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Mechanisms of crosstalk between endocrine systems: Regulation of sex steroid hormone synthesis and action by thyroid hormones
... Considering the multiple biological adverse effects of NSAIDs exposure on aquatic species as endocrine disruption and acute toxicity responses (Parolini, 2020), several approaches on reproduction, metabolism and stress physiological endpoints evaluations may offer reliable tools for assessing endocrine disruption capacity of pharmaceuticals (Ankley et al., 2009)., Liu et al. (2011) point out that evaluating multiple endocrine axes could display many effects of xenobiotics when compared to individual axis evaluation. There is an urgent need to investigate the responses in several endocrine axis in non-mammalian species, such as fish (Thambirajah et al., 2022) and assuming the observations of many physiological interactions and crosstalk mechanisms among endocrine axes as HPT, HPI and HPG (Duarte-Guterman et al., 2014;Milla et al., 2009;Blanton and Specker, 2007;Ś wiacka et al., 2021). ...
... Endocrine disruption evaluations are strong tools to indicate the adverse effects on hormonal functions of organisms (Ankley et al., 2009). TH are responsible for several endocrine responses including development and metabolic processes and are also involved in reproductive functions of vertebrates, including steroidal hormone regulation levels (Duarte-Guterman et al., 2014). While the present investigation observed alteration in TH of A. lacustris females, changes in steroidal hormones were not verified for cortisol, 17β-Estradiol, and testosterone, neither in DCF and IBU groups isolated nor their combination vs. control groups of each exposure period. ...
... Alterations on physiological endpoints such as muscle contraction and heart rate in embryos might be a target of NSAIDs toxicity on cardiovascular development as observed in Danio rerio embryos exposed to 21.9 and 24.1 μgL − 1 of IBU and DCF, respectively (Zhang et al., 2020). The range of physiological responses observed in different life stages of aquatic organisms can give new research directions regarding the prolonged effects of NSAIDs on reproductive endpoints and the HPT axis considering the influence of TH on reproduction of vertebrates (Duarte-Guterman et al., 2014). ...
... Effects of THSD on reproduction are currently only included in one AOP that is under development for fish (AOP 271), although ample evidence describes the cross-talk between the hypothalamic-pituitary-gonadal (HPG) and HPT axis in different classes of vertebrates (see reviews of Duarte-Guterman et al., 2014;Thambirajah et al., 2022;Tovo-Neto et al., 2018). In fish, DIO2 knockout zebrafish (D. rerio) support the link between THSD and reduced fecundity through impaired T4 to T3 conversion, resulting in a delayed sexual maturity, a shortened reproductive period and reduced fecundity and fertility. ...
... laevis, Hyperolius viridiflavus) and affected reproductive parameters such as sperm motility (Hayes, 1997;Goleman et al., 2002;Campbell et al., 2018). However, the impact on sex ratio distributions appeared to be species-dependent and was not observed in wood frogs (Lithobates sylvaticus) exposed to perchlorate (reviewed by Duarte-Guterman et al., 2014). In red-eared slider turtles (T. ...
... gallus) THs appear to exert a reversed impact on gonad maturation with T4-induced hyperthyroidism suppressing testicular and ovarian growth, and inhibiting oogenesis in females and puberty in males. Goitrogens progressed sexual development and egg and sperm production and increased testicular size (reviewed by Duarte-Guterman et al., 2014). In humans, hypothyroidism was linked to impaired ovulation, fertilization, or late pregnancy complications in women, whereas hyperthyroidism with elevated TSH levels increased the risk for child loss. ...
Thyroid hormone system disrupting compounds are considered potential threats for human and environmental health. Multiple adverse outcome pathways (AOPs) for thyroid hormone system disruption (THSD) are being developed in different taxa. Combining these AOPs results in a cross-species AOP network for THSD which may provide an evidence-based foundation for extrapolating THSD data across vertebrate species and bridging the gap between human and environmental health. This review aimed to advance the description of the taxonomic domain of applicability (tDOA) in the network to improve its utility for cross-species extrapolation. We focused on the molecular initiating events (MIEs) and adverse outcomes (AOs) and evaluated both their plausible domain of applicability (taxa they are likely applicable to) and empirical domain of applicability (where evidence for applicability to various taxa exists) in a THSD context. The evaluation showed that all MIEs in the AOP network are applicable to mammals. With some exceptions, there was evidence of structural conservation across vertebrate taxa and especially for fish and amphibians, and to a lesser extent for birds, empirical evidence was found. Current evidence supports the applicability of impaired neurodevelopment, neurosensory development (e.g., vision) and reproduction across vertebrate taxa. The results of this tDOA evaluation are summarized in a conceptual AOP network that helps prioritize (parts of) AOPs for a more detailed evaluation. In conclusion, this review advances the tDOA description of an existing THSD AOP network and serves as a catalog summarizing plausible and empirical evidence on which future cross-species AOP development and tDOA assessment could build.
... Hormone regulation and production are modified by EDCs ( Figure 1) [27]. Since all systems are interconnected, consequences of EDCs on one system may have effects on multiple compartments, leading to failure at the individual level with implications on metabolism, growth, reproduction and/or development [48,49,[51][52][53][54][55][56]. However, for this review, only the HPG and HPT axis were evaluated. ...
... The HPT axis regulates the secretion of thyroid hormones, which are essential for metamorphosis in amphibians, and the development and metabolism in all vertebrates [53,59,[72][73][74]. The hypothalamus secretes the thyrotropin-releasing hormone (TRH), which induces the secretion of the thyroid-stimulating hormone (TSH) in the pituitary [51,55,57]. ...
... In amphibians, the hypothalamus secretes the corticotropin-releasing hormone (CRH) instead of the TRH [55]. Studies in different species of terrestrial and aquatic taxonomic groups such as frogs (e.g., Rana pipiens), fish (e.g., Clarias gariepinus, Danio rerio) and rats (e.g., Rattus norvegicus) revealed that thyroid hormones affect the synthesis and action of steroid hormones, having an impact on gonadal differentiation, hormone levels and reproduction [53,[75][76][77][78][79][80]. At the HPT axis, EDCs will have a negative effect at different stages of the synthesis, secretion and metabolism of the thyroid hormones influencing eventually their serum concentration and thyroid function [58,81,82]. ...
Human pressure due to industrial and agricultural development has resulted in a biodiversity crisis. Environmental pollution is one of its drivers, including contamination of wildlife by chemicals emitted into the air, soil, and water. Chemicals released into the environment, even at low concentrations, may pose a negative effect on organisms. These chemicals might modify the synthesis, metabolism, and mode of action of hormones. This can lead to failures in reproduction, growth, and development of organisms potentially impacting their fitness. In this review, we focused on assessing the current knowledge on concentrations and possible effects of endocrine disruptor chemicals (metals, persistent organic pollutants, and others) in studies performed in South America, with findings at reproductive and thyroid levels. Our literature search revealed that most studies have focused on measuring the concentrations of compounds that act as endocrine disruptors in animals at the systemic level. However, few studies have evaluated the effects at a reproductive level, while information at thyroid disorders is scarce. Most studies have been conducted in fish by researchers from Brazil, Argentina, Chile, and Colombia. Comparison of results across studies is difficult due to the lack of standardization of units in the reported data. Future studies should prioritize research on emergent contaminants, evaluate effects on native species and the use of current available methods such as the OMICs. Additionally, there is a primary focus on organisms related to aquatic environments, and those inhabiting terrestrial environments are scarce or nonexistent. Finally, we highlight a lack of funding at a national level in the reviewed topic that may influence the observed low scientific productivity in several countries, which is often negatively associated with their percentage of protected areas.
... The morphological restructuring for transition from larval stage to juvenile stage is dependent on endocrine drivers, specifically surges in thyroid hormones (TH), regulated by thyroid hormone receptors and retinoic acid receptors (TR and RXR, respectively; reviewed in Paul et al., 2022). Endocrine regulation and body morphogenesis during the larval stage are controlled by the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal/interrenal axes (HPA/ HPI) as well as the hypothalamus-pituitary-gonadal (HPG) axis (Duarte-Guterman et al., 2014). Development and metamorphosis are regulated largely by the release of the thyroid hormones thyroxine (T4) and tri-iodothyronine (T3) and modulated by the corticosteroids (CS) corticosterone (CORT) and aldosterone (ALDO; Denver, 2009). ...
... Endocrine-driven developmental processes are highly conserved in vertebrates (Paul et al., 2022), as are many physiological endpoints associated with both homeostatic and lethal responses to pesticides and contaminant exposure. Larval amphibians are especially susceptible to endocrine disruption due to their reliance on hormonal cues for initiation and timing of metamorphosis and sex determination (Duarte-Guterman et al., 2014). Crosstalk between hormonal axes includes an evolutionary history of HPT and HPG signaling (Thambirajah et al., 2022). ...
Controlled laboratory experiments are often performed on amphibians to establish causality between stressor presence and an adverse outcome. However, in the field, identification of lab-generated biomarkers from single stressors and the interactions of multiple impacts are difficult to discern in an ecological context. The ubiquity of some pesticides and anthropogenic contaminants results in potentially cryptic sublethal effects or synergistic effects among multiple stressors. Although biochemical pathways regulating physiological responses to toxic stressors are often well-conserved among vertebrates, different exposure regimes and life stage vulnerabilities can yield variable ecological risk among species. Here we examine stress-related biomarkers, highlight endpoints commonly linked to apical effects, and discuss differences in ontogeny and ecology that could limit interpretation of biomarkers across species. Further we identify promising field-based physiological measures indicative of potential impacts to health and development of amphibians that could be useful to anuran conservation. We outline the physiological responses to common stressors in the context of altered functional pathways, presenting useful stage-specific endpoints for anuran species, and discussing multi-stressor vulnerability in the larger framework of amphibian life history and ecology. This overview identifies points of physiological, ecological, and demographic vulnerability to provide context in evaluating the multiple stressors impacting amphibian populations worldwide for strategic conservation planning.
... Physiological overlap among axes contribute to the effects which exceed the boundaries of one endocrine axis. The HPG, HPT and HPA axes have common regions for biosynthesis of hormones in the hypothalamus and pituitary gland, as well as several hormones which modulate signal pathways along different axes (Nichols et al., 2011;Castañeda Cortés et al., 2014;Duarte-Guterman et al., 2014). Even so, current, systematic studies on impacts of MCs on the endocrine system are still limited (Chen et al., 2021b). ...
... This might be due to lesser expression of ar in the adrenal after MC-LR exposure. THs can influence the sex steroid hormone axis, and vice versa (Krassas et al., 2010;Flood et al., 2013;Duarte-Guterman et al., 2014). Decreased concentrations of THs can result in a lesser androgen/estrogen ratio, by (1) down-regulation of androgen synthase and inhibition of androgen biosynthesis, and/or (2) up-regulation of cyp19a1, a key enzyme in the conversion of T to E2 (Ślebodziński, 2005;Aghajanova et al., 2009;Flood et al., 2013). ...
Microcystins (MCs) produced by some cyanobacteria can cause toxicity in animals and humans. In recent years, growing evidence suggests that MCs can act as endocrine disruptors. This research systematically investigated effects of microcystin-LR (MC-LR) on endocrine organs, biosynthesis of hormones and positive/negative feedback of the endocrine system in rats. Male, Sprague-Dawley rats were acutely administrated MC-LR by a single intraperitoneal injection at doses of 45, 67.5 or 90 μg MC-LR/kg body mass (bm), and then euthanized 24 h after exposure. In exposed rats, histological damage of hypothalamus, pituitary, adrenal, testis and thyroid were observed. Serum concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT), expressions of genes and proteins for biosynthesis of hormones were lesser, which indicated an overall suppression of the hypothalamus-pituitary-adrenal (HPA) axis. Along the hypothalamus-pituitary-gonadal (HPG) axis, lesser concentrations of gonadotropin-releasing hormone (GnRH) and testosterone (T), but greater concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol (E2) were observed. Except for greater transcription of cyp19a1 in testes, transcriptions of genes and proteins for T and E2 biosynthesis along the HPG axis were lesser. As for the hypothalamus-pituitary-thyroid (HPT) axis, after MCs treatment, greater concentrations of thyroid-stimulating hormone (TSH), but lesser concentrations of free tri-iodothyronine (fT3) were observed in serum. Concentrations of free tetra-iodothyronine (fT4) were greater in rats dosed with 45 μg MCs/kg, bm, but lesser in rats dosed with 67.5 or 90 μg MCs/kg, bm. Transcripts of genes for biosynthesis of hormones and receptors along the HPT axis and expressions of proteins for biosynthesis of tetra-iodothyronine (T4) and tri-iodothyronine (T3) in thyroid were significantly altered. Cross-talk among the HPA, HPG and HPT axes probably occurred. It was concluded that MCs caused an imbalance of positive and negative feedback of hormonal regulatory axes, blocked biosynthesis of key hormones and exhibited endocrine-disrupting effects.
... In contrast to PTU, EE2 was not expected to cause strong effects on thyroidrelated endpoints, although crosstalk between endocrine axes is well known, for example for regulation of eye development (Cohen et al., 2022). Whereas exposure to EE2 did not affect thyroid histopathology of the F 1 generation, adult F 0 zebrafish displayed a slight decrease in the thickness of the thyroid follicular epithelium after exposure to 4.9 ng/L EE2, which might be the result of crosstalk between the hypothalamus-pituitary-gonad (HPG) and HPT axes (Cohen et al., 2022;Duarte-Guterman et al., 2014). Although the effects were by far not as strong as those caused by PTU exposure, crosstalk between endocrine axes seems likely for this endpoint and must be considered in future testing of EDCs. ...
... Data are given as means ± SD (n = 19-24 adult individuals per treatment, four replicates of 5-12 individuals each). Difference from controls (analysis of variance [ANOVA], Tukey's multiple comparison test): *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 within one single assay like the iFEDT appears more appropriate than separate individual analyses (Cyr & Eales, 1996;Duarte-Guterman et al., 2014;Vasudevan et al., 2002). ...
Given the vital role of thyroid hormones (THs) in vertebrate development, it is essential to identify chemicals that interfere with the TH system. Whereas, among non-mammalian laboratory animals, fish are the most frequently utilized test species in endocrine disruptor research, e.g. in guidelines for the detection of effects on the sex hormone system, there is no test guideline (TG) using fish as models for thyroid-related effects; rather, amphibians are being used. Therefore, the goal of the present project was to integrate thyroid-related endpoints for fish into a test protocol combining OECD TGs 229 (Fish Short-Term Reproduction Assay) and 234 (Fish Sexual Development Test). The resulting "integrated Fish Endocrine Disruption Test" (iFEDT) was designed as a comprehensive approach to cover sexual differentiation, early development and reproduction and to be able to identify disruption not only of the sexual/reproductive, but also the TH system. Two 85 d exposure tests were performed using different well-studied endocrine disruptors: propylthiouracil (PTU) and 17α-ethinylestradiol (EE2). Whereas the companion part A of this study (Pannetier et al., 2023a) presents the findings on effects by PTU and EE2 on endpoints established in existing TGs, the present part B discusses effects on novel thyroid-related endpoints such as TH levels, thyroid follicle histopathology as well as eye development. PTU induced a massive proliferation of thyroid follicles in any life-stage, and histopathological changes of the eyes proved to be highly sensitive for TH system disruption especially in younger life-stages. For measurement of THs, further methodological development is required. EE2 not only showed the well-known disruption of the hypothalamic-pituitary-gonadal axis, but also induced effects on thyroid follicles in adult zebrafish (Danio rerio) exposed to higher EE2 concentrations, suggesting crosstalk between endocrine axes. The novel iFEDT has thus proven capable of simultaneously capturing endocrine disruption of both the steroid and thyroid endocrine systems.
... Physiological overlap among axes contribute to the effects which exceed the boundaries of one endocrine axis. The HPG, HPT and HPA axes have common regions for biosynthesis of hormones in the hypothalamus and pituitary gland, as well as several hormones which modulate signal pathways along different axes (Nichols et al., 2011;Castañeda Cortés et al., 2014;Duarte-Guterman et al., 2014). Even so, current, systematic studies on impacts of MCs on the endocrine system are still limited (Chen et al., 2021b). ...
... This might be due to lesser expression of ar in the adrenal after MC-LR exposure. THs can influence the sex steroid hormone axis, and vice versa (Krassas et al., 2010;Flood et al., 2013;Duarte-Guterman et al., 2014). Decreased concentrations of THs can result in a lesser androgen/estrogen ratio, by (1) down-regulation of androgen synthase and inhibition of androgen biosynthesis, and/or (2) up-regulation of cyp19a1, a key enzyme in the conversion of T to E2 (Ślebodziński, 2005;Aghajanova et al., 2009;Flood et al., 2013). ...
Microcystins (MCs) produced by some cyanobacteria can cause toxicity in animals and humans. In recent years, growing evidence suggests that MCs can act as endocrine disruptors. This research systematically investigated effects of microcystin-LR (MC-LR) on endocrine organs, biosynthesis of hormones and positive/negative feedback on the endocrine system in rats. Male, Sprague-Dawley rats were acutely administrated MC-LR by a single intraperitoneal injection at doses of 45, 67.5 or 90 μg MC-LR/kg body mass (bm), and then euthanized 24 h after exposure. In exposed rats, histological damage of hypothalamus, pituitary, adrenal, testis and thyroid were observed. Serum concentrations of corticotropin-releasing hormone, adrenocorticotropic hormone and corticosterone, expressions of genes and proteins for biosynthesis of hormones were less, which indicated an overall suppression of the hypothalamus-pituitary-adrenal (HPA) axis. Along the hypothalamus-pituitary-gonadal (HPG) axis, lesser concentrations of gonadotropin-releasing hormone and testosterone (T), but greater concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol (E2) were observed. Except for greater transcription of cyp19a1 in testes, transcriptions of genes and proteins for T and E2 biosynthesis along the HPG axis were lesser. As for the hypothalamus-pituitary-thyroid (HPT) axis, after MCs treatment, greater concentrations of thyroid-stimulating hormone, but lesser concentrations of free tri-iodothyronine (fT3) were observed in serum. Concentrations of free tetra-iodothyronine (fT4) were greater in rats dosed with 45 μg MCs/kg, bm, but lesser in rats dosed with 67.5 or 90 μg MCs/kg, bm. Transcripts of genes for biosynthesis of hormones and receptors along the HPT axis and expressions of proteins for biosynthesis of T4 and T3 in thyroid were significantly altered. Cross-talk among the HPA, HPG and HPT axes probably occurred. It was concluded that MCs caused an imbalance of positive and negative feedback of hormonal regulatory axes, blocked biosynthesis of key hormones and exhibited endocrine-disrupting effects.
... Environmental chemical-induced gonadal steroid synthesis may compromise the hormonal signaling pathways that are critical for reproductive homeostasis (Denslow and Sepúlveda, 2007;Duarte-Guterman et al., 2014). The gonad is the primary target organ for environmental chemical-induced steroid biosynthesis, and gonadal steroid (e.g., androgen, estrogen, and progesterone) levels via the Fig. 2. Transcript abundances of VTG and ERs, ERα and ERβ, mRNA in the liver of both five female and five male zebrafish in each group after exposure to BPS for 21 days. ...
... Thyroid hormones (i.e., triiodothyronine, T3; thyroxine, T4) play an important role in regulating development, growth, reproduction, and metabolism in fish (Jugan et al., 2010). The amount of thyroid hormones secreted has been reported to affect the release of gonadal steroid hormones, suggesting that crosstalk effects exist between thyroid and gonadal steroid hormones (Duarte-Guterman et al., 2014). Several studies have reported that BPA substitutes, including BPS, disrupt the reproductive neuroendocrine system in zebrafish via estrogen and thyroid receptor signaling, including enzymatic aromatase pathways, in a similar manner to BPA (Kwon et al., 2016;Qiu et al., 2016;Qiu et al., 2019). ...
This study investigates the adverse effects and the associated underlying mechanism of bisphenol S (BPS) exposure on reproductive endocrine activity in adult zebrafish. Fish were exposed for 21 days to different BPS concentrations (0, 8, 40, and 200 µg/mL) determined via the lowest observed adverse effect level (LOAEL, i.e., < EC15 = 250 µg/mL) for zebrafish embryos. Exposure to 200 µg/mL BPS in female zebrafish in the absence of vitellogenic oocytes or the presence of degenerated oocytes in the ovary significantly decreased the biosynthesis of hepatic vitellogenin (VTG) mRNA, while hepatic VTG mRNA in male fish abundance was significantly elevated (P < 0.05). The levels of gonadal steroids were significantly increased in female zebrafish, while in male zebrafish, the levels of endogenous androgens were reduced (P < 0.05). However, the activities of 17β-estradiol and aromatase in male zebrafish were significantly elevated in all BPS exposure groups in male zebrafish (P < 0.05). Interestingly, thyroid hormone levels and residual whole-body BPS levels increased in female and male zebrafish with increasing exposure concentrations. A novel finding is that the response to BPS depends on zebrafish sex and tissue-specific responsiveness to the accumulation of BPS, suggesting that BPS may cause long-term environmental problems in adult zebrafish through tissue-specific suppression and hormonal imbalance.
... тиреоидных гормонов на репродуктивные органы, так и с их влиянием на биодоступность и эффекты других гормонов и факторов роста, которые необходимы для правильного функционирования женской воспроизводительной системы (8)(9)(10). ...
... Thiamethoxam has different interactions with ERα, AR, and TRα and simultaneously induces a plasma T4 decrease and histological damage in the liver and delayed gonadal development in both genders of Chinese rare minnow (Gobiocypris rarus) [86]. THs regulate sex steroid synthesis and action in both the brain and gonads, which are important for gonadal development and brain sexual differentiation and have been studied in many species [87]. THs control the migration and differentiation of neurons, oligodendrocytes, astrocytes, and microglia in the brain [88,89], and both androgens and estrogens play important roles in brain development [90]. ...
Thyroid cancer usually begins with thyroid dysfunction and nodules and has become the most common cancer globally, especially in women. Although the causes of thyroid dysfunction are complex, the presence of environmental pollutants, especially certain pesticides as established mutagens, has been widely accepted. Zebrafish (Danio rerio) have similar toxic reactions and signal transduction pathways to humans and are very similar to humans in physiology, development, and metabolic function. Here, the direct toxicity effects and mechanisms of different insecticides and herbicides on zebrafish thyroid functions and indirect toxicity effects originating from thyroid dysfunction were summarized and compared. The overall toxicity of insecticides on the zebrafish thyroid was greater than that of herbicides based on effective concentrations. Penpropathrin and atrazine were more typical thyroid disruptors than other pesticides. Meanwhile, chiral pesticides showed more sophisticated single/combined toxicity effects on both parental and offspring zebrafish. Besides thyroid hormone levels and HPT axis-related gene expression alteration, developmental toxicity, immunotoxicity, and oxidative damage effects were all observed. These data are necessary for understanding the thyroid interference effect of pesticides on humans and for screening for thyroid disruptors in surface water with zebrafish models for the pre-assessment of human health risks and ecological risk control in the future.
... In the uterine stroma, collagen fibers are organized interspersed with cells and can have their synthesis, degradation, and organization modified by steroid hormones [47,48]. It is known that thyroid hormones may modulate the bioavailability and metabolism of other hormones like steroid hormones and their transport proteins [49]. Whether there is a deregulation of steroid hormones with a predominance of androgens, collagen fibers undergo disarrangements in their distribution throughout the endometrium, which may impair endometrial receptivity during implantation [50]. ...
Pyriproxyfen (PPF) is an insecticide used in agriculture, which is approved for use in drinking water tanks for human consumption. However, some studies indicate that it may act as an endocrine disruptor and affect nontarget organisms. This study aimed to evaluate the effects of PPF on reproduction and general health status in female mice exposed from pre‐puberty to adulthood. In the first experiment, females were treated by gavage from postnatal day (PND) 23 to (PND) 75 and were distributed into three experimental groups: control (vehicle), PPF 0.1 mg/kg, and PPF 1 mg/kg. Female mice were assessed for the age of puberty onset, body mass, water and food consumption, and the estrous cycle. On PDN 75, a subgroup was euthanized, when vital and reproductive organs were collected and weighed. The thyroid, ovary, and uterus were evaluated for histomorphometry. The other subgroup was assessed in relation to reproductive performance and fetal parameters. In a second experiment, the uterotrophic assay was performed with juvenile females (PND 18) using doses of 0.01, 0.1, or 1 mg/kg of PPF. PPF treatment reduced thyroid mass and increased liver mass. Furthermore, there was an increase in ovarian interstitial tissue and, in the uterus, a decrease in the thickness of the endometrial stroma with reduced content of collagen fibers. There was also a reduction of 30% in pregnancy rate in the treated groups and an increase in the frequency of fetal death. This study suggests that, based on this experimental model, the insecticide may pose a reproductive risk for females chronically exposed to the substance from the pre‐pubertal period until adulthood. These results raise concerns about prolonged exposure of women to the same compound.
... Thyroid hormones, such as free T4 (FT4), total T4 (TT4), and thyroid stimulating hormone (TSH), also have roles in pregnancy and fetal development, with both hypothyroidism and hyperthyroidism linked to preterm delivery, pre-eclampsia, intrauterine growth restriction, and developmental disabilities (Silva et al., 2018). There is also sex-steroid and thyroid hormone crosstalk, with thyroid hormones influencing sex-steroid hormone synthesis, transport, and elimination and sex-steroid hormones influencing thyroid hormones through feedback loops (Duarte-Guterman et al., 2014;Ren and Zhu, 2022). As normal hormonal processes need to be intricately maintained during pregnancy, any factors that perturb gestational hormones could pose health concerns and should be identified. ...
Background/Objectives
Pregnant women are exposed to numerous endocrine disrupting chemicals (EDCs) that can affect hormonal pathways regulating pregnancy outcomes and fetal development. Thus, we evaluated overall and fetal sex-specific associations of phthalate/replacement, paraben, and phenol biomarkers with sex-steroid and thyroid hormones.
Methods
Illinois women (n = 302) provided plasma for progesterone, estradiol, testosterone, free T4 (FT4), total T4 (TT4), and thyroid stimulating hormone (TSH) at median 17 weeks gestation. Women also provided up-to-five first-morning urine samples monthly across pregnancy (8–40 weeks), which we pooled to measure 19 phthalate/replacement metabolites (reflecting ten parent compounds), three parabens, and six phenols. We used linear regression to evaluate overall and fetal sex-specific associations of biomarkers with hormones, as well as weighted quantile sum and Bayesian kernel machine regression (BKMR) to assess cumulative associations, non-linearities, and chemical interactions.
Results
In women of relatively high socioeconomic status, several EDC biomarkers were associated with select hormones, without cumulative or non-linear associations with progesterone, FT4, or TT4. The biomarker mixture was negatively associated with estradiol (only at higher biomarker concentrations using BKMR), testosterone, and TSH, where each 10% mixture increase was associated with −5.65% (95% CI: −9.79, −1.28) lower testosterone and −0.09 μIU/mL (95% CI: −0.20, 0.00) lower TSH. Associations with progesterone, testosterone, and FT4 did not differ by fetal sex. However, in women carrying females, we identified an inverted u-shaped relationship of the mixture with estradiol. Additionally, in women carrying females, each 10% increase in the mixture was associated with 1.50% (95% CI: −0.15, 3.18) higher TT4, whereas in women carrying males, the mixture was associated with −1.77% (95% CI: −4.08, 0.58) lower TT4 and −0.18 μIU/mL (95% CI: −0.33, −0.03) lower TSH. We also identified select chemical interactions.
Conclusion
Some biomarkers were associated with early-to-mid pregnancy hormones. There were some sex-specific and non-linear associations. Future studies could consider how these findings relate to pregnancy/birth outcomes.
... In the endocrine regulation of the ovary, StAR, Cyp1a1, Hsd3 and Cyp19a1 proteins appear to be common targets of gonadotropin-mediated upregulation of expression during the vitellogenesis stage (Ings and van der Kraak, 2006;Kagawa et al., 2003;Nakamura et al., 2003;Montserrat et al., 2004;Kazeto et al., 2006;Zhang et al., 2013). In addition to sex hormones, there is increasing evidence of a crosstalk between the reproductive and thyroid systems in teleosts due to the fact that thyroid hormones often exhibit seasonal rhythms associated with reproduction (Duarte-Guterman et al., 2014;De Vincentis et al., 2018). The administration of triiodothyronine (T 3 ) in goldfish significantly enhanced the expression of estrogen receptor alpha (ERa) in the liver, thereby promoting an increase in Vtg levels through its interaction with E 2 (Nelson and Habibi, 2016). ...
Vitellogenesis is the most important stage of ovarian maturation in fish, involving the synthesis and transport of essential yolk substances and their complex mechanisms and coordination process. The liver is the main tissue involved in the vitellogenesis of oviparous animals, but studies of vitellogenesis in fish rarely include the liver and ovary as a whole. The aim of this study was to explore the molecular mechanism and associated regulatory factors behind vitellogenesis in Sichuan bream (Sinibrama taeniatus). The different stages of oogenesis were first identified by successive histological observations. Then, ovary and liver tissues that developed to 115 days (stage II, previtellogenesis stage), 165 days (stage III, vitellogenesis stage) and 185 days (stage IV, late-vitellogenesis stage) were collected for transcriptomic and metabolomic analyses, and serum testosterone (T), 17β-estradiol (E2), vitellogenin (Vtg), triiodothyronine (T3), and thyroxine (T4) levels were measured at the corresponding stages. We found that energy redistribution during vitellogenesis is mainly regulated through glycolysis, fatty acid biosynthesis and the citrate cycle pathway. In the liver, energy metabolism was promoted by activating glucolipid metabolic pathways to provide sufficient ATP, but at the same time, the ovary tends to retain nutrients rather than decompose them to produce energy. In addition, we have identified several key factors involved in the metabolism of neutral lipids, polar lipids, amino acids and vitamins, which are involved in the assembly and transport of important yolk nutrients. The initiation of vitellogenesis was found to be associated with a surge in serum E2 levels, but the sustained increase in Vtg levels in the late stage may be due more to upregulation of the estrogen receptor. These results provide valuable information about the regulation of ovarian development in cultured fish.
... These adaptive responses may result in seasonal breeding patterns (Bronson 2009). Thyroid function, an essential thermoregulatory response in mammals and other vertebrates, can influence reproduction by altering gonadal function (Duarte-Guterman et al. 2014). The interaction between the hypothalamicpituitary-thyroid axis and the hypothalamic-pituitary-gonadal axis ultimately regulates seasonal breeding by balancing the costs of thermo-energetics and reproductive function (Helfer et al. 2019). ...
Owl monkeys are found in a variety of ecosystems ranging from the highlands of Panama and Colombia, to the Amazon, and to the South American Chaco. As such, the only extant nocturnal primate in the Neotropics experiences contrasting thermal challenges throughout its distribution, investing metabolic energy in thermoregulation appropriately. Thermoregulation is metabolically costly and limits the amount of energy individuals have to search for food, shelter, and mates, directly affecting their survival and reproduction. As a result, these ~1 kg monkeys seem to have developed strategies to balance their high investment in thermoregulation. We present a summary and synthesis of research on the thermo-energetics of captive and wild owl monkeys and describe the morphological, physiological, and behavioral adaptations they have evolved across their wide geographic distribution. We conclude by proposing a unifying model for the role ambient temperature has in the evolution of these pair-living, sexually monogamous primates.
... Over the past few decades, there has been increasing concern about brominated flame retardants in the environment as the result of their ability to disrupt the thyroid hormone system . Thyroid hormone plays a crucial role in a variety of physiological functions during both early development and adulthood in vertebrates, such as affecting the development of bones, gonads, as well as central nervous system (Duarte-Guterman et al., 2014;Hulbert, 2000). Considering the subtle changes in thyroid hormone status can have deleterious effects, even relatively low levels of brominated flame retardants in the environment pose potential risks to human and wildlife health (Grani et al., 2019). ...
The pregnane X receptor (PXR) is a kind of orphan nuclear receptor activated by a series of ligands. Environmental endocrine disruptors (EEDs) are a wide class of molecules present in the environment that are suspected to have adverse effects on the endocrine system by interfering with the synthesis, transport, degradation, or action of endogenous hormones. Since EEDs may modulate human/rodent PXR, this review aims to summarize EEDs as PXR modulators, including agonists and antagonists. The modular structure of PXR is also described, interestingly, the pharmacology of PXR have been confirmed to vary among different species. Furthermore, PXR play a key role in the regulation of endocrine function. Endocrine disruption of EEDs via PXR and its related pathways are systematically summarized. In brief, this review may provide a way to understand the roles of EEDs in interaction with the nuclear receptors (such as PXR) and the related pathways.
... Even though the present study did not reveal any effects on gonad histopathology in juvenile zebrafish, THs are known to affect gonadal development and maturation (Duarte-Guterman et al., 2014) Mean length and weight of juvenile F 1 zebrafish exposed to different concentrations of (A, B) PTU or (C, D) EE2 for 60 days. Data are given as means ± SD (n = 78-100 per treatment, four replicates of 15-30 individuals each). ...
There has been increasing interest in endocrine disrupting chemicals (EDCs) among scientists and public authorities over the last 30 years, notably because of their wide use and the increasing evidence of detrimental effects on humans and the environment. However, test systems for the detection of potential EDCs as well as testing strategies still require optimization. Thus, the aim of the present project was the development of an integrated test protocol that merges the existing OECD test guidelines (TGs) 229 (FSTRA - Fish Short-Term Reproduction Assay) and 234 (FSDT - Fish Sexual Development Test) and implements thyroid-related endpoints for fish. The "integrated Fish Endocrine Disruptor Test" (iFEDT) represents a comprehensive approach for fish testing, which covers reproduction, early development and sexual differentiation and will thus allow the identification of multiple endocrine-disruptive effects in fish. Using zebrafish (Danio rerio) as a model organism, two exposure tests were performed with well-studied EDCs: propylthiouracil (PTU), an inhibitor of thyroid hormone synthesis and 17α-ethinylestradiol (EE2), an estrogen receptor agonist. In part A of this publication, the effects of PTU and EE2 on established endpoints of the two existing TGs are reported, whereas part B (Gölz et al. 2023) focusses on the novel thyroid-related endpoints. Results of part A document that, as expected, both PTU and EE2 had strong effects on various endocrine-related endpoints in zebrafish and their offspring. Merging of TGs 229 and 234 proved feasible, and all established biomarkers and endpoints were responsive as expected, including reproductive and morphometric changes (PTU and EE2), vitellogenin levels, sex ratio, gonad maturation and histopathology (only for EE2) of different life-stages. A validation of the iFEDT with other well-known EDCs will allow verifying the sensitivity and usability and confirm its capacity to improve the existing testing strategy for EDCs in fish.
... The mechanism of this sex differentiation strategy of environmental participation is still ambiguous, and it appears to be achieved by the coordinated interaction of different mechanisms. In addition to molecular biology [94], physiology [108, [162][163][164], and cytology [165,166], epigenetics is widely recognized as a crucial player in sex differentiation in ESD/GSD + EE species [167][168][169][170]. ...
Human activities have been exerting a non-negligible impact on aquatic environments globally, resulting in temperature rise, extreme weather events, acidification, and the emergence of hypoxic dead zones. Understanding how fish, the most diverse taxa in vertebrates, acclimate, adapt, survive, and sustain in this changing environment is of great importance for both the protection of diversity and aquatic production. Here, we summarize prominent issues concerning environmental stressors under global climate change and highlight the connections between fish responses and epigenetic modifications. Evidence suggests that epigenetic modifications play a role in almost all aspects of fish biology, e.g. sex determination and differentiation, gonadal development and reproduction, stress response and survival, growth, size and morphology, nutrition metabolism, etc. Therefore, epigenetic inheritance may play a significant role in fish acclimation and adaptation to climate change and in helping offspring cope with environmental stresses across generations. We finally present knowledge gaps in the connection between epigenetics and fish response to climate change, which will guide the priorities of future research work.
... Thyroid hormone imbalances in cattle have severe consequences and may affect the molecular mechanisms that control sexual development and behaviour, menstrual and estrous cycle control, ovulation, maternal capacity, pregnancy maintenance, post-natal and foetal growth, and lactation in cattle (Vasudevan et al., 2002;Leite et al., 2008;Silva et al., 2012). Both the direct action of THs in the reproductive organs and the activity of THs on the bioavailability of other hormones and growth factors, which are also essential for the proper functioning of the female reproductive system, are responsible for these effects (Forhead and Fowden, 2014;Duarte-Guterman et al., 2014, Silva et al., 2018. ...
As the altitude increases, the partial pressure of oxygen decreases, leading to hypoxic conditions and ultimately disturbing body homeostasis and affecting neuroendocrine function in cattle. These physiological changes causes low conception rate, early embryonic death, low fertility, etc. in cattle and other livestock species. So far, cattle's reproductive health associated with high-altitude hypoxic conditions has rarely been studied with respect to reproductive physiology, endocrinology, and physio-biochemical perspective. Hence, this review discusses various physiological changes, hormonal disturbance, placenta development, haematological and biochemical changes etc. which are associated and affecting cattle's reproductive physiology.
... Endocrine disruptors (ED) are exogenous substances or mixtures that alter the function(s) of the endocrine system and consequently cause adverse health effects in an intact organism, or its progeny, or in (sub) populations (WHO, 2012). In amphibians, ED can disrupt crosstalk between thyroid and sexual or immune functions leading to impairment of larval development, immune system maturation and disruption of egg and sperm maturation in adults (Duarte-Guterman et al., 2014;Hayes et al., 2002a;Hayes et al. 2011;Hayes et al. 2002b;Langlois et al., 2010a;Langlois et al., 2010b;Trudeau et al., 2020;McGuire et al., 2021). ED can also induce a metabolic syndrome featuring a pre-diabetes state (Martyniuk et al., 2021). ...
A pre-diabetes syndrome induced by endocrine disruptors (ED) was recently demonstrated in the model amphibian Silurana (Xenopus) tropicalis and was suggested to be a potential cause of amphibian population decline. However, such effects have not been found in wild type frogs exposed to ED and the capacity of amphibians to physiologically develop diabetes under natural conditions has not been confirmed. This study showed that a high fat diet (HFD) model displaying the important characteristics of mammal HFD models including glucose intolerance, insulin resistance and nonalcoholic fatty liver disease (NAFLD) can be developed with green frogs (Pelophylax spp.). Wild green frogs exposed to 10 μg L⁻¹ benzo [a]pyrene (BaP) for 18 h also displayed several characteristics of the pre-diabetes phenotype previously observed in Xenopus including glucose intolerance, gluconeogenesis activation and insulin resistance. The study results confirmed that metabolic disorders induced by ED in wild green frogs are typical of the pre-diabetes phenotype and could serve as a starting point for field studies to determine the role of EDs in the decline of amphibian populations. From an environmental perspective, the response of wild green frogs to different ED (10 μg L⁻¹) suggests that a simple glucose-tolerance test could be used on wild anurans to identify bodies of water polluted with metabolic disruptors that could affect species fitness.
... In rainbow trout (Oncorhynchus mykiss), for example, fish maintained at warmer temperatures of 18-19 • C have been shown to exhibit reduced thyroxine (T 4 ) concentrations, higher T 4 conversion to 3,5,3 ′ -triiodo-L -thyronine (T 3 ), and elevated rates of outerring TH deiodination in liver microsomes (Eales et al., 1982;Johnston and Eales, 1995). While THs are well established mediators of metabolism and development in fish and other vertebrates, THs also influence gonad development and function (Jannini et al., 1995;Dittrich et al., 2011;Habibi et al., 2012;Flood et al., 2013;Sharma and Patiño, 2013;Castañeda Cortés et al., 2014;Duarte-Guterman et al., 2014). Such associations between TH status and reproduction have been recognized for some time in teleost fishes, although studies are only now uncovering the complexity of those interactions (Cyr and Eales, 1996;Matta et al., 2002;Raine, 2011;Habibi et al., 2012;Tovo-Neto et al., 2018;Feng et al., 2022). ...
Many fish experience diminished reproductive performance under atypically high or prolonged elevations of temperature. Such high temperature inhibition of reproduction comes about in part from altered stimulation of gametogenesis by the hypothalamic-pituitary-gonadal (HPG) endocrine axis. Elevated temperatures have also been shown to impact thyroid hormone (TH) signaling, and shifts to TH status under high temperatures may impact gametogenesis via crosstalk with HPG axis pathways. Here, we examined effects of temperature and 3′-triiodo-L-thyronine (T3) on pathways for gonadal steroidogenesis and gametogenesis in Amargosa pupfish (Cyprinodon nevadensis amargosae) from two allopatric populations: 1) the Amargosa River – a highly variable temperature habitat, and 2) Tecopa Bore – an invariably warm groundwater-fed marsh. These populations were previously shown to differ in TH signaling profiles both in the wild and under common laboratory conditions. Sexually-mature pupfish from each population were maintained at 24 °C or 34 °C for 88 days, after which a subset of fish was treated with T3 for 18–24 h. In both populations, mRNA abundances for follicle-stimulating hormone receptor and luteinizing hormone receptor were higher in the ovary and testis at 24 °C compared to 34 °C. Females from Tecopa Bore – but not from the Amargosa River – also had greater ovarian transcript abundances for steroidogenic enzymes cytochrome P450 aromatase, 3β-hydroxysteroid dehydrogenase, and 17β-hydroxysteroid dehydrogenase at 24 °C compared to 34 °C, as well as higher liver mRNA levels of vitellogenins and choriogenins at cooler temperature. Transcript abundances for estrogen receptors esr1, esr2a, and esr2b were reduced at 34 °C in Amargosa River females, but not in Tecopa Bore females. T3 augmented gonadal gene transcript levels for steroid acute regulatory protein (StAR) transporter in both sexes and populations. T3 also downregulated liver estrogen receptor mRNAs in females from the warmer Tecopa Bore habitat only, suggesting T3 modulation of liver E2 sensitivity as a possible mechanism whereby temperature-induced changes in TH status may contribute to shifts in thermal sensitivity for oogenesis.
... Sex-specific effects in the interaction between fluoride and iodine, particularly among mothers with insufficient iodine intake, may disrupt in utero thyroid hormones. Given that the thyroid gland expresses estrogen and androgen receptors, boys and girls may respond differently to thyroid hormone insufficiency [61][62][63]. One study, for example, found that maternal trajectories of thyroid hormones were associated with preschool boys' behavioural development but not girls' [64]. ...
In animal studies, the combination of in utero fluoride exposure and low iodine has greater negative effects on offspring learning and memory than either alone, but this has not been studied in children. We evaluated whether the maternal urinary iodine concentration (MUIC) modifies the association between maternal urinary fluoride (MUF) and boys’ and girls’ intelligence. We used data from 366 mother–child dyads in the Maternal–Infant Research on Environmental Chemicals Study. We corrected trimester-specific MUF and MUIC for creatinine, and averaged them to yield our exposure variables (MUFCRE, mg/g; MUICCRE, µg/g). We assessed children’s full-scale intelligence (FSIQ) at 3 to 4 years. Using multiple linear regression, we estimated a three-way interaction between MUFCRE, MUICCRE, and child sex on FSIQ, controlling for covariates. The MUICCRE by MUFCRE interaction was significant for boys (p = 0.042), but not girls (p = 0.190). For boys whose mothers had low iodine, a 0.5 mg/g increase in MUFCRE was associated with a 4.65-point lower FSIQ score (95% CI: −7.67, −1.62). For boys whose mothers had adequate iodine, a 0.5 mg/g increase in MUFCRE was associated with a 2.95-point lower FSIQ score (95% CI: −4.77, −1.13). These results suggest adequate iodine intake during pregnancy may minimize fluoride’s neurotoxicity in boys.
... The hormones thyroxine (T4) and triiodothyronine (T3) are vital for growth, development, and metabolism. In addition, thyroid hormones are essential components of a cross talk among brain, gonads, sex steroid hormones, and reproductive function-a function which is conserved in almost all vertebrates [39]. Thyroid dysfunction can be due to many factors, such as iodine deficiency and autoimmune diseases, age, disease, etc., [40]. ...
Many endocrine-disrupting chemicals (EDCs) have a ubiquitous presence in our environment due to anthropogenic activity. These EDCs can disrupt hormone signaling in the human and animal body systems including the very important hypothalamic-pituitary-thyroid (HPT) axis causing adverse health effects. Thyroxine (T4) and triiodothyronine (T3) are hormones of the HPT axis which are essential for regulation of metabolism, heart rate, body temperature, growth, development, etc. In this study, potential endocrine-disrupting activity of the most common phthalate plasticizer, DEHP, and emerging non-phthalate alternate plasticizers, DINCH, ATBC, and DEHA against thyroid hormone receptor (TRα) were characterized. The structural binding characterization of indicated ligands was performed against the TRα ligand binding site employing Schrodinger’s induced fit docking (IFD) approach. The molecular simulations of interactions of the ligands against the residues lining a TRα binding pocket, including bonding interactions, binding energy, docking score, and IFD score were analyzed. In addition, the structural binding characterization of TRα native ligand, T3, was also done for comparative analysis. The results revealed that all ligands were placed stably in the TRα ligand-binding pocket. The binding energy values were highest for DINCH, followed by ATBC, and were higher than the values estimated for TRα native ligand, T3, whereas the values for DEHA and DEHP were similar and comparable to that of T3. This study suggested that all the indicated plasticizers have the potential for thyroid hormone disruption with two alternate plasticizers, DINCH and ATBC, exhibiting higher potential for thyroid dysfunction compared to DEHA and DEHP.
... The production of thyroid hormones in fish and other vertebrates is under the control of the hypothalamic-pituitary-thyroid (HPT) axis (Cooke et al., 1994;Tousson et al., 2011;Duarte-Guterman et al., 2014;Kang et al., 2020). The thyrotropin-releasing factor [thyrotropin-releasing hormone (TRH)/corticotropin-releasing hormone (CRH)] stimulates the pituitary to release the thyrotropic hormone (TSH), which in turn, promotes the synthesis and release of thyroid hormones, thyroxine (T4) and triiodothyronine (T3), by thyroid follicles (Larsen et al., 1998). ...
In vertebrates, thyroid hormones are critical players in controlling different physiological processes such as development, growth, metabolism among others. There is evidence in mammals that thyroid hormones are also an important component of the hormonal system that controls reproduction, although studies in fish remain poorly investigated. Here, we tested this hypothesis by investigating the effects of methimazole-induced hypothyroidism on the testicular function in adult zebrafish. Treatment of fish with methimazole, in vivo, significantly altered zebrafish spermatogenesis by inhibiting cell differentiation and meiosis, as well as decreasing the relative number of spermatozoa. The observed impairment of spermatogenesis by methimazole was correlated with significant changes in transcript levels for several genes implicated in the control of reproduction. Using an in vitro approach, we also demonstrated that in addition to affecting the components of the brain-pituitary-peripheral axis, T3 (triiodothyronine) also exerts direct action on the testis. These results reinforce the hypothesis that thyroid hormones are an essential element of multifactorial control of reproduction and testicular function in zebrafish and possibly other vertebrate species.
... However, BPA also interferes with metabolic regulation via disruption of F and CORT, the catecholamine hormones epinephrine and norepinephrine, and the peptide hormones insulin and glucagon (Ma et al., 2019;Yanagihara et al., 2005). The relationship between multiple hormonal regulatory networks underlying a given trait is thus crucial to interpreting the effects of BPA exposure especially from an ecological perspective (Duarte-Guterman et al., 2014;Tilghman et al., 2010). Furthermore BPA analogs like BPS, BPF, and BPAF presumably have similar impacts on hormone physiology as BPA. ...
Bisphenols are used in the manufacture of plastics and are endocrine disrupting compounds detectable in free living organisms and environments globally. The original bisphenol, bisphenol A (BPA), is best known as a xenoestrogen, but it also disrupts other steroid hormones and other classes of hormones including thyroid and pituitary hormones. When its toxicity became better known, BPA was replaced by presumably less toxic alternatives, including bisphenols S, F, and AF. However, recent data suggest that all bisphenols can have endocrine disrupting effects, although their impacts remain unresolved particularly in non-human animals. Our aim was to establish the current state-of-knowledge of the effects of different bisphenols on circulating hormone levels in non-human animals. Our meta-analysis showed that a diverse range of hormones (including thyroid hormones, corticosterone, follicle stimulating hormone, luteinizing hormone, and estradiol) are strongly impacted by exposure to any bisphenol type, and that in laboratory rats (Rattus norvegicus) the effect was modified by life-stage. Although there were qualitative differences, BPA alternatives had as great or greater effects on hormone levels as BPA. However, data coverage across hormones was uneven, and most studies measured the effects of BPA on vertebrate reproductive hormones. Similarly, taxonomic coverage was poor. Over 80% of data originated from laboratory rats and zebrafish (Danio rerio) and there are no data for whole classes of invertebrates and vertebrates (e.g., amphibians). Our results show that all bisphenols reduce circulating levels of a broad range of hormones. However, the current state-of-knowledge is incomplete so that the ecological impacts of bisphenols are difficult to gauge, although based on the available data bisphenols are likely to be detrimental to a broad range of taxa and ecosystems.
... Previous studies on hormone analysis in hair have focused mostly on steroid hormones, especially T, E and F (Supplementary Table 1), though it has been well recognized that steroid hormones can interact with thyroid hormones in both humans and animals (13,14). Simultaneously including estrogens, androgens, progestogens, corticosteroids, thyroid hormones and melatonin, the present method may broaden the information that can be obtained from hair analysis and provide a much more comprehensive picture of the hormonal status of the individual (Fig. 1). ...
Objective: Endogenous hormones regulate numerous physiological processes in humans. Some of them are routinely measured in blood, saliva and/or urine for the diagnosis of disorders. The analysis of fluids may however require multiple samples collected at different time points to avoid the high variability in the concentration of some hormones. In contrast, hair analysis has been proposed as an interesting alternative to reveal average hormone levels over longer period. In this work, we developed and validated an analytical method for analyzing 36 endogenous steroid and thyroid hormones and one pineal hormone in human hair using ultra-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS).
Methods: Sample preparation involved hair decontamination, pulverization, methanol extraction, and purification with C18-solid phase extraction. Extracts were then divided into two portions, respectively injected into an UPLC-MS/MS system, and analyzed using two different instrumental methods. The method was applied to a healthy female population aged 25-45 years.
Results: The method was validated on supplemented hair samples for the 37 targeted hormones, and its application to the population under study allowed to detect 32 compounds in 2 to 100% of the samples. Complete reference intervals (2.5th-97.5th percentiles) were established for estrone, 17β-estradiol, androstenedione, dehydroepiandrosterone, progesterone, 17α-hydroxyprogesterone, cortisone, cortisol and 3,3’,5-triiodo-L-thyronine. Hair cortisone, cortisol, tetrahydrocortisone and tetrahydrocortisol concentrations were highly correlated with each other, with Kendall's τ correlation coefficients ranging from 0.52 to 0.68.
Conclusion: Allowing the detection of 32 hormones from different chemical classes, the present method will allow to broaden hormonal profiling for better identifying endocrine disorders.
... It is generally believed that behavioral virilization tends to externalize problems, such as oppositional defiant disorders and aggressive behaviors (46), although studies have shown that internalizing and externalizing problems often co-occur in children (47,48). More and more studies have shown that there is interaction and cross-talk between thyroid hormones and sex steroid hormones (49), and this effect is more direct in males (50). Thyroid hormones are reported to be associated with testicular development, growth, and maturation. ...
Context
Maternal thyroid hormone trajectories are better predictor of offspring’s neurodevelopment than hormone levels in single trimester of pregnancy. Programming effect of uterine hormonal environment on offspring’s health is usually sex-specific.
Objective
To examine the sex-specific effect of thyroid hormone trajectories on preschoolers’ behavioral development.
Design
Based on Ma’ anshan Birth Cohort (MABC) in China, pregnant women were recruited at their first antenatal checkup from May 2013 to September 2014.
Setting
Ma’ anshan Maternal and Child Health Hospital in China.
Patients or Other Participants
1860 mother-child pairs were included in the analysis. Children were followed up at age of 4.
Main Outcome Measures
Maternal thyroid hormones (TSH, FT4) and TPOAb in the first, second and third trimesters of pregnancy were retrospectively assayed. Preschoolers’ behavioral development was assessed by Achenbach Child Behavior Checklist (CBCL/1.5~5).
Results
Maternal TSH and FT4 levels were respectively fitted into high, moderate and low trajectories. In boys, maternal high TSH trajectory was related to withdrawn (OR = 2.01, 95% CI: 1.16, 3.50) and externalizing problems (OR = 2.69, 95% CI: 1.22, 5.92), and moderate TSH trajectory was associated with aggressive behavior (OR = 3.76, 95% CI: 1.16, 12.23). Maternal high FT4 trajectory was associated with anxious/depressed (OR = 2.22, 95% CI: 1.08, 4.56) and total problems (OR = 1.74, 95% CI: 1.13, 2.66), and low FT4 trajectory was associated with aggressive behavior (OR = 4.17, 95% CI: 1.22, 14.24).
Conclusions
Maternal thyroid hormone trajectories impact preschool boys’ behavioral development.
... gland plays an important role in regulation of many body functions. Some researchers studied the role of thyroid hormones for a proper function of reproductive system 10 . ...
Exposure to heat stress can cause a significant increase in the death rate and disease susceptibility of poultry birds, ultimately impacting the profitability of the poultry industry. Despite being a more economical choice, Japanese quails (Coturnix japonica) are not immune to the harmful effects of heat stress. Quails may experience negative effects on their reproductive performance due to excessive reactive molecules caused by heat stress. However, they have developed various mechanisms to maintain their reproductive abilities in such conditions. The neuroendocrine system in birds plays a vital role in regulating their reproductive responses to thermal stress, and it is also connected to other environmental factors such as photoperiod that can impact their reproductive performance. Hormones are crucial in the complex interactions necessary for sexual maturation and reproductive responses to heat stress in Japanese quails living in stressful thermal conditions.
The semi-frequent replacement of the epidermis (ecdysis) is a characteristic trait of reptiles. Whereas all reptiles regularly engage in some degree of skin shedding, skin morphology in snakes necessitates the synchronous replacement of the entire epidermis and facilitates the subsequent removal of the old layer as a single sheet. To date, the ubiquitous process has garnered little attention from researchers because snakes shed with unpredictable timing and frequency and are exceedingly cryptic during ecdytic cycles; previously impeding detailed physiological or ecological investigations of the process in the clade. Because of the lack of study, ecdysis is often viewed as a maintenance function; occurring whenever change in body size necessitates the generation of a new epidermal layer. However, recent observations that skin shedding plays a role in conspecific sexual signaling in some snakes suggest that the predominate view of ecdysis as a growth function may be overly simplistic. By studying population-scale patterns of shed, I was able to describe the timing and frequency of ecdysis in a population of Timber Rattlesnakes, solving a long-standing problem in continued study of ecdysis; predicting the occurrence of shed events. Coupling my knowledge of patterns of shed timing with novel methodologies for inducing shed, I was able to induce ecdytic cycles in a laboratory setting and herein provide the first measurements of the metabolic effort and duration of shedding in any reptile. I integrated data on the frequency, duration, and metabolic effort of shed into an individual-based computer model of the Timber Rattlesnake to address larger questions about the selective pressures that may shape patterns of shed in snakes.
I found that Timber Rattlesnakes shed infrequently (1-2 times per year) and often in close proximity to the mating season regardless of sex. However, the physiological conditions that best correlated to shed frequency differed between males (body condition) and females (reproductive condition). Each shed event required a significant metabolic (3% of the total annual energy budget) and temporal (~28 days at 25⁰C with ~50% of that including some degree of visual limitation from occluded spectacles) investment. In my computer simulations, I found that time spent in shed limited lifetime energy budgets (decreasing lifetime resource acquisition via foraging) and that the energetic effort of ecdysis may serve to limit shed frequency in low resource environments. In my observations of patterns of shed in the wild and through simulations of expected female fecundity under alternate shed frequencies, I found evidence that ecdysis may play a vital role in the reproductive biology of rattlesnakes.
Ecdysis is a vital and omnipresent feature of reptilian biology. My data are the first to demonstrate that the frequency of the process is constrained in a population. I provide evidence for the role of growth and body condition, time-energy budgets, environmental conditions, and reproductive events in dictating patterns of shed. As such, patterns of shed may be population specific and serve as an indicator of the important environmental and biophysical forces which shape life histories across populations and species.
Human activities have been exerting widespread stress and environmental risks in aquatic ecosystems. Environmental stress, including temperature rise, acidification, hypoxia, light pollution, and crowding, had a considerable negative impact on the life histology of aquatic animals, especially on sex differentiation (SDi) and the resulting sex ratios. Understanding how the sex of fish responds to stressful environments is of great importance for understanding the origin and maintenance of sex, the dynamics of the natural population in the changing world, and the precise application of sex control in aquaculture. This review conducted an exhaustive search of the available literature on the influence of environmental stress (ES) on SDi. Evidence has shown that all types of ES can affect SDi and universally result in an increase in males or masculinization, which has been reported in 100 fish species and 121 cases. Then, this comprehensive review aimed to summarize the molecular biology, physiology, cytology, and epigenetic mechanisms through which ES contributes to male development or masculinization. The relationship between ES and fish SDi from multiple aspects was analyzed, and it was found that environmental sex differentiation (ESDi) is the result of the combined effects of genetic and epigenetic factors, self-physiological regulation, and response to environmental signals, which involves a sophisticated network of various hormones and numerous genes at multiple levels and multiple gradations in bipotential gonads. In both normal male differentiation and ES-induced masculinization, the stress pathway and epigenetic regulation play important roles; however, how they co-regulate SDi is unclear. Evidence suggests that the universal emergence or increase in males in aquatic animals is an adaptation to moderate ES. ES-induced sex reversal should be fully investigated in more fish species and extensively in the wild. The potential aquaculture applications and difficulties associated with ESDi have also been addressed. Finally, the knowledge gaps in the ESDi are presented, which will guide the priorities of future research.
Chub mackerel, Scomber japonicus, is heavily farmed and harvested due to its demand as a high-quality protein source rich in fatty acids. However, the effects of environmental cues on sexual maturation of the fish remain understudied. We aim to elucidate the effect of light manipulation on the hormones related to reproduction and on the stress response in the species. Mackerel were exposed to different photoperiods (12 h light:12 h dark or 14 h light:10 h dark) and light wavelengths (provided by white fluorescent bulbs or green LEDs). Total RNA extracted from the brain was assayed with quantitative polymerase chain reaction (a powerful technique for advancing functional genomics) and blood plasma was analyzed via immunoassay using ELISA kits. The mRNA expression of gene-encoding gonadotropin-releasing hormone, gonadotropin hormone, follicle-stimulating hormone, and luteinizing hormone were significantly increased through the use of an extended photoperiod and green wavelength, which also increased testosterone and 17β-estradiol plasma levels. Plasma levels of cortisol and glucose, which are indicators of a stress response, were significantly decreased through green LED exposure. Our results indicate that environmental light conditions affect the production of pituitary and sex hormones, and reduce the stress response in S. japonicus.
Anuran metamorphosis is characterized by profound morphological changes including remodeling of tissues and organs. This transition is initiated by thyroid hormones (THs). However, the current knowledge of changing levels of THs during metamorphosis relies on pooled samples using methods known for high variability with sparse reporting of measured variation. Moreover, establishing a clear linkage between key gene expression bioindicators and TH levels throughout the metamorphic process is needed. Using state-of-the-art ultra-high performance liquid chromatography isotope-dilution tandem mass spectrometry, we targeted 12 THs and metabolites in the serum of Rana [Lithobates] catesbeiana (n=5-10) across seven distinct postembryonic stages beginning with premetamorphic tadpoles (Gosner stage 31-33) and continuing through metamorphosis to a juvenile frog (Gosner stage 46). TH levels were related to TH-relevant gene transcripts (thra, thrb, and thibz) in back skin of the same individual animals. Significant increases from basal levels were observed for thyroxine (T4) and 3,3’,5-triiodothyronine (T3) at Gosner stage 41, reaching maximal levels at Gosner stage 44 (28 ± 10 and 2.3 ± 0.5 ng/mL, respectively), and decreasing to basal levels in juvenile frogs. In contrast, 3,5-diiodothyronine (T2) increased significantly at Gosner stage 40 and was maintained elevated until stage 44. While thra transcript levels remained constant and then decreased at the end of metamorphic climax, thrb and thibz were induced to maximal levels at Gosner stage 41, followed by a decrease to basal levels in the froglet. This exemplifies the exquisite timing of events during metamorphosis as classic early response genes are transcribed in anticipation of peak TH concentrations. The distinct T2 concentration profile suggests a biological role of this biomolecule in anuran postembryonic development and an additional aspect that may be a target of anthropogenic chemicals that can disrupt anuran metamorphosis and TH signalling. Hence, as a second aim of the study, we set out to find additional bioindicators of metamorphosis, which can aid future investigations of developmental disruption. Using a sensitive nanoLC-Orbitrap system an untargeted analysis workflow was applied. Among 6,062 endogenous metabolites, 421 showed metamorphosis-dependent concentration dynamics. These potential bioindicators included several carnitines, prostaglandins and some steroid hormones.
Perchlorate, nitrate, and thiocyanate are common thyroid disruptors in daily life and alter testosterone levels in animals. However, little is known about the effects of perchlorate, nitrate, and thiocyanate on serum total testosterone (TT) in the general population. The study was designed to assess the associations between urinary levels of perchlorate, nitrate, and thiocyanate and serum total testosterone (TT) in the general population. The present study utilized data from the 2011–2016 National Health and Nutritional Examination Survey (NHANES). A total of 6201 participants aged 6–79 with information on urinary perchlorate, nitrate, thiocyanate, and serum total testosterone were included. We conducted multiple linear regression models and Bayesian Kernel Machine Regression (BKMR) models to estimate the associations by sex-age groups. Children (ages 6–11) have higher levels of perchlorate and nitrate than the rest. After adjusting for covariates, urinary perchlorate was significantly negatively associated with serum TT in male adolescents (β = −0.1, 95 % confidence interval: −0.2, −0.01) and female children [−0.13, (−0.21, −0.05)]. Urinary nitrate was significantly negatively associated with serum TT in female children, while urinary thiocyanate was significantly positively associated with serum TT in female adults aged 20 to 49 [0.05 (0.02, 0.08)]. BKMR analysis indicated that no other interactions were found between urinary perchlorate, nitrate, and thiocyanate. Our findings suggested that urinary perchlorate, nitrate, and thiocyanate levels may relate to serum total testosterone levels in specific sex-age groups. We identified male adolescents and female children as are most sensitive subgroups where testosterone is susceptible to interference.
Anuran metamorphosis is characterized by profound morphological changes including remodeling of tissues and organs. This transition is initiated by thyroid hormones (THs). However, the current knowledge of baseline levels of THs during metamorphosis relies on pooled samples using methods known for high variability with little reporting of measured variation. Moreover, establishing a clear linkage between key gene expression bioindicators and TH levels throughout the metamorphic process is needed. Using state-of-the-art ultra-high performance liquid chromatography isotope-dilution tandem mass spectrometry, we target 12 THs -and metabolites in the serum of Rana [Lithobates] catesbeiana (n=5-10) across seven distinct postembryonic stages beginning with premetamorphic tadpoles (Gosner stage 31-33) and continuing through metamorphosis to a juvenile frog (Gosner stage 46). TH levels are then related to TH-relevant gene transcripts (thra, thrb, and thibz) in back skin of the same individual animals. Significant increases from basal levels were observed for thyroxine (T4) and 3,3',5-triiodothyronine (T3) at Gosner stage 41, reaching maximal levels at Gosner stage 44 (28+-10 and 2.3+-0.5 ng/mL, respectively), and decreasing to basal levels in juvenile frogs. In contrast, 3,5-diiodothyronine (T2) increased significantly at Gosner stage 40 and was maintained elevated until stage 44. While thra transcript levels remained constant and then decreased at the end of metamorphic climax, thrb and thibz were induced to maximal levels at Gosner stage 41, followed by a decrease to basal levels in the froglet. This exemplifies the exquisite timing of events during metamorphosis as classic early response genes are transcribed in anticipation of peak TH concentrations. Interestingly T2 showed a distinct concentration profile suggesting a specific biological role of this biomolecule in anuran postembryonic development. This finding also underlines the sensitivity of the developmental process, and it is, indeed, well-known that external factors such as anthropogenic chemicals can disrupt anuran metamorphosis. Hence, as a second aim of the study, we set out to find additional bioindicators of metamorphosis, which can aid future investigations of developmental disruption. Using a sensitive nanoLC-Orbitrap system an untargeted analysis workflow was applied. Among 6,062 endogenous metabolites, 421 showed metamorphosis-dependent concentration dynamics. These potential bioindicators included several carnitines, prostaglandins and some steroid hormones.
Polycyclic aromatic hydrocarbons (PAHs) are well-known contaminants with widespread distribution in environment and food. Phenanthrene is one of the most abundant PAHs in food and aquatic environment and generates reproductive and developmental toxicity in zebrafish. Nonetheless, whether phenanthrene caused sex-specific thyroid disruption in adult zebrafish is unclear. To determine this, adult zebrafish (male and female) were treated with phenanthrene (0, 0.85, 8.5, and 85 μg/L) for 60 days. After the treatment period, we assessed the concentrations of thyroid hormones (THs) and expression levels of genes in the hypothalamic-pituitary-thyroid (HPT) axis. The results showed that phenanthrene exposure can lead to thyroid disruption in both male and female zebrafish. Exposure to phenanthrene dramatically reduced the levels of L-thyroxine (T4) and L-triiodothyronine (T3) in both male and female zebrafish, with a similar trend in both. However, the genes expression profiles of hypothalamic-pituitary-thyroid (HPT) axis were sex-specific. In all, the present study demonstrated that phenanthrene exposure could result in sex-specific thyroid disruption in adult zebrafish.
Background:
Hypothyroidism causes ovarian dysfunction and infertility in women, in addition to being associated with hyperprolactinemia and reduced hypothalamic expression of kisspeptin (Kp). However, it remains unknown whether and how kisspeptin is able to reverse the ovarian dysfunction caused by hypothyroidism.
Methods:
Hypothyroidism was induced in adult female Wistar rats using 6-propyl-2-thiouracil for three months. In the last month, half of the animals received Kp10. Blood samples were collected for dosage of free thyroxine (T4), thyroid stimulating hormone (TSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2), and uteruses and ovaries were collected for histomorphometry. Body and ovarian weight and the number of corpora lutea were also evaluated. Half of the brains were evaluated by immunohistochemistry to kisspeptin and the other half had the arcuate nucleus of hypothalamus (ARC) and preoptic area (POA) microdissected for gene evaluation of Kiss1, Nkb, Pdyn, and Gnrh1. The pituitary gland and corpora lutea were also dissected for gene evaluation.
Results:
Hypothyroidism kept the animals predominantly acyclic and promoted a reduction in ovarian weight, number of corpora lutea, endometrial thickness, number of endometrial glands and plasma LH, in addition to increasing the luteal mRNA expression of Star and Cyp11a1 and reducing 20αHsd. An increase in plasma PRL and P4 levels was also caused by hypothyroidism. Kp immunoreactivity and Kiss1 and Nkb mRNA levels in the ARC and Kiss1 in the AVPV of hypothalamus were reduced in hypothyroid rats. Hypothyroid animals had lower pituitary gene expression of Gnrhr, Lhb, Prl, and Drd2, and an increase in Tshb. The treatment with Kp10 restored estrous cyclicality, plasma LH, ovarian and uterine morphology, and Cyp11a1, 3βHsd and 20αHsd mRNA levels in the corpora lutea. Kp10 treatment did not alter gene expression for Kiss1 or Nkb in the ARC of hypothyroid rats. Nevertheless, Kp10 increased Lhb mRNA levels and reduced Tshb in the pituitary compared with hypothyroid group.
Conclusions:
The present findings characterize the inhibitory effects of hypothyroidism on the hypothalamic-pituitary-gonadal axis in female rats and demonstrate that Kp10 is able to reverse the ovarian dysfunction caused by hypothyroidism, regardless of hyperprolactinemia.
In vertebrates, thyroid hormones (THs) play an important role in the regulation of growth, development, metabolism, photoperiodic responses and migration. Maternally transferred THs are important for normal early phase embryonic development when embryos are not able to produce endogenous THs. Previous studies have shown that variation in maternal THs within the physiological range can influence offspring phenotype.
Given the essential functions of maternal THs in development and metabolism, THs may be a mediator of life‐history variation across species.
We tested the hypothesis that differences in life histories are associated with differences in maternal TH transfer across species. Using birds as a model, we specifically tested whether maternally transferred yolk THs covary with migratory status, developmental mode and traits related to pace‐of‐life (e.g. basal metabolic rate, maximum life span).
We collected un‐incubated eggs (n = 1–21 eggs per species, median = 7) from 34 wild and captive bird species across 17 families and six orders to measure yolk THs [both triiodothyronine (T3) and thyroxine (T4)], compiled life‐history trait data from the literature and used Bayesian phylogenetic mixed models to test our hypotheses.
Our models indicated that both concentrations and total amounts of the two main forms of THs (T3 and T4) were higher in the eggs of migratory species compared to resident species, and total amounts were higher in the eggs of precocial species, which have longer prenatal developmental periods, than in those of altricial species. However, maternal yolk THs did not show clear associations with pace‐of‐life‐related traits, such as fecundity, basal metabolic rate or maximum life span.
We quantified interspecific variation in maternal yolk THs in birds, and our findings suggest higher maternal TH transfer is associated with the precocial mode of development and migratory status. Whether maternal THs represent a part of the mechanism underlying the evolution of precocial development and migration or a consequence of such life histories is currently unclear. We therefore encourage further studies to explore the physiological mechanisms and evolutionary processes underlying these patterns.
Estimation of points of departure (PoDs) from high-throughput transcriptomic data (HTTr) represents a key step in the development of next-generation risk assessment (NGRA). Current approaches mainly rely on single key gene targets, which are constrained by the information currently available in the knowledge base and make interpretation challenging as scientists need to interpret PoDs for thousands of genes or hundreds of pathways. In this work, we aimed to address these issues by developing a computational workflow to investigate the pathway concentration-response relationships in a way that is not fully constrained by known biology and also facilitates interpretation. We employed the Pathway-Level Information ExtractoR (PLIER) to identify latent variables (LVs) describing biological activity and then investigated in vitro LVs' concentration-response relationships using the ToxCast pipeline. We applied this methodology to a published transcriptomic concentration-response data set for 44 chemicals in MCF-7 cells and showed that our workflow can capture known biological activity and discriminate between estrogenic and antiestrogenic compounds as well as activity not aligning with the existing knowledge base, which may be relevant in a risk assessment scenario. Moreover, we were able to identify the known estrogen activity in compounds that are not well-established ER agonists/antagonists supporting the use of the workflow in read-across. Next, we transferred its application to chemical compounds tested in HepG2, HepaRG, and MCF-7 cells and showed that PoD estimates are in strong agreement with those estimated using a recently developed Bayesian approach (cor = 0.89) and in weak agreement with those estimated using a well-established approach such as BMDExpress2 (cor = 0.57). These results demonstrate the effectiveness of using PLIER in a concentration-response scenario to investigate pathway activity in a way that is not fully constrained by the knowledge base and to ease the biological interpretation and support the development of an NGRA framework with the ability to improve current risk assessment strategies for chemicals using new approach methodologies.
In vertebrates, thyroid hormones, including thyroxine (T4) and triiodothyronine (T3), are critical players in controlling different physiological processes such as development, growth, metabolism among others. There is evidence in mammals that thyroid hormones are also an important component of the hormonal system that controls reproduction, although studies in fish remain poorly investigated. Here we tested this hypothesis by investigating the effects of methimazole-induced hypothyroidism on the testicular function in adult D. rerio. Treatment of fish with methimazole, in vivo, significantly affected the progression of zebrafish spermatogenesis by inducing the accumulation of pre-meiotic cells, delaying cell differentiation and meiosis, as well as reducing the number of spermatozoa. The observed impairment of spermatogenesis by methimazole was correlated with significant changes in transcript levels for several genes involved in the control of reproduction. Using an in vitro approach, we also demonstrated that in addition to affecting the components of the brain-pituitary-peripheral axis, T3 also exerts direct action at the level of the testis. These results support the hypothesis that thyroid hormones are an essential component of multifactorial control of reproduction and testicular function in zebrafish and possibly other vertebrates.
During embryogenesis, incubation temperature and the hormonal environment influence gonadal differentiation of some reptiles, including all crocodilians. Current evidence suggests that aromatase, the enzyme that converts androgens to estrogens, has a role in sexual differentiation of species that exhibit temperature-dependent sex determination (TSD). During the temperature-sensitive period (TSP) of sex determination, we compared aromatase activity in the brain and gonads of putative male and female alligator embryos to determine if aromatase activity in the embryonic brain could provide the hormonal environment necessary for ovarian development in a TSD species. In addition, we assessed the pattern of aromatase activity in the brain and gonads of embryos treated with estradiol-17beta (E-2) and incubated at male-producing temperatures to compare enzyme activity in E2 sex-reversed females to control males and females. This has particular significance regarding wildlife species living in areas contaminated with suspected environmental estrogens. Gonadal aromatase activity remained low during the early stages of the TSP in both sexes and increased late in the TSP only in females. Aromatase activity in the brain increased prior to gonadal differentiation in both sexes. These results suggest that aromatase activity in the brain is not directly responsible for mediating differentiation of the gonad. E-2 exposure at male producing temperatures resulted in sex-reversed females that had intermediate gonad function and masculinized brain activity. This study indicates the need to examine multiple end points and to determine the persistence of developmental alterations in contaminant-exposed wildlife populations.
We have cloned the iodothyronine deiodinases type 2 (Dio2) and type 3 (Dio3), and the thyroid hormone receptors (TRα and TRβ) from the brain of the European sea bass and studied their tissue distribution by RT- PCR. These four transcripts were expressed in all central areas including neuroendocrine centres and the pituitary, as well as in photoreceptor organs and gonads.
We determined whether environmentally relevant concentrations of ammonium perchlorate alter development and metamorphosis in Xenopus laevis. Eggs and larvae were exposed to varying concentrations of ammonium perchlorate or control medium for 70 d. Most treatment-related mortality was observed within 5 d after exposure and was due in large part to reduced hatching success. The 5-and 70-d median lethal concentrations (LC50s) were 510 36 mg ammonium perchlorate/L and 223 13 mg ammonium perchlorate/L, respectively. Ammonium perchlorate did not cause any concentration-related developmental abnormalities at concentrations below the 70-d LC50. Ammonium perchlorate inhibited metamorphosis in a concentration-dependent manner as evident from effects on forelimb emergence, tail resorption, and hindlimb growth. These effects were observed after exposure to ammonium perchlorate concentrations in the parts-per-billion range, at or below concentrations reported in surface waters contaminated with ammonium perchlorate. Ammonium perchlorate significantly inhibited tail resorption after a 14-d exposure in the U.S. Environmental Protection Agency (U.S. EPA) Endocrine Disruptor Screening and Testing Committee (EDSTAC) Tier I frog metamorphosis assay for thyroid disruption in amphibians. We believe that ammonium perchlorate may pose a threat to normal development and growth in natural amphibian populations.
Significance
Androgens are primarily considered detrimental to women’s health. However, androgen-receptor KO mouse models have been used to establish that androgens are actually necessary for normal ovarian function and female fertility. Despite these observations, how androgens regulate female fertility is not known. Here we show that androgens promote follicular development via two mechanisms: ( i ) prevention of follicular atresia by inducing the expression of an antiapoptotic microRNA (miR), miR-125b ; and ( ii ) promotion of follicle growth by increasing follicle-stimulating hormone receptor levels in a transcription-independent fashion. These data considerably change our understanding of androgen effects in female reproduction, and help explain the ovarian physiology seen in patients with too little or too much androgen.
Thyroid hormones participate in regulating growth and homeostatic processes in vertebrates, including development and adult functioning of the reproductive system. Here we report a new stimulatory role of thyroid hormone on the proliferation of Sertoli cells (SCs) and single, type A undifferentiated spermatogonia (Aund) in adult zebrafish testes. A role for T3 in zebrafish testis is suggested by in situ hybridization studies, which localized thyroid receptor α (thrα) in SCs and the β (thrβ) mRNA in Sertoli and Leydig cells. Using a primary zebrafish testis tissue culture system, the effect of T3 on steroid release, spermatogenesis, and the expression of selected genes was evaluated. Basal steroid release and Leydig cell gene expression did not change in response to T3. However, in the presence of FSH, T3 potentiated gonadotropin-stimulated androgen release as well as androgen receptor (ar) and 17α-hydroxylase/17,20 lyase (cyp17a1) gene expression. Moreover, T3 alone stimulated the proliferation of both SCs and Aund, potentially resulting in newly formed spermatogonial cysts. Additional tissue culture studies demonstrated that Igf3, a new, gonad-specific member of the IGF family, mediated the stimulatory effect of T3 on the proliferation of Aund and SCs. Finally, T3 induced changes in connexin 43 mRNA levels in the testis, a known T3-responsive gene. Taken together, our studies suggest that T3 expands the population of SCs and Aund involving Igf signaling and potentiates gonadotropin-stimulated testicular androgen production as well as androgen sensitivity.
Abstract Drastichová J., Z.Svobodová, M.Groenland, R. Dob‰íková, V. Îlábek, D. Weissová, M. Szotkowská: Effect of Exposure to Bisphenol A and 17ß-estradiol on the Sex Differentiation in Zebrafish (Danio rerio). Acta Vet. Brno 74, 2005: 287-291. The effects of bisphenol,A and 17ß-estradiol on sex ,differentiation were investigated in the zebrafish, Danio rerio. The 20-day-old fry with undifferentiated gonads were fed with food containing bisphenol A at the dose of 500, 1000, 2000 mg⋅kg, diet was 1.4:1 (p = 0.31), 3.8:1 (p = 0.01) and 11.5:1 (p < 0.01). Bisphenol A induced feminization of the fry at the two highest doses tested. Endocrine disrupters, 17ß-estradiol, fish, sex ratio Assessment of fish reproductive performance,is increasingly used to evaluate the impact
Several environmental xenobiotics have been found to affect the metamorphosis of amphibians. In this study we exposed tadpoles of the Common frog Rana temporaria from hatching to metamorphosis to two known endocrine disruptors, the estrogenic pharmaceutical 17� -ethinylestradiol and the antiandrogenic/antiestrogenic fungicide prochloraz to determine their effect on 1) days to metamorphosis and size at metamorphosis, 2) body concentrations of triiodothyronine (T3) and corticosterone, and 3) thyroid morphology. We found effects of both compounds on each of these response variables. A low dose of prochloraz (115 μg/l) and all doses of ethinylestradiol also caused a delay in metamorphosis. T3 levels were elevated in metamorphs exposed to high concentration of prochloraz (252 μg/l) but the group showed a delay in metamorphosis. A low dose of prochloraz (115 μg/l) and all doses of ethinylestradiol also caused a delay in metamorphosis but no changes in T3 levels. The delayed metamorphs weighed more than controls. Thyroid histology revealed significant differences in the high prochloraz exposure group only. Ethinylestradiol and prochloraz, however not in environmentally relevant doses, may therefore impact the thyroid axis, and may cause other sublethal effects especially in combination with other stressors likely encountered.
On Day 5 of incubation fertilized eggs of single-comb White Leghorn hens were injected with an aromatase inhibitor (AI) and the sex reversal effect and levels of mRNA of P45017α-hydroxylase(P45017α) and P450aromatase(P450arom) were evaluated by observation of gonadal phenotype and by Northern and slot blot analysis. Individual genetic sex was evaluated by Southern blot analysis of red blood cells using a female sex chromosomal W-specific DNA probe. Saline injection had no sex reversal effect, whereas AI injection resulted in 50% sex reversal from genetic female but no effect on male. Levels of P45017αmRNA were high in both ovary and testis in the control group but these levels were lowered significantly in ovary, testis, and sex-reversed gonad (testis) in the AI-treated group. On the other hand, levels of P450arommRNA in the ovary were higher than those in the testis of the control group. AI treatment significantly suppressed ovarian levels of P450arommRNA. Although estradiol alone failed to prevent the phenotypic male to female change, coadministration of estrogen suppressed the sex-reversal effect of AI and restored mRNA levels of P450aromin the ovary to control levels. These results suggest that expression of P450arommRNA and estrogen plays an important role in sex differentiation of the female gonad of the chicken.
In the red-eared slider turtle (Trachemys scripta), a species with temperature-dependent sex determination (TSD), the expression of the aromatase gene during gonad development is strictly limited to the female-producing temperature. The underlying mechanism remains unknown. In this study, we identified the upstream 5'-flanking region of the aromatase gene, gonad-specific promoter, and the temperature-dependent DNA methylation signatures during gonad development in the red-eared slider turtle. The 5'-flanking region of the slider aromatase exhibited sequence similarities to the aromatase genes of the American alligator, chicken, quail, and zebra finch. A putative TATA box was located 31 bp upstream of the gonad-specific transcription start site. DNA methylation at the CpG sites between the putative binding sites of the fork head domain factor (FOX) and vertebrate steroidogenic factor 1 (SF1) and adjacent TATA box in the promoter region were significantly lower in embryonic gonads at the female-producing temperature compared the male-producing temperature. A shift from male- to female-, but not from female- to male-, producing temperature changed the level of DNA methylation in gonads. Taken together these results indicate that the temperature, particularly female-producing temperature, allows demethylation at the specific CpG sites of the promoter region which leads the temperature-specific expression of aromatase during gonad development.
The main objectives of the present study were to investigate the effects of 6-n-propyl-2-thiouracil (PTU) on Sertoli cell pro- liferation, germ cell number, and testis size in Nile tilapias (Oreochromis niloticus). In this regard, young fish ( 1gB W and 3.5 cm total in length) were treated for a period of 40 d with different concentrations (100 and 150 ppm) of PTU. The animals were killed and analyzed on d 1, 30, 40, 98, and 208 after the beginning of the treatment. On d 30 and 40 the sper- matogenic process was delayed in fish treated with PTU com- pared with the control group. Also at these periods, treated tilapia had decreased (P < 0.05) body weight and total length. On d 98 body weight and total length had recovered in PTU- treated fish and were similar (P > 0.05) to those of the controls. However, testis weight and gonadosomatic index (testis mass/ body weight) were approximately 100% higher (P < 0.05) in treated tilapia. Similarly, the area occupied by seminiferous tubules, the number of Sertoli cells and germ cells per cyst, and the number of Leydig cells per testis were significantly (P < 0.05) greater in treated fish. Nevertheless, nuclear vol- ume and individual Leydig cell volume were significantly lower (P < 0.05) in tilapia receiving PTU treatment. Compared with controls, at 208 d all parameters analyzed presented the same trend as that observed at 98 d. In general, at 98 d the different PTU concentrations used during the treatment pe- riod induced similar effects. However, at 208 d the mean val- ues observed for several parameters were significantly higher (P < 0.05) in fish exposed to 150 ppm. Probably due to the higher density of Sertoli cells per cyst in treated tilapia, these cells presented a smaller (P < 0.05) nucleolus and a trend to decrease its support capacity (efficiency). However, the mei- otic index (germ cell loss during the two meiotic divisions) was similar (P > 0.05) in the three groups of fish investigated. Remarkably, the results found in tilapia were similar to those found for rats treated with PTU. This suggests strongly that the mechanisms of control of Sertoli cell and Leydig cell pro- liferation seem to be preserved during vertebrate evolution. (Endocrinology 143: 970 -978, 2002)
Most anurans have no identified sex-markers; therefore, al- ternative methods for identification of early changes in sex ratios are required. In this study, Lithobates sylvaticus and Si- lurana tropicalis tadpoles were sampled at different develop- mental stages covering the entire process of sex differentia- tion. Three candidate genes known to be involved in sex dif- ferentiation in other vertebrate species were selected to develop a method to identify phenotypic sex in frogs: cyto- chrome p450 aromatase (cyp19), forkhead box L2 (foxl2) and the cytochrome 17-alpha-hydroxylase/17,20 lyase (cyp17). Cloning of these genes revealed nucleotide identity values ranging between 75–97% when compared to other amphib- ian species. Gene expression of cyp17, cyp19 and foxl2 in L. sylvaticus adult gonads and gonad-mesonephros complex (GMC) of tadpoles was analyzed by real-time RT-PCR. Results showed clear sexually dimorphic patterns in the expression of the 3 genes. Our analysis reveals that GMC gene expres-sion levels of cyp19 alone can be used as a robust predictor of phenotypic sex in L. sylvaticus tadpoles. In addition, we validated this method measuring cyp19 mRNA levels in S. tropicalis GMCs. We propose measuring cyp19 as a tool to study the effects of chemical contaminants (including endo-crine disrupting compounds) on amphibian gonadal devel-opment and sex ratios in the future.
Numerous studies using laboratory-reared tadpoles have shown the importance of thyroid hormones (TH), thyroid receptors (TR), and deiodinase (Dio) enzymes during anuran metamorphosis. Our study focuses on the analysis of thyroid-related genes in tadpoles of wild Wood Frogs (Lithobates sylvaticus (LeConte, 1825); also known as Rana sylvatica (Cope, 1889)) during metamorphosis. Results showed that, in concordance with laboratory-reared studies, thyroid receptor beta (trb) gene expression profiles presented the most marked changes. At climax and compared with premetamorphic stages, brains, tails, and gonad–mesonephros complex (GMC) tissues increased trb expression levels 5-, 21-, and 41-fold, respectively (p < 0.05). In addition, gene expression levels of brain deiodinase type II and III showed opposite trends, where 3-fold decrease and 10-fold increase were, respectively, found. This finding supports the idea that thyroid hormone, as it has been demonstrated in laboratory-reared tadpoles, is also involved in natural metamorphosis in wild tadpoles. Interestingly, and contrary to our predictions, we observed that whole brain corticotropin-releasing factor (crf) and crf receptor 1 (crfr1) gene expression levels significantly decrease through metamorphosis in wild L. sylvaticus tadpoles. Further analyses are required to determine if a role of TH in the timing of anuran gonadal development exists, as well as the importance of cell-specific and tissue-specific expression of crf and crfr1 to metamorphosis.
Various synthetic chemicals released to the environment can interfere with the endocrine system of vertebrates. Many of these endocrine disrupting compounds (EDCs) exhibit estrogenic activity and can interfere with sexual development and reproductive physiology. More recently, also chemicals with different modes of action (MOAs), such as antiestrogenic, androgenic and antiandrogenic EDCs, have been shown to be present in the environment. However, to date EDC-research primarily focuses on exposure to EDCs with just one MOA, while studies examining the effects of simultaneous exposure to EDCs with different MOAs are rare, although they would reflect more real, natural exposure situations. In the present study the combined effects of estrogenic and antiestrogenic EDCs were assessed by analyzing the calling behavior of short-term exposed male Xenopus laevis. The estrogenic 17α-ethinylestradiol (EE2), and the antiestrogenic EDCs tamoxifen (TAM) and fulvestrant (ICI) were used as model substances. As previously demonstrated, sole EE2 exposure (10-10 M) resulted in significant alterations of the male calling behavior, including altered temporal and spectral parameters of the advertisement calls. Sole TAM (10-7 M, 10-8 M, 10-10 M) or ICI (10-7 M) exposure, on the other hand, did not affect any of the measured parameters. If frogs were co-exposed to EE2 (10-10 M) and TAM (10-7 M) the effects of EE2 on some parameters were abolished, but co-exposure to EE2 and ICI (10-7 M) neutralized all estrogenic effects. Thus, although EDCs with antiestrogenic MOA might not exhibit any effects per se, they can alter the estrogenic effects of EE2. Our observations demonstrate that there is need to further investigate the combined effects of EDCs with various, not only opposing, MOAs as this would reflect realistic wildlife situations.
Several environmental xenobiotics have been found to affect the metamorphosis of amphibians. In this study we exposed tadpoles of the Common frog Rana temporaria from hatching to metamorphosis to two known endocrine disruptors, the estrogenic pharmaceutical 17-ethinylestradiol and the antiandrogenic/antiestrogenic fungicide prochloraz to determine their effect on 1) days to metamorphosis and size at metamorphosis, 2) body concentrations of triiodothyronine (T 3) and corticosterone, and 3) thyroid morphology. We found effects of both compounds on each of these response variables. A low dose of prochloraz (115 μg/l) and all doses of ethinylestradiol also caused a delay in metamorphosis. T 3 levels were elevated in metamorphs exposed to high concentration of prochloraz (252 μg/l) but the group showed a delay in metamorphosis. A low dose of prochloraz (115 μg/l) and all doses of ethinylestradiol also caused a delay in metamorphosis but no changes in T 3 levels. The delayed metamorphs weighed more than controls. Thyroid histology revealed significant differences in the high prochloraz exposure group only. Ethinylestradiol and prochloraz, however not in environmentally relevant doses, may therefore impact the thyroid axis, and may cause other sublethal effects especially in combination with other stressors likely encountered.
The present study investigated the effects of triiodothyronine (T3) on pituitary gonadotropin (GTH) subunits, thyroid stimulating hormone (TSH) β subunit, and growth hormone (GH) mRNA levels, as well as gonadal steroid secretion during different stages of reproduction in goldfish. Goldfish pituitary cells cultured with T3 exhibited lower tshβ mRNA levels in all reproductive stages and lower luteinising hormone β (lhβ) mRNA levels in early recrudescence, whereas gh and fshβ mRNA levels were not altered. T3 injections significantly reduced circulating oestrogen (OE2) concentrations in early and mid recrudescent male goldfish, but were without effect on the circulating level of OE2 in female fish. T3 injections also reduced circulating levels of testosterone in both male and female goldfish during the mid stage of gonadal recrudescence. In vitro culture of goldfish ovarian follicles at the late stage of gonadal recrudescence, in the presence of T3, resulted in reduced OE2 secretion; no consistent effect of T3 on testosterone secretion was observed in cultured goldfish ovarian follicles and testis. These findings support the hypothesis that T3 impairs reproduction by inhibiting production of gonadal steroids and pituitary luteinising hormone production in goldfish. Mol. Reprod. Dev. 79: 592-602, 2012. © 2012 Wiley Periodicals, Inc.
Increasing evidence derived from experimental and clinical studies suggests that the hypothalamic-pituitary-thyroid axis (HPT) and the hypothalamic-pitutitary-ovarian axis (HPO) are physiologically related and act together as a unified system in a number of pathological conditions. The suggestion that specific thyroid hormone receptors at the ovarian level might regulate reproductive function, as well as the suggested influence of estrogens at the higher levels of the HPT axis, seems to integrate the reciprocal relationship of these two major endocrine axes. Both hyper- and hypothyroidism may result in menstrual disturbances. In hyperthyroidism the most common manifestation is simple oligomenorrhea. Anovulatory cycles are very common. Increased bleeding may also occur, but it is rare. Hypothyroidism in girls can cause alterations in the pubertal process; this is usually a delay, but occasionally it can result in pseudoprecocious puberty. In mature women hypothyroidism usually is associated with abnormal menstrual cycles characterized mainly by polymenorrhea, especially anovulatory cycles, and an increase in fetal wastage.
Temporal profiles of thyroidal status and reproductive function have been compared for many species of teleost and non-teleost fish of both genders. Despite major interspecies differences in reproductive biology and reproductive strategy, and problems associated with evaluation of thyroidal status, significant temporal relationships exist for most species between thyroidal status and gonadal state over at least certain phases of the reproductive cycle. While suggestive, these general correlations do not establish any causal relationship between the two systems. Experimental studies carried out mainly on female teleosts, but including species with different reproductive strategies, indicate that a certain thyroidal status may be required for early gonadal (oocyte) development and reproduction to proceed. For the rainbow trout, T3 is more active in this regard than T4. T3 is particularly effective at low GTH concentrations, and may play a key role at the onset of gonadal development and commitment to reproduction. One component of T3 action involves cellular mechanisms independent of de novo protein synthesis. T3 may achieve this effect by blocking PDE and thereby decreasing the rate of degradation of GTH-generated intracellular cAMP. In other species, THs may be required during the later stages of vitellogenesis. At this stage TH actions seem to depend on de novo protein synthesis. Final oocyte maturation and possibly spawning behaviour may also be influenced by TH even though the TH plasma levels are low at this time. After reproduction there is usually an increase in thyroidal status associated with the growth phase of the life cycle. In several species, including salmonids, there is a reciprocal relationship between thyroidal status and plasma E2 levels. Experimental data show that E2 contributes to the depression in plasma T3 by modifying several aspects of the peripheral metabolism of TH and inhibiting hepatic 5′-deiodinase (5′D) converting T4 to T3. T and other androgens tend to enhance T3 formation and thyroidal status, and as such may contribute to somatic growth following reproduction (Fig. 4). TH are associated with metabolism and energy balance; reproductive hormones are responsible for the development of gonads and reproduction. Because reproduction is energetically demanding, direct and indirect interactions between the two systems are anticipated. The general role of T3 may be to signal metabolic competence to proceed with the next stage of reproduction. The most fundamental specific role may be to enhance GTH actions in initiating early gonadal development, but in some species TH may play permissive roles in vitellogenesis, final gonadal maturation and spawning. However, TH are also growth-promoting. At certain phases of the reproductive cycle, when energy reserves are being depleted and energy is being channelled to the gonads, it may be advantageous for steroid hormones (E2) to contribute to suppression of thyroidal status. Clearly, sweeping generalizations concerning the relationship between reproductive function and thyroidal status are likely to be misleading and unrealistic. Because of the great differences in reproductive biology, strategies of energy allocation, environment and behaviour between fish species, it is necessary to investigate each taxon in its own right.
This paper reviews the current knowledge concerning the endocrine and environmental regulations of both gonadal sex differentiation
in gonochoristic and sex inversion in hermaphroditic fish. Within the central nervous system, gonadotropins seem to play a
role in triggering sex inversion in hermaphroditic fish. In gonochorists, although potentially active around this period,
the hypothalamo-pituitary axis is probably not involved in triggering sex differentiation. Although steroids and steroidogenic
enzymes are probably not the initial triggers of sex differentiation, new data, including molecular approaches, have confirmed
that they are key physiological steps in the regulation of this process. Environmental factors can strongly influence sex
differentiation and sex inversion in gonochoristic and hermaphroditic fish, respectively. The most important environmental
determinant of sex would appear to be temperature in the former species, and social factors in the latter. Interactions between
environmental factors and genotype have been suggested for both gonochoristic and hermaphroditic fish.
To test the hypothesis of female homogamety in Rana pipiens, males produced by gynogenesis or testosterone treatment were mated with normal females. Gynogenesis, which was expected to produce all females, was found to yield a ratio of 3:6:1 females to males and thus was a source of phenotypic males having the female genotype. In addition, the sex of R. pipiens tadpoles can be altered to produce all females or all males by the administration of estrogen or testosterone, respectively, at 50 μg/liter from Taylor-Kollros stage I to stage VII (for females) or stage IX (for males). Matings using certain testosterone-treated males produced primarily female offspring, demonstrating that these males were in reality sex-reversed females, thus establishing the XX-XY sex determining mechanism for R. pipiens. The few males produced by such matings illustrate other aspects of leopard frog reproductive biology.
It has been well established that thyroid hormones play an important role in regulating the onset of puberty and reproductive function in birds. In mammals it has been shown that transient hypothyroidism induced with the reversible goitrogen 6-N-propyl-2-thiouracil (PTU) can result in tremendous increases in testis size and sperm production and that the timing of hypothyroidism must correspond to the period of Sertoli cell proliferation. As the period of Sertoli cell proliferation is not precisely known in the fowl, an experiment was conducted to determine whether chicken testes have a similar window of sensitivity to PTU treatment. Broiler breeder male chicks (Peterson) were placed in floor pens at one day of age and reared according to the breeder's management guide for the entire 28-wk duration (controls) or up to the point of dietary treatment with PTU (0.1% w:w) for 6 wk that began at 2-wk intervals (2-8, 4-10, 6-12, 8-14, and 10-16 wk of age); after treatment, birds were returned to feed restriction and photostimulated at 20 wk of age. Birds were bled and killed, and testes were collected at 4-wk intervals. At 28 wk, one testis was fixed for histological examination and one was immediately placed in liquid N2 for sperm counts. Treatment with PTU from 6 to 12 wk of age resulted in a 96% increase in mean testis weight at 28 wk of age (treated 39.3 +/- 4.1 g per testis vs. control 20.0 +/- 1.6 g per testis). These testes exhibited normal morphology and increased relative sperm production. Treatment with PTU from either 8 to 14 or 10 to 16 wk of age resulted in approximately a 35% increase in testis mass at 28 wk of age relative to the control value (27.2 +/- 2.0 g and 27.7 +/- 3.6 g vs. 20.0 +/- 1.6 g per testis, respectively). However, both of these groups clearly demonstrated precocious puberty and abnormal spermatogenesis. These results suggest that appropriately timed PTU treatment may result in permanent increases in testis size and sperm production in the domestic fowl.
The androgen 5 alpha-dihydrotestosterone (DHT) is a steroidogenic metabolite that has received little attention in non-mammalian species. DHT is produced by the reduction of the double-bond of testosterone by a group of enzymes called 5 alpha-reductases of which there can be multiple isoforms (i.e., srd5a1, srd5a2, and srd5a3). Data from amphibians suggest that the expression of the srd5a genes occurs in early development, and continues until adulthood; however insufficient data exist in fish species, where DHT is thought to be relatively biologically inactive. Here, we demonstrate that fathead minnow (FHM; Pimephales promelas) developing embryos and adults express srd5a enzyme isoforms. During FHM embryogenesis, both srd5a1 and srd5a3 mRNA levels were significantly correlated in expression levels while srd5a2 showed a more unique pattern of expression. In adult FHMs, males had significantly higher levels of srd5a2 in the liver and gonad compared to females. In the male and female liver, transcript levels for srd5a2 were more abundant compared to srd5a1 and srd5a3, suggesting a prominent role for srd5a2 in this tissue. Interestingly, the ovary expressed higher mRNA levels of srd5a3 than the testis. Thus, data suggest that srd5a isoforms can show sexually dimorphic expression patterns in fish. We also conducted a literature review of the biological effects observed in embryonic and adult fish and amphibians after treatments with DHT and DHT-related compounds. Treatments with DHT in teleost fishes and amphibians have resulted in unexpected biological responses that are characteristic of both androgens and anti-androgens. For example, in fish DHT can induce vitellogenin in vitro from male and female hepatocytes and can increase 17β-estradiol production from the teleost ovary. We propose, that to generate further understanding of the roles of DHT in non-mammals, studies are needed that (1) address how DHT is synthesized within tissues of fish and amphibians; (2) examine the full range of biological responses to endogenous DHT, and its interactions with other signaling pathways; and (3) investigate how DHT production varies with reproductive stage. Lastly, we suggest that the Srd5a enzymes can be targets of endocrine disruptors in fish and frogs, which may result in disruptions in the estrogen:androgen balance in aquatic organisms.
Metamorphosis in the flounder has often been compared with the transition of tadpoles into frogs. The dorsal fin rays of the Japanese flounder (Paralichthys olivaceus) elongate during prometamorphosis when thyroid hormone levels are low, and are resorbed during metamorphic climax when thyroid hormone levels are high. Using an in vitro system for the culture of the flounder fin rays, we have examined how various hormones affect the resorption process. Both thyroxine (T4) and triiodothyronine (T3) directly stimulated fin ray shortening, T3 being more potent than T4. Other hormones, such as prolactin, cortisol and sex steroids, did not directly affect the resorption process but modified the tissue's response to thyroid hormones. Similar observations were obtained from in vivo studies. We also monitored the changes in the whole body concentrations of various hormones during early development and metamorphosis, and related these with the thyroid hormone profiles in order to get a better picture of their interactions. The gaps in the present status of research on the role of thyroid hormones during metamorphosis in the Japanese flounder are also discussed.
Developmental constraints are limitations on phenotypic variability resulting from developmental mechanisms that produce biases in phenotypic variants and hence evolution. These constraints ultimately limit the available phenotypes on which selection can act. Because hormones play important roles in many developmental processes, there is a great potential for hormonal mechanisms to produce (or act as) developmental constraints. In the current study, I present two examples to show how hormones may produce developmental constraints on evolution in the Anura. One example (a universal constraint in the Anura), examines evidence that thyroid hormones are required for sex differentiation and reproduction in frogs. The thyroid hormone requirement for these processes may prevent the evolution of neoteny in anurans. The second example (a local constraint) examines the mechanisms underlying sexual dichromatism in the genus Hyperolius (Hyperoliidae) and shows how the evolution of sexual dichromatism is limited by the hormonal mechanisms regulating pigmentation
Although the important role of thyroid hormones in regulating metamorphosis of amphibian larvae is well known, it has not been clearly established if thyroid hormones have any function in the activities of adult amphibian tissues. We now describe a strong effect of 3,3',5-triiodothyronine (T3) on adult Xenopus liver cells. Low doses of T3 rapidly (within 6–12 h) potentiate the activation of vitellogenin (Vit) genes by estradiol-17β (E2) in primary cultures of adult male and female Xenopus hepatocytes. This effect is developmentally regulated and is first manifested during metamorphic climax. In an attempt to explain this potentiation, we find that T3 also upregulates thyroid hormone receptor β, but not α, transcripts and rapidly enhances the autoinduction of estrogen receptor (ER) mRNA in adult Xenopus hepatocytes. In transient transfection of the Xenopus cell line XTC-2 with an estrogen response element — chloramphenicol transacetylase (ERE-CAT) construct T3 was found to potentiate the transcription by E2 from the transfected ERE, thus suggesting that it enhances the accumulation of functional ER. We conclude that T3 can function in adult amphibian tissues, and discuss the significance of thyroid hormone potentiation of responses to estrogen in reproductive processes.
Oestrogens are now recognised to be able to initiate rapid, fast responses, in addition to their classical, longer term actions. There is a growing appreciation of the potential implications of this mode of action for oestrogenic signalling in both neuronal and non-neuronal systems. As such there has been much effort to determine the mechanisms that are critical for transducing these rapid effects into cellular responses. Recently, an orphan G-protein coupled receptor (GPCR), termed GPR30, was identified as an oestrogen sensitive receptor in cancer cells. This receptor, now term G-protein estrogen receptor 1 (GPER1) has been the subject of many investigations, and a role for this receptor in the nervous system is now emerging. In this review, we wish to highlight some of the more recent advances in our understanding of the distribution and subcellular localisation of this receptor in the brain, as well as some of the evidence for the potential role that this receptor may play in the brain. We will then go on to discuss some of the controversies surrounding the pharmacology of this receptor, and attempt to reconcile them by suggesting that the "agonist-specific coupling" model of GPCR function may provide a potential explanation for some of the divergent reports of GPER1 pharmacology. This article is protected by copyright. All rights reserved.
The hippocampus is an area of the brain that undergoes dramatic plasticity in response to experience and hormone exposure. The hippocampus retains the ability to produce new neurons in most mammalian species and is a structure that is targeted in a number of neurodegenerative and neuropsychiatric diseases, many of which are influenced by both sex and sex hormone exposure. Intriguingly, gonadal and adrenal hormones affect the structure and function of the hippocampus differently in males and females. Sex differences in the effects of steroid hormones to modulate hippocampal plasticity should not be completely surprising as the physiology of males and females is different, with the most notable difference that the females gestate and nurse the offspring. Furthermore, reproductive experience (pregnancy and mothering) results in permanent changes to the maternal brain, including the hippocampus in females. Adult neurogenesis in the hippocampus is regulated by both gonadal and adrenal hormones in a sex and experience-dependent way. This review outlines the ability of gonadal and stress hormones to modulate multiple aspects of neurogenesis (cell proliferation and cell survival) in both male and female rodents. The function of adult neurogenesis in the hippocampus is linked to spatial memory and depression and this review provides early evidence of the functional links between hormonal modulation of neurogenesis to regulate cognition and stress. This article is protected by copyright. All rights reserved.