and of T3 to 3,3\'-T2. | ||
Activity in hypothyroidism | - Decrease in liver and kidney. - increase in thyroid. | - Increase in all tissues. | - Decrease in brain. | ||
Activity in hyperthyroidism | - Unknown in liver and kidney. - Increase in thyroid. | - Decrease in most tissues. - Increase in thyroida. | - Increase in brain. | ||
Low-T3 syndrome | - Decrease | - No change | |||
Active site residues | - Selenocysteine histidine and phenylalanine. | - (Seleno-)cysteine? | - Selenocysteine | ||
Human gene structure and location | - 1p32-p33, 17.5 kb and 4 exons. | - 14q24.3, 2 exons, and 7.4-kb intron. | - 14q32 | ||
Promoter elements | - TRE, RXR, no CAAT or TATA box. | -- | |||
Propylthiouracil inhibitor | ++++ | + | +/- | ||
Aurothioglucose inhibitor | ++ | ||||
Iopanoic acid inhibitor | +++ | ++++ | +++ | ||
Thiouracils | ++++ | -/+ | - | ||
iodoacetate | + | ? | |||
flavonoids | + | +++ |
General characteristics of the iodothyronine deiodinases.
Membrane transporters mediate cellular uptake and efflux of TH [12,40,49]. The ability to transport TH has been described in members of different transporter groups including the monocarboxylate transporters (MCT), L-type amino acid transporters (LAT), Na+/Taurocholate cotransporting polypeptide (NTCP), and organic anion transporting polypeptides (OATP) [50]. With the exception of MCT8, these transporters do not exclusively transport TH and they all have slightly different affinities for specific forms of TH. To date six different THTs are known to be present in the placenta: MCT8, MCT10, LAT1, LAT2, OATP1A2 and OATP4A1 but their relative contributions to placental TH transport are unknown [50-55]. Also, their anatomical localization, ontogeny in the human placenta and relative affinity for the TH and thyronines are very complex. MCT8, MCT10, OATP1A2, OATP4A1 and LAT1 are expressed in villous syncytiotrophoblasts, and MCT8, MCT10 and OATP1A2 in cytotrophoblasts [50]. Although transporters in the apical syncytiotrophoblast membrane are well placed to maximize maternal cellular TH uptake early in gestation, the large numbers and variety of THTs are intriguing [51,53,55]. Moreover, the expression of MCT8 mRNA increased with advancing gestation [55] but there is limited information regarding the ontogeny of the other THTs. In addition, it is likely that the lower expression of MCT8, MCT10, OATP1A2 and LAT1 before 14 week compared to term, as well as the nadir in OATP4A1 expression in the late 1st and early 2nd trimester, may play a role in the necessary limitation of maternal-fetal TH transfer, particularly around the time of onset of endogenous fetal TH production in the early 2nd trimester [56]. Increased expression of THTs in late gestation is consistent with the proposal that there is continued/ increased maternal to fetal supply of TH in the 3rd trimester despite increasing fetal TH production [57]. It is also likely that increased expression of these transporters with gestation may also fulfil the increased need for other biological substances for fetal growth and development, such as amino acids. The most factors regulating the placental expression of these transporters are unknown until now. There are suggestions in rodents that the activity of system-L and the expression of MCT8 in non-placental tissues are influenced by thyroid status [58] suggesting that TH may be a regulator of its own transporters [50]. During the passage of THs from the maternal circulation to the fetal circulation, each THT is likely to have a specific role in each different plasma membrane layer, which might include cellular influx, efflux, or both [59]. To sum, THTs of the various placental cell types serve as channels that help to maintain the differences in the composition of THs and their metabolites between maternal and fetal circulations (figure1 [2,45-47] and tables 2 & 3 [51,52,55,59,60,61]). The relative contributions of these THTs to the transplacental transport of thyroid hormones are still a subject for research.
Transportera | Iodothyronine derivates | Specificityb |
MCT8 | T3, T4, rT3, T2 | +++ |
MCT10 | T3, T4 | ++ |
OATP1A1 | T3, T4, rT3, T2, T4S, T3S, rT3S, T2S | + |
OATP1A2 | T4, T3, rT3 | |
OATP1A3 | T4, T3 | |
OATP1A4 | ||
OATP1A5 | ||
OATP1B1 | T4, T3, T3S, T4S, rT3S | |
OATP1B2 | T3, T4 | |
OATP1B3 | rT3, T4S, T3S, rT3S | |
OATP1C1 | T4, rT3, T3, T4S | ++ |
OATP2B1 | T4 | + |
OATP3A1 (V1/V2) | ++ | |
OATP4A1 | T3, T4, rT3 | + |
OATP4C1 | T3, T4 | |
OATP6B1 | ||
OATP6C1 | ||
LAT1 | T3, T4, rT3, T2 | |
LAT2 | ||
NTCP | T4, T3, T4S, T3S | ++ |
Types of thyroid hormone transporters and their iodothyronine derivates.
Transporter family | Monocarboxylate transporters | System L amino acidtransporters | Organic anion transporting polypeptides | |||
MCT8 | MCT10 | LAT1 | LAT2 | OATP1A2 | OATP4A1 | |
Heterodimer | N/A | 4F2hc | N/A | |||
Additional molecules transported | N/A | Aromatic amino acids | Large neutral amino acids | Amphipathic organic compounds | ||
Localization in first and second trimestera | ST, CT, EVT | N/A | ||||
Localization in third trimesterb | ST | N/A | STap | N/A | STap | |
Km T4 (μM) | 4.7c | "/>Km T3d | 7.9 | 8.0 | "/>Km T3 | |
Km T3 (μM) | 4.0c | ≤4.0d | 0.8 | 6.5 | 0.9 | |
Km rT3 (μM) | 2.2c | N/A | 12.5 | N/A | ||
Km T2 (μM) | N/A | 7.9 | N/A |
Expression of the thyroid hormone transporters in human placenta.
Sulfation (S) appears to be an important pathway for the reversible inactivation of THs during fetal development [2,13,45-47]. Monique Kester and the group from Erasmus University have used a rat model to study the regulation of fetal TH status and have also extended their studies to human pregnancy [62]. The sulfotransferases catalyze the sulfation of the hydroxyl group of compounds, using 3\'-phosphoadenosine-5\'-phosphsulfate (PAPS) as the universal sulfate donor [63]. This co-factor PAPS is synthesized from two ATP molecules and inorganic sulfate. Neither the DII or DIII iodothyronines catalyze the deiodination of sulfated iodothyronines nor sulfation strongly facilitates the inner ring deiodination of T4 and T3 by DI, but blocks the outer ring deiodination of T4 (activation) [13,64]. The outer ring deiodination of rT3 by DI is not affected by sulfation [64]. Sulfation thus induces the irreversible degradation of TH. Thus, rapid inner ring deiodinations of T4S, T3S and out ring deiodination of rT3S lead to high concentrations of these sulfates in plasma of adult humans [13,65].
High concentrations of the different iodothyronine sulfates, T4S (thyroxine sulfate), T3S (triiodothyronine sulfate), rT3S (reverse triiodothyronine sulfate) and T2S (diiodothyronine sulfate), have been documented in human fetal and neonatal plasma as well as in amniotic fluid [65,66], and similar findings have been reported for sheep [67]. This has classically been explained by the low hepatic DI expression in the human fetus until the postnatal period [68] and lack of hepatic DI expression until birth in rats [69]. Also, in the rat placenta, where there are insignificant sulfotransferases activities but high DIII activity, irreversible inactivation of DIII appears to be the predominant pathway of iodothyronine metabolism [13]. In the rat fetal liver, sulfotransferase activity is present from the end of the third trimester (GD 17), a time when DI activity is relatively absent [69]. The TH-sulfates may accumulate under such circumstances to form a ‘reservoir’ of inactive TH from which active hormone may be liberated, in a tissue specific and gestational dependent manner by the action of arylsulfases [13]. To date, six members of this family (ARSAeARSF) have been identified in humans [13,70]. It is interesting that DIII is abundantly expressed in the human placenta [39] and deiodinates T4 and T3 to 3,3\'-T2 and rT3, respectively, thus providing substrates for these actions. In the human fetal circulation, T4S and in particular T3S, may represent a reservoir of inactive TH, from which active hormone may be liberated as required (vide supra) [13]. The iodothyronine sulfates in human fetal circulation and amniotic fluid may be derived, at least in part, from sulfation of THs by thermostabile phenol sulfotransferases in the uterus and placenta [13,45]. This may provide a route for the supply of maternal TH to the fetus in addition to placental transfer. Alternatively, iodothyronine sulfates may accumulate in the fetal circulation because of the absence of hepatic transporters which mediate their removal from plasma. It has been demonstrated recently that hepatic uptake of the different iodothyronine sulfates in rats is mediated at least in part through the NTCP and OATP families [71]. Thus, the TH-sulfation mechanism might be useful for non-invasive prenatal diagnostics of fetal thyroid function which is autonomously regulated. The overviews presented here are consistent with the evolving view that sulfation is a major chemical defense system in the maternal-fetal thyroid axis and will hopefully provide a basis for understanding more about these enzymes.
Although the thyroid gland predominantly secretes T4, T3 is the most active TH, since it has a higher affinity by the nuclear thyroid hormone receptors (TRs; α, β) (Figure 2A) [75], which mediate most actions of these hormones [72,73]. THs are released by the thyroid gland to the circulation where they are carried bound to proteins such as thyroxin binding globulin (TBG), transthyretin (TTR) or serum albumin (Table 4) [74]. The level of albumin, which has the lowest T4 affinity and enables a fast release of T4 [76], gradually decreases during pregnancy [77]. TBG is an active carrier and has a possibility to switch between the high-affinity and the low-affinity form [78]. TBG levels are the highest in the second and third trimester of pregnancy [79,80] and the same holds true for TH-binding ratio [81] and thyroid-binding capacity [82], which decreases as soon as 3-4 days after delivery.
A) Schematic representation of major thyroid hormone receptors (TRα, β) domains and functional sub-regions. (B) General model for genomic and non-genomic actions of TH in both adult and fetus; Schematic representation of thyroid hormones (THs; T4 and T3) genomic actions, initiated at the nuclear receptors (TRβ), and non-genomic actions, initiated at cytoplasmatic receptors (TRβ, TRα) and at the plasma membrane on the membrane receptors, particularly integrin αvβ3 receptor. T4 binding (but not T3) to cytoplasmic TRα may cause a change of state of actin. T3 binding (but not T4) to cytoplasmic TRβ activates the phosphatidylinositol 3-kinase (PI-3K) pathway leading to alteration in membrane ion pumps and to transcription of specific genes. TH binding to the integrin receptor results in activation of mitogen-activated protein kinase (MAPK/ERK1/2). Phosphorylated MAPK (pMAPK) translocates to the nucleus where it phosphorylates transcription factors including thyroid receptors (TRβ), estrogen receptor (ER) and signal transducer activators of transcription (STAT). Generally, activity is regulated by an exchange of corepressor (CoR) and coactivator (CoA) complexes.
TH-binding protein | Cellular location |
Transthyretin | Plasma |
T4-binding globulin | |
Serum albumin | |
Lipoproteins | |
Myosin light chain kinase | Cytoplasmic |
Pyruvate kinase, subtype M1 | |
Pyruvate kinase, subtype M2 | |
Prolyl 4-hydroxylase, b-subunit | |
Aldehyde dehydrogenase |
Types of thyroid hormone-binding proteins.
T4 and T3 enter the cell through transporter proteins such as MCT8 and 10 or OATPs. Inside the cells, deiodinases (DI, II) convert T4, the major form of thyroid hormone in the blood, to the more active form T3. DIII produces rT3 and T2 from T4 and T3, respectively [1,73,83]. T3 binds to nuclear TRs, TRα and TRβ, that activate transcription by binding, generally as heterodimers with the retinoid X receptor (RXR) (Table 5) [87], to thyroid hormone response elements (TREs) located in regulatory regions of target genes [84]. Activity is regulated by an exchange of corepressor (CoR) and coactivator (CoA) complexes. Negative TREs (nTRE) can mediate ligand-dependent transcriptional repression, although in this case the role of coactivators and corepressors is not well defined [73,85]. TRs can also regulate the activity of genes that do not contain a TRE through “cross-talk” with other transcription factors (TF) that stimulate target gene expression [28,86]. Both receptors and coregulators are targets for phosphorylation (P) by signal transduction pathways stimulated by hormones and growth factors [84,85]. Thus, the nuclear actions of T3 are sensitive to inhibitors of transcription and translation and have a latency of hours to days [9,73]. Thus, the genomic action will play a critical role in the cellular proliferations and differentiations.
Although T3 is known to exert many of its actions through the classical genomic regulation of gene transcription, a number of T3 effects occur rapidly and are unaffected by inhibitors of transcription and protein synthesis [88,89]. However, the levels of circulating THs are tightly regulated and stable and thus rapidly mediated responses must involve regulation of pre-receptor ligand metabolism, ligand membrane transport or receptor availability leading to local cell type specific variation in thyroid hormone signaling [87]. Non-genomic actions of THs have been described at the plasma membrane, in the cytoplasm and in cellular organelles [15,21,83,90,91]. They have included the modulation of Na+, K+, Ca2+ and glucose transport, activation of protein kinase C (PKC), protein kinase A (PKA) and mitogen-activated protein kinase (ERK/MAPK) and regulation of phospholipid metabolism by activation of phospholipase C (PLC) and D (PLD) [92-94]. Generally, binding of T3 to a subpopulation of receptors located outside the nuclei can also cause rapid “non-genomic” effects through interaction with adaptor proteins, leading to stimulation of signaling pathways. T4 can also bind to putative membrane receptors such as integrin receptor (αVβ3) inducing MAPK activity [18,73,95,96]. Thus, several observations suggest that the rapid nongenomic effects of TH are widespread and may be involved in multiple physiological processes in many different cell types [87]. However, no specific membrane associated TR isoform or thyroid hormone binding G protein-coupled receptors (GPCR) have been identified or cloned and thus the area remains controversial.
Compare face | Ligand | Receptor | Dimerization partners | Associated factors or signalling pathways | Actions |
Classical, genomic actions (hours to days) | |||||
Nuclear transcription | T3 | TRα and TRβ | RXR and TRs | - NCoR/SMRT Basal | - Transcriptional repression |
- SRC/p160/TRAPs | - Transcriptional activation and repression | ||||
Non-classical non-genomic actions (seconds to minutes) | |||||
Cell surface receptor | T4/T3 | Putative GPCR | Raf1/MEK/MAPK | TR phosphorylation and altered transcriptional activity p53 phosphorylation and general transcriptional activity | |
MEK/STATs | Increased STAT mediated transcription | ||||
Mitochondrial gene transcription | T3 | TRαp43 | mtRXR and mtPPAR | Co-factors? | Increased mitochondrial gene expression |
Mitochondrial oxidation | T3 | TRαp28 | ANT, UCPs | Increased thermogenesis | |
T2 | Cytochrome-c Va | Increased oxidative phosphorylation |
General thyroid hormone actions.
There also are reports of nongenomic effects on cell structure proteins by THs. Actin depolymerization blocks DII inactivation by T4 in cAMP-stimulated glial cells, suggesting that an intact actin cytoskeleton is important for this downregulation of deiodinase activity [9,97]. Interestingly, T4, but not T3, can promote actin polymerization in astrocytes [98] and thus may influence the downregulation of DII activity by a secondary mechanism, perhaps by targeting to lysosomes [9,99]. Moreover, the regulation of actin polymerization and F-actin contents also could contribute to the effects of TH on arborization, axonal transport, and cell-cell contacts during brain development, where the regulation of these factors is fundamental for the organization of guidance molecules such as laminin on the astrocyte plasma membrane and modulates integrin–laminin interactions [3]. T4 was required for integrin clustering and attachment to laminin by integrin in astrocytes [100]. These data suggest that the non-genomic action may play an important role in promoting the normal development.
THs are essential for normal neonatal development in both humans and rodents [3,23,101-104] and the experimental work indicated that THs are transported from the mother to the fetus, albeit in limited amounts, and that the fetal brain is exposed to THs before initiation of fetal TH synthesis [1]. In addition, the maternal TH regulates early fetal brain development in human and animal models [2]. The TH of maternal origin can cross the placenta and reach the fetus [2,105,106] and that TRs are expressed in the fetal rat brain before the onset of fetal thyroid function [107]. Thus, the THs are essential for brain maturation from early embryonic stages onward [103,104,108]. However, TH-dependent stages of fetal brain development remain to be characterized. Notably, the maternal thyroid is the only source of T4 and T3 for the brain of the fetus because its thyroid gland does not start contributing to fetal requirements until midgestation in man, and days 17.5–18 in rats [109]. Therefore, the amount of maternal T4 that the fetus receives early in pregnancy will determine TH action in its brain because it depends on maternal T4 for its intracellular supply of the active form of the hormone, T3. However, fetal brain total T3 levels are low (ca. 100 pM) at this time [1], but receptor occupancy approximates 25% since free T3 concentrations are high in the nucleus relative to the cytosol [110]. In general, materno-fetal transfer of THs has been demonstrated in early fetal stages [111] and continues, at least in the case of fetal inability, to produce sufficient TH until term [44]. Actually, brain cells can protect themselves against higher fetal T4 and T3 values by decreasing DII and increasing DIII activity [2]. Taken together, thyroid activity undergoes many changes during normal pregnancy including [1,112-115]: (a) a significant increase in serum thyroxine-binding globulin, thyroglobulin, total T4, and total T3; (b) an increase in renal iodide clearance; and (c) stimulation of the thyroid by human chorionic gonadotropin (hCG). These changes can make diagnosis of thyroid dysfunction during pregnancy difficult.
THs are important for growth and differentiation of a variety of organs, including the brain. In developing brain, THs stimulate and coordinate processes such as neuronal proliferation, migration, growth of axons and dendrites, synapse formation and myelination [1,2]. Disturbance of these processes leads to abnormalities in the neuronal network and may result in mental retardation and other neurological defects, including impaired motor skills and visual processing [115]. If TH deficiency occurs at the perinatal stage, such as in congenital hypothyroidism, timely treatment may rescue most of the symptoms. A shortage of THs starting at the early stages of pregnancy, such as in cretinism, results in neurological deficits that cannot be rescued by exogenous TH addition at later stages [25].
The role of THs in brain development has been studied most extensively in the cerebellum [23,116]. The cellular proliferation and migration processes are disturbed by TH deficiency as investigated predominantly in rodents, where most of cerebellar maturation occurs in the early postnatal period [2]. In the hypothyroid cerebellum, the number and length of Purkinje cell dendrites is severely reduced [1]. At the same time the granule cell parallel fiber growth is reduced, leading to a reduction in axodendritic connections between the Purkinje cells and the granule neurons [117]. Additionally, other cell types such as astrocytes, Golgi epithelial cells, basket cells, and oligodendrocytes show abnormalities under hypothyroid conditions [116]. Several TH target genes have been identified over the years, including genes coding for myelin proteins, cytoskeletal proteins, neurotrophins and their receptors, transcription factors, and intracellular signaling proteins [118] and recent transcriptome analyses continue to increase their number [119-121]. Some of these genes only respond to thyroid status for a short and specific period during development, a feature that is typical for many TH target genes in brain [122]. Interestingly, a reduction or absence of TH during brain maturation yields molecular, morphological and functional alterations in the cerebral cortex, hippocampus and cerebellum [123-132].
Neonatal hyperthyroidism was described as a critical disease marked mainly by cardiac symptoms, poor weight gain and severe neurological manifestations [1,133-137]. Fetal thyrotoxicosis is the result of thyroid-stimulating antibody transfer to the fetus in the setting of maternal Grave’s disease [2,138]. It may present with a variety of clinical features, which include persistent sinus tachycardia, fetal hydrops, intrauterine growth restriction, goiter and fetal demise [1,139]. The vast majority of cases of excessive serum TH concentration seen in pregnancy are due to the overproduction of THs (Graves’ disease, toxic nodular goiter); in the postpartum period, thyrotoxicosis may be due to exacerbation of Graves’ hyperthyroidism or to the release of thyroid hormone due to an acute autoimmune injury to the thyroid tissue (postpartum thyroiditis-PPT) [2,140].
The management of hyperthyroidism in pregnancy, which most often is caused by Graves’ disease, has been reviewed recently [141,142]. Hyperthyroidism occurs in about 0.2–0.4% of all pregnancies. Hyperthyroidism should be distinguished from gestational transient thyrotoxicosis, which is due to the TSH-receptor stimulating effects of hCG [143,144]. This hCG-induced hyperthyroidism is mostly mild and need not be treated. Only rare cases with extremely high hCG (i.e. due to a hydatidiform mole) might induce severe thyrotoxicosis [145]. The signs and symptoms of hyperthyroidism due to Graves’ disease may aggravate in the first trimester and thereafter may become mild. Untreated hyperthyroidism is associated with severe effects on maternal and neonatal outcome. The risk for premature fetal loss, preeclampsia, preterm delivery, intrauterine growth retardation and low birth weight is significantly increased [144]. It has to be considered that the transfer of stimulating receptor antibodies (TSAbs) are transferred from the mother to the child, and therefore the fetus is at risk to develop Graves’ disease. Close monitoring of the fetus is, therefore, strictly recommended, even in mothers treated by thyroidectomy before pregnancy but have still elevated TSAbs [142].
Different cases of hyperthyroidism.
Taken together, there are two known causes of central hyperthyroidism [1,146]; (1) TSH-producing pituitary tumors (TSHomas) and (2) the syndrome of pituitary resistance to thyroid hormone (PRTH). In general, thyrotoxicosis is the syndrome resulting from an excess of circulating free T4 and/or free T3 [147,148]. Babies likely to become hyperthyroid have the highest TSH receptor antibody titer whereas if TSH receptor antibodies are not detectable, the baby is most unlikely to become hyperthyroid (Figure 3) [1,2,149]. In the latter case, it can be anticipated that the baby will be euthyroid, have transient hypothalamic-pituitary suppression or have a transiently elevated TSH, depending on the relative contribution of maternal hyperthyroidism versus the effects of maternal antithyroid medication, respectively [150].
about the developmental thyroid hormone mechanisms (deiodinases, transporters, sulfotransferases and receptors) in human [1,2,50,52,127,130,151-154], rat [1,2,41,60,135,154-156] and chicken [7,157-170]. Note that the chicken is born early compared to the rat and human, as well as the rat is born early compared to the human (Table 6).
Human | Rodent (rat) | Chicken | |||
Week post conception | Day post conception | Incubation day | |||
1 W | - DIII is detected in uterine wall. | 1 GD | DII and DIII are observed in uterine wall. | 5 h (blastula stage) | - TRα mRNA is noticed and the levels markedly increased during neurulation. |
3 W | - Thyroid gland begins. | 7 -8.5 GD | - Time of implantation process. - Very high DIII activity is detected in decidual tissue. | 24 h | - mRNA levels of DI, DII and DIII are detected in whole embryos. |
4-6 W | - TBG is observed in thyroid follicle cells at GD 29. - TRH is detected in fetal whole-brain at 4.5 weeks of gestation. - T4 is transferred via the placenta and has been found in the gestational fluid sac from 4 to 6 W. | 9 GD | - Thyroid gland is first visible as an endodermal thickening in the primitive buccal cavity. - TH is detected in rat embryotrophoblasts | 48 h | - OATP1c1 expression appears. |
5-11 W | - Maternal-embryo transfer of THs has been detected in embryonic coelomic fluid and amniotic fluid. - All the mRNAs encoding THTs are expressed in placenta from 6 W and throughout pregnancy. | ||||
8 W | - T4, T3 and rT3 are detected in coelomic/amniotic fluids. - TRs, DII and DIII are noticed in fetal brain. | 10 GD | - T4, T3 and TRβ are detected in embryo/trophoblast unit. | E2-E4 | - T3, THTs, Ds and TRs are expressed in whole embryos. |
10 W | - TSH is first detected in the fetal pituitary. | E4 | - OATP1c1 expression is more than 10-fold higher in the telencephalon and diencephalon compared to the mesencephalon and rhombencephalon. - DII mRNA levels are highest in the diencephalon. | ||
8-10 W | - The fetus is able to produce THs during this period, but prior to that time, is totally dependent on maternal THs. | E5 | - TRα mRNA is widely distributed in fore-, mid- and hind-brain. | ||
11 W | - TBG levels are detected in fetal serum and increased through gestation. | E6 | - T4 and T3 are detected in embryonic brain. | ||
8-11 W | - TRH is detected in fetal hypothalamus. | E7 | - DII activity is observed in the brain before the onset of thyroid function and increases significantly. | ||
12 W | - T4 and T3 are observed in serum and brain. - Total serum T4 and T3 are low, free T4 is relatively high. - rT3 is noticed in serum relatively high. - TH synthesis begins in fetal thyroid. - Decreased mRNA expression of OATP1A2 but no change for OATP4A1 at 9–12 W compared to term. | 13 GD | - Placental circulation established. - TRs and TH are observed in fetal brain. - DIII and DII are detected in uterus and placenta. | E8 | - DII mRNA is noticed in cell clusters throughout the brain, particularly in rhombencephalon. - OATP1c1 levels are declined substantially in all brain regions. |
14 W | - Expressions of mRNAs encoding MCT8, MCT10, OATP1A2 and LAT1 are significantly lower prior to 14 W compared to term | 14 GD | - TRH mRNA is detected in neurons of the fetal hypothalamus. | E4-E8 | - DIII mRNA levels are markedly different in the telencephalon and diencephalon but remain stable, while the levels in mesencephalon and rhombencephalon show a sharp decrease and increase, respectively, during these days. |
15 GD | - Pituitary TSH mRNA expression begins. - TRH mRNA is detected in the developing paraventricular nuclei of the hypothalamus. | E9-10 | - Several elements of the TH action cascade are present in the brain of embryos long before their own thyroid gland starts hormone secretion. | ||
16 W | - DIII is observed in placenta and fetal epithelial cells. - DIII and TRs are detected in fetal liver. - DI is noticed in heart and lung. - Significant fetal TH secretion begins. | 16-19.5 GD | - TRs are observed in liver, heart and lung. - DI and DII are noticed in fetal tissues. - TRH is produced in low levels in hypothalamus and increases approximately threefold by GDI9.5. | E10 | - The thyroid gland is fully functional. |
16-20 W | - Duplication of TBG concentrations. | 17 GD | - TH synthesis begins in fetal thyroid - TSH protein and Sulfotransferase are observed. | E13 | - Brain DII is elevated at the peak of neuroblast proliferation. |
18 -22 GD | - The total T4 and T3 concentrations in fetuses are increased drama-tically because of maturation of hormone synthesis of the fetal thyroid gland. - The coordination between THTs and Ds is regulated both transplacental TH passage from mother to fetus and the development of the placenta itself through the progress of gestation. | E14 | - The strong increase in intracellular T3 has been observed. | ||
20 W | - A steady increase in serum TH levels begins and continues to term. | 19 GD | - Significant fetal TH secretion begins. - Marked rise in serum TH but levels at birth still below those in adult. | E15 | - Plasma T4 levels start rising markedly around this day. |
22-32 W | - Serum total and free T4 and T3 near and below adult levels, respectively. - The HPT axis begins to mature during the second half of gestation. - LAT1 and OATP4A1 have been localized only during the third trimester. | 22 GD | - Birth state. - Thyroid system is less developed. - As much as 17.5% of THs found in the newborn are of maternal origin. | E16 | - The decrease in DI activity in gonads is combined with the relatively high DIII activity. - A significant increase in T3 production and in DII-activity and -mRNA expression are combined with a decreased in DIII activity. |
40 W | - Birth state. - Complete maturation of thyroid system. - MCT8 has been localized in the placenta in all three trimesters of pregnancy. - High concentrations of the different iodothyronine sulfates, T4S, T3S, rT3S and T2S, have been documented in human fetal and neonatal plasma as well as in amniotic fluid during the pregnancy. | 10 PND | - Brain development equivalent to human birth. | E13/14–E17 (synaptogenesis) | - Brain DII activity is moderately elevated, whereas DIII activity and mRNA expression are highest between these days, followed by a dramatic decrease thereafter. |
10-20 PND | - Serum TH levels continue to rise and are higher than adult levels between these days. | E18 | - DI and DIII are expressed in the granule cells, whereas DII is found mostly in the molecular layer and the Purkinje cells at that time. | ||
14-50 PND | - The levels of pituitary and serum TSH slowly decrease from PND 14–16 until reaching adult levels at PND 40. - TRH levels increase to adult levels by PNDI7–29, then decrease transiently between PND 31–41; adult levels are once again reached at PND 50. - Adult TRH mRNA expression patterns are present at PND 22. | E19 | - The increase in brain T3 production correlates with the appearance of TRβ expression in the cerebellum, telencephalon and optic lobes. | ||
E20 (at the moment of pipping) | - The brain is quite well developed at the time of hatching. - The gradual increases in plasma T4 and hepatic DI are detected. - DIII levels are decreased in spleen and increased in skin and the lungs towards hatching. - T3 production seems to be elevated markedly in liver. - The rise of T4 is much more pronounced than in plasma. - Diminished T4 sulfation is detected. | ||||
30 PND | Complete maturation of thyroid gland. | E14-E19/20 | - The T3 breakdown capacity by DIII is high in liver but low in kidney. | ||
E15/16-E20 | - T4 levels in plasma increase gradually during these days. - In contrast to TRα expression which increases gradually towards hatching, expression of TRβ shows an abrupt elevation in late development, especially in the cerebellum. - The majority of tissues express DIII together with either DI or DII. | ||||
E17-E20 | - The levels of DIII activity present in liver are rapidly drop by more than 90%. - DI levels in testis and ovary strongly decrease around hatching. | ||||
E18–E20 | - Brain DII activity is moderately decreased, whereas DIII activity is low. | ||||
E19-E20 | - The low T3/T4 ratio is associated with high T3 breakdown in liver and with high T4 inactivation or T3 secretion in kidney. | ||||
E20-C0 | - DI activity gradually increases, reaching a maximum around these period, and decreases slowly to posthatch levels thereafter. | ||||
C1 (first day post-hatch) | - The expression of DI is limited to the mature granule cells and that of DIII to the Purkinje cells exclusively, whereas DII remains clearly present in the molecular layer. | ||||
C2 | - Highest DI-activities and -mRNA expressions are detected in the liver, kidney, and intestine. | ||||
C1-C7 | - The circulating T3/T4 ratio started to increase gradually during the first week after hatching. |
Summary about the developmental thyroid hormone mechanisms (deiodinases, transporters, sulfotransferases and receptors) in human, rat and chicken.
The actions of THs are highly pleiotropic, affecting many tissues at different developmental stages. As a consequence, their effects on proliferation and differentiation are highly heterogeneous depending on the cell type, the cellular context, and the developmental or transformation status.
Maternal THs are important in promoting normal fetal development especially the placental and CNS development. Clinical epidemiological and basic findings clearly show that maintaining normal TH regulation from the beginning of pregnancy is important to reduce the risk of obstetric complications and to ensure optimal neurodevelopment of the offspring.
In normal pregnancy, transplacental TH passage is modulated by plasma membrane THTs, Ds, sulfotransferases, TRs and several different proteins within placental cells.
In pathological/abnormal pregnancies with either maternal or fetal THs disturbances (hypo- or hyper-thyroidism), the placenta lacks the full compensatory mechanisms necessary to optimize the maternal–fetal transfer of THs to achieve the normality of TH levels in the fetus.
Further studies are still needed to improve our understanding of the mechanisms mediating the transplacental transport of THs in both human and animals, particularly the role of the different THTs, and the mechanisms that ensure that sufficient amounts of THs are protected from D3 inactivation during their transit across the placenta. Such knowledge would facilitate the development of interventions to increase TH passage in pathological situations, in order to ensure normal fetal development. A better understanding of these mechanisms would also permit us to refine the timing and dosage of the increase in levothyroxine therapy in hypothyroid pregnant women and to establish whether thyroxine on its own is indeed the best form of TH replacement in pregnancy.
Elucidation of tissue-, cell-, and sex-specific expression of individual Ds and THTs during the development of both human and animals, in the adult, during aging and when sick.
I hope that new insights into the complex actions by which the THs and their receptors control cell proliferation and differentiation will be provided in the near future.
Today, information has become the main component of what we produce, do, buy, and consume. Having an economic value in almost all products and services that meet the needs of today’s societies, it has been now obligatory for individuals and organizations to obtain information technologies and to actively use them in both work and social life domains. Hence, in the current information age, where information is seen as power, this situation has made it imperative for organizations to become increasingly information-based and to benefit from information technologies in many processes and activities.
The intensive use of information technologies in many functions and processes has also required some changes in organizations [1]. This is due to the fact that information technologies, unlike traditional technologies, do not only change the technical fields but also affect the communication channels, decision-making functions and mechanisms, control, etc. [2]. Consequently, one of the most striking developments is on organizational structures that are becoming increasingly flattened and horizontal. Relatedly, information technologies have begun to take over the role of middle management, which supports decision-making processes of senior management and has reduced the importance of this level [3, 4, 5]. Similarly, while information technologies enable managers to obtain faster, more accurate, and more information [6, 7, 8], it also provides lower-level managers with more information about the general situation of the organization, the nature of current problems, and important organizational matters [9, 10, 11, 12].
Moreover, information technologies also have an important potential in determining whether organizations have a mechanical or an organic structure [13]. Within the mechanical organizational structures, people do not have much autonomy, and behaviors expected from employees are being careful and obedience to upper authority and respect for traditions. In such organizations, predictability, consistency, and stability are desirable phenomena. In contrast, people in organic structures have more freedom in shaping and controlling their activities, and being enthusiastic, creative, and taking risks have important places among the desired behaviors [14].
Accordingly, information technologies begin to influence the cultural values of the organization over time, through these transformations they create on organizational structures, processes, and operations. In other words, the fact that organizational structures are mechanical or organic causes the formation of diverse cultural values in organizations [15]. Therefore, the desired cultural values in mechanical organizations are quite different from those in organic structures [1, 16, 17]. In this context, this chapter deals with the influences of information technologies on cultural characteristics of organizations along with the reflections of the use of these technologies on organizational structures and their functioning.
When we look at studies on the relations between organizational culture and information technologies, we generally see the studies on the effects of culture on technology adaptation or use [18, 19, 20, 21], as well as on the effects of certain specific information technologies and applications (e.g., e-mail use, group support practices, etc.) on some aspects of any organizational culture [22, 23, 24, 25, 26, 27, 28, 29, 30, 31]. However, the number of studies that consider the use of information technologies as a “whole” and that address “why” and “how” its effects on organizational culture occurred is still limited. And so, this chapter aims to examine and discuss the overall effects of the usage and intensity of information technologies established in organizations on the cultural life within.
In this context, the chapter plan is as follows: Firstly, the basic concepts related to information and information technologies are included. Emphasis is placed on the meaning differences between knowledge and information, and their connections to information technologies are tried to be explained briefly. Secondly, the effects of information technologies on organizational structure are given particular attention. The reason for this is that as a system of values, beliefs, assumptions, and practices [32], organizational culture encompasses many features closely related to structures of organizations. Thirdly, possible links between organizational structure and organizational culture are included. Fourthly, important theoretical approaches and studies on the relationships between information technologies and organizational culture are provided. Finally, by deepening a bit more and by emphasizing key points, some important arguments are discussed.
In the literature, the concepts of information and knowledge are sometimes expressed by a single term, “information.” However, although the concepts of knowledge and information are intertwined, they are two different concepts that have different meanings and describe different phenomena. The reason for this is that knowledge is also included in the concept of information as it is transformed into a commodity when it begins to be processed, stored, and shared by information technologies.
Becoming the basic elements of today’s economic, social, and cultural systems, information is obtained in a certain hierarchy. The images are at the beginning of the process, and the process is completed with a hierarchical staging in the form of data, information, and knowledge, respectively [33]. Image is located in the first step of the process. Humans copy the picture of any object and event they previously perceived by sensory organs. When faced with a similar phenomenon in the later stages of life, these pictures in the mind are redesigned. We call these pictures of realities occurring in the human mind as images [33]. The next stage, the data, contains symbols that represent events and their properties. For this reason, data are expressed as figures and/or facts without content and interpretation [34]. Information that constitutes the next stage of the process and is mixed with knowledge and used interchangeably is expressed as a reporting of one system’s own status to another system [33]. In information, associated data are combined for a specific purpose. Therefore, we can explain information as meaningful data [35]. Knowledge, on the other hand, is defined as personalized information that allows people to fully and accurately grasp what is happening around them and manifests itself in the form of thoughts, insights, intuition, ideas, lessons learned, practices, and experiences [36]. According to Kautz and Thaysen [37] who stated that knowledge is found only in the people’s minds, knowledge is, therefore, a subjective formation. In other words, knowledge is the form of information enriched with interpretation, analysis, and context [38]. However, here, it should be emphasized again by highlighting a very important issue that knowledge is also accepted as information when this knowledge begins to be processed, stored, shared, and used over information technologies. Therefore, after this, when talking about information, one should consider not only the information created by the data brought together in a meaningful way but also the knowledge shared and used over information technologies.
On the other hand, information technologies, used as the most important tool of generating value today, are defined as the technologies that enable processes such as recording and storing data, producing information through certain operational processes, and accessing, storing, and transmitting this produced information effectively and efficiently [39, 40, 41, 42, 43, 44, 45, 46]. The term information technologies is used to cover computer and electronic communication technologies, as they are now inseparably intertwined in literature and everyday use and are generally used in this way [47]. In this context, data processing systems, management information systems (MIS), office automation systems, executive support systems, expert systems, intranet and extranet, electronic mail (e-mail), group applications (groupware), database management systems, decision support systems, artificial intelligence, and telecommunication systems can be given as examples of information technologies [33, 48, 49].
Towards the end of the twentieth century, the rapid changes with the impact of developments in information technologies led to the emergence of customer satisfaction-based, learning, knowledge-based, and constantly changing organizations [50]. The fact that organizations have become considerably information-based and benefit from information technologies intensively in their activities and processes has made also the changes in their organizational structures mandatory [1]. Accordingly, the effects of information technologies on organizational structure will be summarized under the subtitles of differentiation, centralization, and standardization/formalization, which are the three main components of organizational structure [15].
Differentiation within an organization occurs in three ways: Specialization/division of labor, horizontal and vertical differentiation, and hierarchy and size [15]. Specialization refers to the amount of different expertise or types of work [51, 52]. Specialization generally increases the number of subunits and makes it harder to understand the larger structure that people contribute to with their skills and expertise [53]. Information technologies have the potential to reduce this tendency by providing more access to information and experts at this point. In this way, access to information resources provides synergy [54].
Vertical and horizontal differentiation refers to the amount of hierarchical levels in an organization [55]. Information technologies, with the support of problem solving and decision-making, lead to the emergence of more flattened organizational structures as they require fewer levels within the hierarchy [56]. Since information technologies give employees in lower positions more autonomy to harmonize their activities, this can allow them to find and try better methods while performing their work. In this context, we can increasingly see that organizational structures have become horizontal and strengthened and that virtual organizations have begun to emerge as the most cost-effective structure [17].
In terms of hierarchy and size, Heinze and Stuart [4] argue that the mid-level management staff is unnecessary, increases bureaucracy, reduces efficiency, and has no function in organizations any more. Since most of the tasks performed by mid-level executives can be fulfilled by computers, both less costly and faster, information technology has begun to take over the role of mid-level management, which supports the decision-making process of senior management [5]. Sharing the same opinion, Fulk and DeSanctis [57] also stated that the largely witnessed situation in modern organizational designs is the reduction of intermediate-level managers and administrative support.
Centralization points to the extent to which decision-making power within an organization is scattered or centered [58]. Due to increasing local and global competition, many companies have started to leave their strategic decision-making task further down the organization to benefit from the expert people with more precise and timely local knowledge [10]. Information technologies affect these efforts directly in two ways. Firstly, information technologies increase local knowledge by contributing to obtaining closer information about market trends, opportunities, and customers. Secondly, information technologies can create synergies for organizations because, thanks to information technologies, communication and coordination between distributed decision makers, central planners, and senior managers can be realized more effectively and efficiently [59].
However, whether information technologies will lead to centralization or decentralization is a very controversial question. Regarding centralization, it enables managers to acquire faster, more accurate, and more information, reduces uncertainty, and allows them to make decisions that they cannot make before [6, 7, 8]. Conversely, by the use of other forms of information technologies (e.g., electronic bulletin boards), decentralization provides more information to lower- and mid-level managers about the general situation of the organization and the nature of current matters and problems [9, 10, 11, 12]. Raymond et al. [60] argued that because information technologies facilitate the use and transmission of information by all levels and units in the organization, it enables top management, which is the decision authority, to be disabled in certain areas and the decentralization of control. Thach and Woodman [61] maintained that this is due to the fact that as a result of sharing information at lower levels with the help of information technologies, this power of senior management has decreased to a certain extent, and the knowledge and participation of the staff in organizational matters have increased.
The literature shows that information technologies allow both centralization and decentralization. Researchers are in the agreement that information technologies make it possible for organizational managers to leave their decision-making power to a large part of the hierarchical levels without compromising the quality and timeliness of the decision [62, 63]. Keen [64] combined the concepts of centralization and decentralization and used the term “federated organization” in which organizations do not have to choose either because information technologies simultaneously allow centralization-decentralization [64, 65].
Formalization is the process of detailing how activities are coordinated for organizational purposes in order for employees and organizational units to respond routinely to recurring situations [51, 66]. Formalization involves rules, instructions, shared values, and norms [67]. In fact, formalization is based on the objective of more efficiency and less uncertainty [13].
Information technologies provide the ability to reduce the negative effects of formalization by facilitating the documenting and retrieving of information on organizational occurrences and endeavors that make behaviors and processes more consistent through formalization [63]. The more information technologies assist in reducing search times and preventing downtime, the more the administrative cost of formalization decreases and the productivity increases, which ultimately benefits the path to innovation [68].
Different organizational structures lead to the development of different cultural values [15]. The fact that the structure which an organization has established to control its activities and is defined as a formal system consisting of duties and authority relations is mechanical or organic causes the emergence of completely different cultural values, rules, and norms [69]. While mechanical structures are vertical, highly centralized, and almost everything in them are standardized, organic structures are horizontal, decentralized, and based on mutual adaptation [14]. People feel relatively less autonomous in vertical and centralized organizations, and being careful, obeying the upper authority, and respecting traditions are among the desired behaviors. Therefore, in a mechanical organizational structure, there are cultural values where predictability and stability are important [69]. In contrast, in horizontal and decentralized organizations, people can freely choose their own activities and control them. Creativity, courage, and risk-taking are given importance as desired behaviors. Therefore, organic structures contribute to the formation of cultures that value innovation and flexibility [15].
Organizational structure is also important for the development of cultural values that support integration and coordination. In a structure with stable task and role relations, sharing of rules and norms is more since there will be no communication problems and the information flow will be fast [70]. In organizations where the sharing of cultural values, norms, and rules is at a high level, the level of performance also increases [15]. Particularly in team or matrix structures where face-to-face communication is intense, the sharing of these cultural values and common reactions to the problems develop more rapidly [9].
Whether an organization is centralized or not causes different cultural values to emerge. In decentralized structures, authority is divided into subordinate levels, and an environment is created for the formation of cultural values in which creativity and innovation are rewarded [13]. Employees are allowed to use the organization’s resources and work in projects that they want, by spending some of their time in these projects, thus contributing to the production of innovative and creative products and services [15]. The structures of such organizations constitute the cultural values that give their employees the message “as long as it is in the interest of the organization, it is okay to do things in an innovative and the way you want.”
Conversely, in some organizations, it may be more important for employees not to decide on their own and all activities to be followed and controlled by their superiors. In such cases, a centralized structure is preferred to create cultural values that will ensure accountability and obedience [71]. Through norms and rules, all employees are expected to behave honestly and consistently and inform their superiors about wrongs or mistakes, because this is the only acceptable form of behavior within these structures [72].
Since working on the factors that determine the consequences of the adoption and use of information technologies, researchers have focused on people’s beliefs, values, assumptions, and codes of conduct. As a result, they have given names to this research field such as “socio-technical systems,” “social system,” “social structure,” and most recently “culture” [73]. For example, Markus and Robey [23] using “social elements” and Barley [26] using “social system” or “social structure” tried to explain this phenomenon. When examined more closely, it is seen that the details that these authors emphasize while depicting the case are the assumptions, beliefs, and values that exist in common among the group members, and this corresponds to the definition of organizational culture.
Research examining the relationships between information technologies and values, beliefs, and norms belonging to a particular group has gone through certain stages and used rich and complex research models to explain the relationships in each of these stages [74]. In the first studies on information technology applications, it has been suggested that information technologies cause changes in various organizational phenomena including structural features and thus have certain effects on organizations [74]. For instance, in some studies on adoption of groupware software, several researchers have used this deterministic approach to describe how groupware use affects communication and collaboration among employees and their productivity [27, 28]. These studies assume that certain results will certainly emerge after the adoption of information technologies, without considering the motives or activities that shape the use of information technologies by managers and employees. Like much more deterministic studies, these authors often assumed that information technologies would have predetermined influences on the adoption of information technologies, regardless of the environment in which information technologies were applied, how they were applied, and the users’ specific behaviors and particular purposes.
The second group of views concerning the relationships between organizational culture and information technologies includes the fact that information technologies are seen as a tool that can be used for any change that managers desire to make in organizational practices [22]. In studies in this approach, researchers believe that there is a wide range of possibilities to identify changes in organizational culture, structure, processes, and performance [22, 75]. Researchers from this tradition presume that with the right choice of information technologies and appropriate system design, managers can achieve whatever goals they desire.
These works were mostly adopted in the 1980s and reflect a perspective that managers think can manipulate organizational culture in the way they want. Often called “management and control,” “a functional or instrumental approach” to organizational culture, this methodology has caused serious debate in the literature [76]. This approach attributes great powers to the management level in this regard, which conflicts with anthropologists’ views that culture cannot be consciously controlled and goes much deeper to understand it [76]. Robey and Azevido [77] also do not accept the rational thought on the assumption that culture can be manipulated directly in this way.
Studies with this rational perspective in the information technology literature assume that managers can use information technologies as a leverage to make changes in the norms of behavior, strategy, structure, and performance among members within the organization. For example, in studies on group support systems (GSS), we find managers’ beliefs that they can use collaborative technologies to create a more cooperative organizational culture. This perspective was not accepted by Karsten [78] and some experimental research on GSS [30, 79]. Organizational necessity is no longer accepted, as it is viewed by information technology researchers as an overly simple approach [23, 80].
Researchers who take another approach suggest that information technologies and organizational culture can interact with each other to produce various results [22, 23]. These results can be in the form of adoption and effective use of information technologies (if there is a harmony between organizational culture and information technologies) or user reluctance, refusal, or sabotage (if no fit). Researchers who have been working on information systems since the 1980s have focused on understanding information technology features and functionality that cause effective or problematic information technology applications and the interaction between users’ values, assumptions, and other elements of organizational culture. In this regard, Romm et al. [81] argued that many forms of information technologies comprise cultural assumptions embedded within themselves and these assumptions may conflict with existing values of a particular organization. The authors argued that these embedded assumptions present information technologies as a “cultural boundary” and that a cultural analysis should be made to predict compliance or incompatibility. The authors in this approach warn managers to think of organizational culture as a binding limitation in information technology applications. In a warning by Pliskin et al. [76], managers are advised not to try to change the culture of the organization. Regarding this issue, Orlikowski [30] cites Lotus Notes (a group software) application at Alpha Corporation, a consultancy company. In this example, this system, which was established by the CEO of the company only with the benefits to be obtained, did not create the expected effects, became unsuccessful, and disappointed due to reasons such as no cultural analysis and inadequate training. Employees responded to the use of Notes with resistance and refrained from using it. The reason for this was that the employees in this organization, which had a competitive culture where information was seen as a power, avoided sharing information with others. As a result, this incompatibility between the collaborative culture that Notes had in itself and the competitive culture of the organization in question had failed this application of information technologies.
In a different approach, it is stated that information technologies and culture are not fixed and they are more flexible in terms of change [23, 75]. Managers in this approach may set specific goals for the use of information technologies, but actual results of the use of information technologies are not deterministic, and results cannot be predicted or controlled even under the best conditions [23]. The effects of information technologies are not deterministic because technology has interpretable flexibility considering that it can have different meanings for different employees. Similar technology can be interpreted in a different way by distinct people, based on certain assumptions, beliefs, and values. Robey and coauthors [24, 25], for instance, showed that it would be an empty attempt for organizational managers to try to intentionally manipulate the effects of these technologies, since there are many ways that diverse employees can configure a particular technology in different social environments.
Gopal and Prasad [31] also achieved similar results in their work on group support system (GSS), claiming that for researchers seeking fixed laws or regulations on how information technologies affect user behaviors, this would be an impossible goal to pursue. Conversely, the results of using information technologies depend on the symbolic meanings that information technologies have for a particular user. This work of Gopal and Prasad [31] expresses similar results with the work of Barley [26] and Robey and Sahay [25]. The authors stated that the symbolic meanings of certain technologies for users affect their perceptions of information technologies and their specific behaviors.
In the light of the above-mentioned approaches, arguments, and important studies in the literature, it will be useful to discuss some important points by deepening a little more and by emphasizing the key features related to the concepts of information, information technologies, and organizational culture.
First, organizational culture is a complex phenomenon that develops and changes in a historical process [32, 82, 83]. Thus, although it might seem like a plain and simple concept, organizational culture includes many subdimensions and processes. When considered as a complex pattern of these interactions of many factors with each other, it is also a difficult process to identify the direct and indirect effects of information technologies on organizational culture within this cluster of relationships and interactions. Moreover, culture is not a phenomenon that changes and develops in a short time and is therefore open to manipulations of managers. On the contrary, from this point of view, it is not possible to easily achieve control over cultural changes, and it is necessary to go much deeper [76]. So, it is not rational to expect that the rapid developments and changes in information technologies will cause changes in cultural characteristics at the same speed. In this sense, it could be inaccurate to seek direct relationships between two phenomena in question, whose rates of change are quite different.
Second, for cultural changes, there must also be changes in the basic assumptions, beliefs, and values on which the culture is built [84]. It would be misleading to expect little or intensive use of information technologies to cause changes in these rooted assumptions. For the desired changes in these basic assumptions, beliefs, and values, it is necessary to design the structure accordingly, to recruit employees who are qualified for the targeted culture, and to set ethical values and property rights to employees in accordance with this culture [15]. In this sense, information technologies may only catalyze the contribution of organizational structure to organizational culture.
Third, there are many and different types of hardware and software that fall under the scope of information technologies. It is not logical to accept all of them as homogeneous technologies in all aspects (with the same functions and features, similar usage areas, standard conditions they are applied, similar intentions, and behaviors of all users), and it can be, therefore, misleading to carry out research under a single “IT” concept from this perspective. The reason for this is that, as stated in the sections above, cultural features of each information technology application or product embedded in it might be different. The interactions between the cultural characteristics of the environment in which information technologies are applied and the unique cultural contents of information technologies may cause different results on the culture of the organization.
Fourth, contrary to what is believed, some of cultural features that we anticipate to support information technology applications and products may be interpreted otherwise by diverse people contingent on different assumptions, beliefs, and values. In fact, Robey et al. [24, 25] showed that managers cannot control the effects of these technologies, since different users can configure a particular technology in numerous ways in different social environments. Also, Gopal and Prasad [31] argued that this would be an impossible achievement for researchers looking for fixed laws or regulations on how information technologies affect user behaviors.
Fifth, information technologies were defined above as technologies that enable processing, storage, and sharing of information. The key concept in this definition is “knowledge-based” information and not the technology itself. Therefore, what makes information technologies essential and important is the information itself. According to the definition of knowledge, the most significant characteristic that differentiates it from information is its being a product of the human mind [37]. Because knowledge is the interpretation of information and expresses the value produced from it, qualifying information technologies as good-bad, useful-useless, and necessary-unnecessary can be a meaningless evaluation. So, the basic thing that creates value-added for organizations is not the technology used but the information itself, which is processed, stored, and shared on this technology. In this context, even if it is the latest, most advanced, and most expensive technology in the world, if the organization does not have a qualified human resource capable of producing knowledge that will create value-added, an appropriate organizational structure and culture that will activate this creative potential, and a management approach, all investments in these technologies will also be wasted.
This chapter has aimed to examine the impacts of information technologies on organizations’ cultures, and for this purpose, a special emphasis is given to the concept of “organizational structure” within the theoretical framework presented above. The most important reason for this is that relevant literature shows that organizational culture and organizational structure are in a very close relationship. Indeed, when the question items in the Denison organizational culture scale [85], which is the most frequently used in the literature, are examined, it is possible to see that most of these items point to many features of organizational structure concerning centralization, formalization, and differentiation dimensions. Therefore, it is a very rational approach to expect that information technologies can have direct and indirect effects on organizational cultures based on the influences of information technologies on structures of organizations. However, it should be underlined that different and controversial approaches and findings in the literature mentioned above on the relations between information technologies and organizational culture generate question marks in the minds as well.
In this regard, it is already quite difficult to draw a clear picture of the impacts of information technologies on cultural characteristics of organizations. The number of studies on the subject in the literature is still very limited. Accordingly, it is necessary to underline the great need for interdisciplinary studies in this field. But still, this study argues that the main factor that determines the actual impact and value of information technologies, which have become an integral part of human life in today’s world, is the information itself rather than technology, and it should be kept in mind that information technologies can only function as a means or tool in this knowledge-based social, economic, and cultural life. In other words, the determinant of the benefits, meaning, and importance of information technologies might be the conditions created by organizational factors such as cultural environment and organizational structure where knowledge is created, developed, and used and human resources have become the most important capital element and source of wealth.
The author declares no conflict of interest.
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\n\nPolicy last updated: 2018-09-11
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