ArticleLiterature Review

Mechanisms of crosstalk between endocrine systems: Regulation of sex steroid hormone synthesis and action by thyroid hormones

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... 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]. ...
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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.
... 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). ...
Article
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). ...
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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.
... Accumulating evidence from animal studies has indicated that neonatal thyroid function influences gonadal differentiation and reproductive function (1)(2)(3)(4). Administration of large doses of thyroxine to neonatal female rats has been shown to delay vaginal opening and first estrus (5). Neonatal 3,5,3'triiodothyronine excess in male rats was associated with a decrease in adult testis size (6), and might promote the apoptosis of germ cells in the neonatal testis (7). ...
... The inverse associations between THs and female AGI might be explained by the effects of THs on sex steroid hormone synthesis (1). Female AGD development during the fetal masculinization window was also suggested to be affected by androgen concentrations (39). ...
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Background Evidence from animal studies has indicated that neonatal thyroid function is vital for the reproductive development. Anogenital distance (AGD), a sensitive biomarker of the fetal hormonal milieu, can be used to predict adult reproductive disorders. However, few human studies have examined the association between neonatal thyroid function and AGD. We aimed to explore their associations in a birth cohort study. Methods Concentrations of thyroid stimulating hormone (TSH) and thyroid hormones (THs), including total triiodothyronine (TT 3 ), total thyroxine (TT 4 ), free triiodothyronine (FT 3 ), and free thyroxine (FT 4 ) were measured in cord plasma in the Shanghai-Minhang Birth Cohort. The offspring AGD (AGD AP [anus–penis] and AGD AS [anus–scrotum] for boys and AGD AC [anus–clitoris] and AGD AF [anus–fourchette] for girls), body weight and anogenital index (AGI = AGD/weight [mm/kg]) were obtained at each follow-up visit. In total, 344 children (194 boys and 150 girls) with cord plasma concentrations of THs and TSH and at least one AGD measurement at birth and at 6, 12, and 48 months of age were included. Multiple linear regression and generalized estimating equation (GEE) models were used to examine the associations of cord plasma concentrations of THs and TSH with AGI. Results Multiple linear regression models showed inverse associations of TT 4 , FT 3 , and FT 4 with female AGI, although statistical significance was only reached at birth, 6 and 48 months of age. These associations were also found in GEE models: higher TT 4 and FT 4 concentrations were associated with lower AGI AC (TT 4 : β = -0.27, 95% CI: -0.50, -0.03 for middle vs . lowest tertile; FT 4 : β = -0.38, 95% CI: -0.61, -0.16 for middle and β = -0.30, 95% CI: -0.55, -0.04 for highest vs . lowest tertile). Besides, girls with the highest tertile of FT 3 concentrations had lower AGI AF than those with the lowest tertile (the highest vs . lowest tertile: β = -0.22, 95% CI: -0.36, -0.08). Positive associations between TSH and AGI at birth and at 12 months of age were observed in boys. Conclusions This study provides further evidence on the effects of neonatal thyroid function on reproductive development at an early life stage.
... Indeed, direct crosstalk, where a component of a signaling pathway is shared by two or more signaling pathways, among the HPT and HPG axes is evident in all clades of vertebrates from fish to reptiles to mammals (Cooke et al., 2004;Cyr and Eales, 1996;Duarte-Guterman et al., 2014;Flood et al., 2013;Sun et al., 2016). Despite these interactions among axes, the HPT and HPG axes are often studied independently, with the HPT axis mainly known for its role in metabolism, growth, and development while the HPG axis is well-known for its role in sexual development, reproduction, and behavior. ...
... Comparatively little is known regarding estrogen effects on the HPT axis of non-mammalian vertebrates. Several studies on TH-dependent amphibian metamorphosis in Pipids and Ranids using 17β-estradiol or the synthetic estrogens, 17α-ethinylestradiol or DES, at physiological or supraphysiological levels, noted a decrease in the rate of metamorphosis (Brande-Lavridsen et al., 2010;Duarte-Guterman et al., 2014;Gray and Janssens, 1990;Hogan et al., 2008;Sharma and Patiño, 2010;Tompsett et al., 2012). When measured, no significant differences in total or free T 3 in plasma were observed (Brande-Lavridsen et al., 2010) despite competitive estrogen binding to Ttr (Yamauchi et al., 2000). ...
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Thyroid hormones (THs) are important regulators of growth, development, and homeostasis of all vertebrates. There are many environmental contaminants that are known to disrupt TH action, yet their mechanisms are only partially understood. While the effects of Endocrine Disrupting Chemicals (EDCs) are mostly studied as “hormone system silos”, the present critical review highlights the complexity of EDCs interfering with TH function through their interactions with other hormonal axes involved in reproduction, stress, and energy metabolism. The impact of EDCs on components that are shared between hormone signaling pathways or intersect between pathways can thus extend beyond the molecular ramifications to cellular, physiological, behavioral, and whole-body consequences for exposed organisms. The comparatively more extensive studies conducted in mammalian models provides encouraging support for expanded investigation and highlight the paucity of data generated in other non-mammalian vertebrate classes. As greater genomics-based resources become available across vertebrate classes, better identification and delineation of EDC effects, modes of action, and identification of effective biomarkers suitable for HPT disruption is possible. EDC-derived effects are likely to cascade into a plurality of physiological effects far more complex than the few variables tested within any research studies. The field should move towards understanding a system of hormonal systems’ interactions rather than maintaining hormone system silos.
... Moreover, estrogen actions are regulated by two different types of intracellular receptors, ERα and ERβ (Johnson, 1990;Proszkowiec-Węglarz et al., 2005). Furthermore, thyroid hormone (TH) plays an important role in regulating the gonadal growth/development and reproductive axis in female birds (Duarte-Guterman et al., 2014;Sechman et al., 2011;Sechman, 2013). Thyroid suppression in adult hens is associated with reduced ovary weight and egg production and even laying cessation (McNabb, 2007;Peebles et al., 1994). ...
... Moreover, exogenous T3 decreased E2 levels and caused atretic follicles (McNabb, 2007). In addition, T3 is associated with changes of 3β-HSD and P450arom mRNA expression in ovary (Duarte-Guterman et al., 2014;Sechman et al., 2011;Sechman, 2013). ...
Article
Lead (Pb) is well-recognized for its great hazards to human and wildlife health. It has negative influences on multiple organs and systems of birds. Especially, lead exposure caused adverse impacts on bird reproduction. In this study, one week old female Japanese quails were randomly allocated into four groups and each group was respectively fed with 0, 50 ppm, 500 ppm and 1000 ppm Pb in drinking water for 36 days to determine the effects of chronic lead exposure on ovarian development and function. The results showed that Pb did accumulate in the ovary and ovarian development was delayed by high dose lead exposure (500 ppm and 1000 ppm). Moreover, high Pb dosage induced ovarian histopathological damages characterized by granulosa cells disorganization, follicle atresia and interstitial cell degeneration. Meanwhile, the concentration of estradiol (E2) was significantly decreased and mRNA levels of genes involved with ovarian steroidogenesis were significantly down-regulated by high concentration Pb. In addition, Pb exposure caused increasing cell apoptosis and significant changes of the expression of genes involved with cell death in the ovary. High dose Pb exposure also inhibited thyroid hormone release and disrupted ovarian thyroid deiodination apart from causing thyroid histopathological injury such as follicular deformation and atrophy. The study indicated that Pb might cause ovarian malfunction by inducing ovary and thyroid microstructural damages, thyroid hormone and estrogen release inhibition and ovarian steroidogenesis disruption.
... Emerging and legacy contaminants can also potentially interfere with the role of thyroid hormones in reproduction, as suggested by Duarte-Guterman et al. (2014). Crosstalk between the HPT and HPG axes can potentially complicate our understanding and interpretation of the responses of fish to contaminants and their implication for fish health, particularly in complex exposure scenarios such as experienced by fish in the AOC. ...
... The potential for cross regulation among the various neurological and endocrine systems in vertebrates is established (León-Olea et al. 2014;Castañeda Cortés et al. 2014). Specifically, there is evidence, albeit some of it conflicting, that crosstalk occurs between the thyroid and reproductive systems (Yu et al. 2015;Raine 2011;Marlatt et al. 2012;Langlois et al. 2011;Duarte-Guterman et al. 2014;Bandyopadhyay et al. 1991). Gong et al. (2016) mentioned several studies that linked effects on thyroid hormones to reduced fecundity in goldfish (Habibi et al. 2012), effects on multiple reproductive hormones in goldfish, including reduced E2 concentrations (Nelson et al. 2010), and effects on sexual maturation in female walleye (Sander vitreus) from downstream of a pulp and paper mill (Picard-Aitken et al. 2007). ...
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The St. Lawrence River, at Cornwall Ontario, has accumulated sediment contaminants, mainly mercury (Hg) and polychlorinated biphenyls (PCBs), from industrial point sources over many years. Although those sources are past, the river at Cornwall remains an Area of Concern (AOC). Because of remediation and other changes in the AOC, improved knowledge of contaminants in wild-fish and their putative links to health effects could help decision makers to better assess the AOC’s state. Thus, we compared tissue concentrations of Hg, PCBs, morphometric measures of health, and biomarkers of exposure, metabolic-, and reproductive health in native brown bullhead (Ameiurus nebulosus) from the AOC to those of upstream reference fish. Linear discriminant analysis separated the adult fish of both sexes among upstream and downstream sites without misclassification. Burdens of total-Hg (all sites) and PCB toxic equivalents (downstream sites) exceeded the guidance for the protection of wildlife consumers. There were subtle effects of site on physiological variables, particularly in female fish. Total-Hg in tissue correlated negatively to plasma testosterone and 17β-estradiol in female fish at Cornwall: moreover, concentrations of both hormones were lower within the AOC compared to reference site fish. A similar effect on vitellogenin, which was uncorrelated to E2/T at the downstream sites, indicated the potential for reproductive effects. Downstream fish also had altered thyroidal status (T3, TSH, and ratio of thyroid epithelial cell area to colloid area). Despite spatial and temporal variability of the endocrine-related responses, these subtle effects on fish health within the AOC warrant further study.
... Metabolic disruption can also lead to reduced reproduction. While often not considered along with the thyroid axis, there is accumulating evidence indicating important regulation of the thyroid and reproductive axes (shown by the X; see also Flood et al., 2013 andDuarte-Guterman et al., 2014). The principal stimulatory neuropeptide gonadotropin-releasing hormone (GnRH) stimulates the pituitary synthesize the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (hatched arrows and associated pathways). ...
... In such events, skipping reproduction and allocating resources to growth might postpone reproductive event at the following year (Lardner and Loman, 2003), and maintaining reproduction might lead to progeny with reduced growth capacities (Regnault et al., 2018). Amphibians are particularly exposed to agrochemicals through water during periods critical for optimal metabolism, growth or reproduction, (Fan et al., 2007a(Fan et al., , 2007bHayes et al., 2011;Duarte-Guterman et al., 2014). ...
Article
Concern over global amphibian declines and possible links to agrochemical use has led to research on the endocrine disrupting actions of agrochemicals, such as fertilizers, fungicides, insecticides, acaricides, herbicides, metals, and mixtures. Amphibians, like other species, have to partition resources for body maintenance, growth, and reproduction. Recent studies suggest that metabolic impairments induced by endocrine disrupting chemicals, and more particularly agrichemicals, may disrupt physiological constraints associated with these limited resources and could cause deleterious effects on growth and reproduction. Metabolic disruption has hardly been considered for amphibian species following agrichemical exposure. As for metamorphosis, the key thyroid hormone-dependent developmental phase for amphibians, it can either be advanced or delayed by agrichemicals with consequences for juvenile and adult health and survival. While numerous agrichemicals affect anuran sexual development, including sex reversal and intersex in several species, little is known about the mechanisms involved in dysregulation of the sex differentiation processes. Adult anurans display stereotypical male mating calls and female phonotaxis responses leading to successful amplexus and spawning. These are hormone-dependent behaviours at the foundation of reproductive success. Therefore, male vocalizations are highly ecologically-relevant and may be a non-invasive low-cost method for the assessment of endocrine disruption at the population level. While it is clear that agrichemicals disrupt multiple endocrine systems in frogs, very little has been uncovered regarding the molecular and cellular mechanisms at the basis of these actions. This is surprising, given the importance of the frog models to our deep understanding of developmental biology and thyroid hormone action to understand human health. Several agrichemicals were found to have multiple endocrine effects at once (e.g., targeting both the thyroid and gonadal axes); therefore, the assessment of agrichemicals that alter cross-talk between hormonal systems must be further addressed. Given the diversity of life-history traits in Anura, Caudata, and the Gymnophiona, it is essential that studies on endocrine disruption expand to include the lesser known taxa. Research under ecologically-relevant conditions will also be paramount. Closer collaboration between molecular and cellular endocrinologists and ecotoxicologists and ecologists is thus recommended.
... This proof of conservation of the endocrine system on the one hand and the separated testing strategies on the other was the basic motivation for ERGO to develop the AOP network based on a cross-vertebrate class effects approach. The thyroid system was selected due to reasons already outlined, however cross-talk investigations with other conserved endocrine axes like the hypothalamus pituitary gonadal (HPG) axis could be included in the cross-class approach in the future as well [45]. Figure 3. Conservation of TH signaling in vertebrates. ...
... This proof of conservation of the endocrine system on the one hand and the separated testing strategies on the other was the basic motivation for ERGO to develop the AOP network based on a cross-vertebrate class effects approach. The thyroid system was selected due to reasons already outlined, however cross-talk investigations with other conserved endocrine axes like the hypothalamus pituitary gonadal (HPG) axis could be included in the cross-class approach in the future as well [45]. ...
Article
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ERGO (EndocRine Guideline Optimization) is the acronym of a European Union-funded research and innovation action, that aims to break down the wall between mammalian and non-mammalian vertebrate regulatory testing of endocrine disruptors (EDs), by identifying, developing and aligning thyroid-related biomarkers and endpoints (B/E) for the linkage of effects between vertebrate classes. To achieve this, an adverse outcome pathway (AOP) network covering various modes of thyroid hormone disruption (THD) in multiple vertebrate classes will be developed. The AOP development will be based on existing and new data from in vitro and in vivo experiments with fish, amphibians and mammals, using a battery of different THDs. This will provide the scientifically plausible and evidence-based foundation for the selection of B/E and assays in lower vertebrates, predictive of human health outcomes. These assays will be prioritized for validation at OECD (Organization for Economic Cooperation and Development) level. ERGO will re-think ED testing strategies from in silico methods to in vivo testing and develop, optimize and validate existing in vivo and early life-stage OECD guidelines, as well as new in vitro protocols for THD. This strategy will reduce requirements for animal testing by preventing duplication of testing in mammals and non-mammalian vertebrates and increase the screening capacity to enable more chemicals to be tested for ED properties.
... 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). ...
Article
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). ...
Article
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]. ...
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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]. ...
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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). ...
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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. ...
Article
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). ...
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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.
... 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 . ...
... In zebrafish, T3 increased transcript abundance of igfbp1 (Safian et al., 2016); the testes transcript also associated with TO severity. While there have been several studies on thyroid hormone actions and fish reproductive health (Duarte-Guterman et al., 2014;Tovo-Neto et al., 2018), more research is necessary to understand these interactions. ...
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Smallmouth bass Micropterus dolomieu were sampled from three sites within the Lake Erie drainage (Elk Creek, Twentymile Creek, and Misery Bay, an embayment in Presque Isle Bay). Plasma, tissues for histopathological analyses, and liver and testes preserved in RNALater® were sampled from 30 smallmouth bass (of both sexes) at each site. Liver and testes samples were analyzed for transcript abundance with Nanostring nCounter® technology. Evidence of estrogenic endocrine disruption was assessed by the presence and severity of intersex (testicular oocytes; TO) and concentrations of plasma vitellogenin in male fish. Abundance of 17 liver transcripts associated with reproductive function, endocrine activity, and contaminant detoxification pathways and 40 testes transcripts associated with male and female reproductive function, germ cell development, and steroid biosynthesis were also measured. Males with a high rate of TO (87–100%) and plasma vitellogenin were noted at all sites; however, TO severity was greatest at the site with the highest agricultural land cover. Numerous transcripts were differentially regulated among the sites and patterns of transcript abundance were used to better understand potential risk factors for estrogenic endocrine disruption. The results of this study suggest endocrine disruption is prevalent in this region and further research would benefit to identify the types of contaminants that may be associated with the observed biological effects.
... ED are exogenous substances or mixtures that alter the function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or in (sub)populations (WHO, 2012). In amphibians, ED can disrupt thyroid and gonadotrop axis crosstalk leading to impairment of larval development and disruptions 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). ED can also induce metabolic disorders in amphibians that decrease fitness. ...
Article
Animals must partition limited resources between their own growth and subsequent reproduction. Endocrine disruptors (ED) may cause maternal metabolic disorders that decrease successful reproduction and might be responsible for multi- and transgenerational effects in amphibians. We found that the frog Silurana (Xenopus) tropicalis, exposed to environmentally relevant concentrations of benzo [a]pyrene and triclosan throughout its life cycle, produced F1 females with delayed sexual maturity and decreased size and weight. These F1 females displayed a marked metabolic syndrome associated with decreased fasting plasma cholesterol and triglyceride concentrations and decreased gonadal development. F1 females from F0 exposed animals also had decreased reproductive investment highlighted by a decrease of oocyte lipid reserves associated with significant F2-tadpole mortality. F2 females from F0 exposed animals also displayed a marked metabolic syndrome but were able to correctly direct liver lipid metabolism to the constitution of fat bodies and oocyte yolk stores. In addition, the F2 females produced progeny that had normal mortality levels at 5 days post hatching compared to the controls suggesting a good reproductive investment. Our data confirmed that these ED, at concentrations often found in natural ponds, can induce multi- and transgenerational metabolic disorders in the progeny of amphibians that are not directly exposed. We present a hypothesis to explain the transmission of the metabolic syndrome across generations through modification of egg reserves. However, when high mortality occurred at the tadpole stage, surviving females were able to cope with metabolic costs and produce viable progeny through sufficient investment in the contents of oocyte reserves.
... Evidence supports in mammals a complex cross talk of intercellular networks and intracellular signaling pathways between TH and sex steroids throughout the life-span of the individual; TH can affect gonadal maturation, steroid synthesis and reproduction (30,31) as well as the function of the hypothalamus-pituitary-adrenal (HPA) (32). In the following sections we mention the sex differences reported in any of the parameters of HPT axis and on the effects of sex steroids on their regulation. ...
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The hypothalamus-pituitary-thyroid-axis (HPT) is one of the main neuroendocrine axes that control energy expenditure. The activity of hypophysiotropic thyrotropin releasing hormone (TRH) neurons is modulated by nutritional status, energy demands and stress, all of which are sex dependent. Sex dimorphism has been associated with sex steroids whose concentration vary along the life-span, but also to sex chromosomes that define not only sexual characteristics but the expression of relevant genes. In this review we describe sex differences in basal HPT axis activity and in its response to stress and to metabolic challenges in experimental animals at different stages of development, as well as some of the limited information available on humans. Literature review was accomplished by searching in Pubmed under the following words: “sex dimorphic” or “sex differences” or “female” or “women” and “thyrotropin” or “thyroid hormones” or “deiodinases” and “energy homeostasis” or “stress”. The most representative articles were discussed, and to reduce the number of references, selected reviews were cited.
... However, other data indicate that developing gonads are sensitive to THs. Triiodothyronine treatments increases the expression of genes associated with androgens, or suppress those associated with estrogens, depending on the species investigated (Duarte-- Guterman et al., 2014;Flood et al., 2013). Perchlorate is a competitive inhibitor of iodine uptake and inhibits TH synthesis in the thyroid follicular cells. ...
Article
A wide range of chemicals have been identified as endocrine disrupting chemicals (EDCs) in vertebrate species. Most studies of EDCs have focused on exposure of both male and female adults to these chemicals; however, there is clear evidence that EDCs have dramatic effects when mature or developing gametes are exposed, and consequently are associated with in multigenerational and transgenerational effects. Several publications have reviewed such actions of EDCs in subgroups of species, e.g., fish or rodents. In this review, we take a holistic approach synthesizing knowledge of the effects of EDCs across vertebrate species, including fish, anurans, birds, and mammals, and discuss the potential mechanism(s) mediating such multi- and transgenerational effects. We also propose a series of recommendations aimed at moving the field forward in a structured and coherent manner.
... Importantly, nuclear receptors have a natural tendency to functionally interact with each other, thus making their corresponding pathways cross-dependent of one another [26]. For instance, this is the case for GC and estrogen signalling [27,28], TH and estrogens [27,[29][30][31], and GC and androgens [32]. At the mechanistic level, NRs can synergistically bind or compete to DNA at shared response elements [33,34]. ...
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Background: Most work in endocrinology focus on the action of a single hormone, and very little on the cross-talks between two hormones. Here we characterize the nature of interactions between thyroid hormone and glucocorticoid signaling during Xenopus tropicalis metamorphosis. Methods: We used functional genomics to derive genome wide profiles of methylated DNA and measured changes of gene expression after hormonal treatments of a highly responsive tissue, tailfin. Clustering classified the data into four types of biological responses, and biological networks were modeled by system biology. Results: We found that gene expression is mostly regulated by either T3 or CORT, or their additive effect when they both regulate the same genes. A small but non-negligible fraction of genes (12%) displayed non-trivial regulations indicative of complex interactions between the signaling pathways. Strikingly, DNA methylation changes display the opposite and are dominated by cross-talks. Conclusion: Cross-talks between thyroid hormones and glucocorticoids are more complex than initially envisioned and are not limited to the simple addition of their individual effects, a statement that can be summarized with the pseudo-equation: TH ∙ GC > TH + GC. DNA methylation changes are highly dynamic and buffered from genome expression.
... Interactions between sex hormone synthesis and the HPT axis [56] or epigenetic control of these systems may interact with perchlorate exposure to determine lipid accumulation in fishes. Some EDCs influence gene expression, including expression of genes related to lipid storage [15,16]. ...
Article
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Perchlorate is a water-soluble contaminant found throughout the United States and many other countries. Perchlorate competitively inhibits iodide uptake at the sodium/iodide symporter, reducing thyroid hormone synthesis, which can lead to hypothyroidism and metabolic syndromes. Chronic perchlorate exposure induces hepatic steatosis and non-alcoholic fatty liver disease (NAFLD) in developing threespine stickleback ( Gasterosteus aculeatus ). We hypothesized that perchlorate would also induce zebrafish ( Danio rerio ) to develop phenotypes consistent with NAFLD and to accumulate lipids throughout the body. We exposed zebrafish embryos to four concentrations of perchlorate treated water (10μg/L, 10mg/L, 30mg/L, and 100mg/L) and a control (0mg/L) over the course of 133 days. Adult zebrafish were euthanized, sectioned, H&E and Oil Red-O stained, and analyzed for liver morphology and whole body lipid accumulation. In a representative section of the liver, we counted the number of lipid droplets and measured the area of each droplet and the total lipid area. For whole body analysis, we calculated the ratio of lipid area to body area within a section. We found that zebrafish exposed to perchlorate did not differ in any measured liver variables or whole body lipid area when compared to controls. In comparison to stickleback, we see a trend that control stickleback accumulate more lipids in their liver than do control zebrafish. Differences between the species indicate that obesogenic effects due to perchlorate exposure are not uniform across fish species, and likely are mediated by evolutionary differences related to geographic location. For example, high latitude fishes such as stickleback evolved to deposit lipid stores for over-winter survival, which may lead to more pronounced obesogenic effects than seen in tropical fish such as zebrafish.
... Moreover, the present study observed an association between E2 concentrations and dio3 expression in the unfertilized egg as well as between T and thrαb indicating a possible interplay between the two hormone systems. Thyroid hormone receptors belong to the steroid-thyroid super family that also contains receptors for ligands, such as steroids, retinoids and vitamins Tsai and O'Malley, 1994) indicating cross-talk between the hormone systems through receptor binding (Duarte-Guterman et al., 2014). However, little is known about the extent of this in teleosts. ...
Article
Hormones and mRNA transcripts of maternal origin deposited in the egg may affect early embryonic development in oviparous species. These hormones include steroids, such as estradiol-17β (E2), testosterone (T), 11-ketotestosterone (11-kt), 17α,20ß-dihydroxy-4-pregnen-3-one (DHP), and cortisol, which also play an important role in fish reproduction. In European eel, Anguilla anguilla, which does not reproduce naturally in captivity, vitellogenesis in female broodstock is commonly induced by administration of salmon or carp pituitary extract (PE) as an exogenous source of gonadotropins, while follicular maturation is stimulated by a priming dose of PE followed by provision of DHP as a maturation inducing hormone. In this regard, the main purpose of the present study was to evaluate effects of induced follicular maturation on reproductive success in European eel, focusing on maternal transfer and dynamics of steroids and mRNA transcripts of growth- and development-related genes throughout embryogenesis. The results showed that maternal blood plasma concentrations of E2, T and DHP were reflected in the unfertilized eggs. Moreover, a negative relationship between concentrations of E2 and DHP in eggs and embryos and quality parameters measured as fertilization success, cleavage abnormalities, embryonic survival, and hatch success was found. Concomitant mRNA transcript abundance analysis including genes involved in stress response (hsp70, hsp90), somatotropic axis (gh, igf1, igf2a, igf2b), lipid (cpt1a, cpt1b, pigf5) and thyroid metabolism (dio1, dio2, dio3, thrαb, thrβa, thrβb) varied among unfertilized egg batches. For the majority of genes, mRNA abundance increased during the maternal-to-zygotic transition in connection to activation of the transcription of the embryos own genome. mRNA abundance of dio1, cpt1a and cpt1b throughout embryogenesis was related to embryonic developmental competence. Notably, mRNA abundance of dio3 was positively associated with E2 concentrations, while the mRNA abundance of thrαb was negatively related to T concentrations in the unfertilized eggs, which may suggest an interaction between the thyroid and steroid hormone systems. Altogether, maternal plasma concentrations of E2 and DHP were reflected in the eggs, with high concentrations of these steroids in the eggs being negatively associated with embryonic developmental competence. Additionally, high transcript levels of two of the investigated genes (dio1, cpt1b) were positively associated with embryonic developmental competence. This study reveals maternal transfer of steroids and mRNA transcripts to the eggs, which may be significant contributors to the variability in embryonic survival observed in European eel captive reproduction.
... These differences in biological activity at the molecular level may be associated with different structures and physical properties with different chemodynamics. Furthermore, DINCH showed significant impacts on steroidogenesis, testicular development, and function in some studies [53,54], and an in vitro study by Engel et al. showed that DINCH metabolites had a weak estrogenic property [55]; these results support our results. However, further findings, including in vivo and in vitro should be done to confirm the correct epigenetic mechanism. ...
Article
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Uterine leiomyomas are estrogen-dependent benign tumors with unknown etiologies. Phthalates are endocrine-disrupting chemicals and ubiquitous in the environment; thus, it has been suggested that they play a role in the development of uterine leiomyoma. We aimed to investigate whether the pathogenesis of uterine leiomyoma is related to methylation changes in promoter regions of estrogen receptor α (ESR1) and progesterone receptor (PGR) genes in response to phthalates and alternative plasticizers exposure. Urinary concentrations of 20 phthalate metabolites and seven metabolites of di-2-ethylhexyl terephthalate (DEHTP) and di (isononyl) cyclohexane-1,2-dicarboxylate (DINCH) were measured by UHPLC-MS/MS in thirty leiomyoma patients, who provided both paired leiomyoma and myometrium tissues. Methylation levels of ESR1 and PGR were analyzed by pyrosequencing assay. A total of 12 phthalate metabolites and 5 alternative metabolites (3 DEHTP and 2 DINCH) were detected >70% among study participants. The methylation of ESR1 and PGR were significantly lower in leiomyoma tissues compared to those in myometrium (18.10 ± 4.41 vs. 28.72 ± 4.95; 2.32 ± 0.81 vs. 3.27 ± 0.56, respectively). ESR1 methylation in leiomyoma was negatively associated with mono-2-carboxylmethyl-hexyl phthalate (2cx-MMHP) and mono-3-carbocyl-propyl phthalate (MCPP) after adjusting for confounding factors. However, 1-mono-2-ethyl-5-oxohexyl-benzene-1,4-dicarboxylate (5OXO-MEHTP), one of the alternatives, showed positive association with ESR1 methylation in leiomyoma. PGR methylation in leiomyoma was significantly associated with mono butyl phthalate (MnBP), but negatively associated with cyclohexane-1,2-dicarboxylate-mono-7-hydroxy-4-methyl-heptyl ester (cx-MINCH). Our results suggest that phthalates exposure may contribute to leiomyoma pathogenesis via ESR1 and PGR methylation changes.
... . Amphibian metamorphosis and gonad development are governed by the thyroid (TH) and sex steroid hormones, respectively (Cruz & Fabrezi, 2020;Nakamura, 2010;Tata, 2006). Recent studies suggest that thyroid hormones (THs) are involved in gonad development (Duarte-Guterman et al., 2014;Flood et al., 2013;Goldberg et al., 2019). The treatment of exogenous TH stimulates the expression of androgen-related genes while suppressing the expression of estrogen-related genes (Duarte-Guterman & Trudeau, 2011;Duarte-Guterman et al., 2012). ...
Article
Amphibian endocrine systems interact with each other during normal development. Interference with one of the endocrine systems may influence others. We studied the effect of a thyroid inhibitor (ethylenethiourea [ETU]) on metamorphosis and ovary development of three species, Sphaerotheca pashchima, Indosylvirana caesari, and Euphlyctis cyanophlyctis with different larval durations. We treated the tadpoles of these species with 50, 100, and 200 mg/L concentrations of ETU and studied their larval duration, size at metamorphosis, and ovary development. The results revealed that ETU affects metamorphosis, depending on the species and concentration. ETU delayed metamorphosis of E. cyanophlyctis tadpoles and did not affect metamorphosis in S. pashchima tadpoles. Lower concentrations of ETU stimulated metamorphosis in I. caesari tadpoles while high concentration delayed metamorphosis. In the tadpoles (E. cyanophlyctis) treated with higher concentrations of ETU, ovary development was advanced with an increased size of the diplotene oocytes. Oocyte size was smaller in the tadpoles (of I. caesari) treated with lower concentrations of ETU. These results demonstrated that the tadpoles of these species show different responses to the thyroid inhibitor, possibly due to the differences in the larval duration and sensitivity. Inhibition or acceleration of metamorphosis did not interfere in the ovary development of E. cyanophlyctis and I. caesari. These results will be useful in understanding the impact of endocrine disruptors on the interaction between thyroid and sex steroid hormones. Highlights Thyroid hormone inhibitor (ethylenethiourea) affects metamorphosis, depending on the species and concentration. Inhibition or stimulation of the metamorphosis does not influence ovary development and the size of froglets.
... Sex and thyroid hormone pathways are integral in regulating gonadal physiology and the timing of breeding with implications for reproductive success; thus disruptors of these hormone pathways may result in reproductive changes (Duarte-Guterman et al., 2014). In addition to the greater number of male frogs produced following exposure to DBE-DBCH, there was also an increase in intersex gonads in frog tadpoles , providing the first direct evidence that DBE-DBCH can affect gonadal physiology. ...
Article
Following the ban of many historically-used flame retardants (FRs), numerous replacement chemicals have been produced and used in products, with some being identified as environmental contaminants. One of these replacement flame retardants is 1,2-dibromo-4-(1,2-dibromoethyl)-cyclohexane (DBE-DBCH; formerly abbreviated as TBECH), which to date has not been identified for risk assessment and potential regulation. DBE-DBCH technical mixtures consist largely of α- and β-diastereomers with trace amounts of γ- and δ-DBE-DBCH. The α- and β-isomers are known contaminants in various environmental media. While current global use and production volumes of DBE-DBCH are unknown, recent studies identified that DBE-DBCH concentrations were among the highest of the measured bromine-based FRs in indoor and urban air in Europe. Yet our mass balance fugacity model and modeling of the physical-chemical properties of DBE-DBCH estimated only 1% partitioning to air with a half-life of 2.2 d atmospherically. In contrast, our modeling characterized DBE-DBCH adsorbing strongly to suspended particulates in the water column (∼12%), settling onto sediment (2.5%) with minimal volatilization, but with most partitioning and adsorbing strongly to soil (∼85%) with negligible volatilization and slow biodegradation. Our modeling further predicted that organisms would be exposed to DBE-DBCH through partitioning from the dissolved aquatic phase, soil, and by diet, and given its estimated logKow (5.24) and a half-life of 1.7 d in fish, DBE-DBCH is expected to bioaccumulate into lipophilic tissues. Low concentrations of DBE-DBCH are commonly measured in biota and humans, possibly because evidence suggests rapid metabolism. Yet toxicological effects are evident at low exposure concentrations: DBE-DBCH is a proven endocrine disruptor of sex and thyroid hormone pathways, with in vivo toxic effects on reproductive, metabolic, and other endpoints. The objectives of this review are to identify the current state of knowledge concerning DBE-DBCH through an evaluation of its persistence, potential for bioaccumulation, and characterization of its toxicity, while identifying areas for future research.
... In vertebrates, the hypothalamus-pituitarygonadal (HPG) axis regulates reproduction: gonadotropin releasing hormone (GnRH) from the hypothalamus stimulates the pituitary to release gonadotropins (GTH) [luteinizing hormone (LH) and follicle stimulating hormone (FSH)] which act on gonads to regulate gametogenesis and steroidogenesis [e.g., in mammals (204) and fish (205)]. There is growing evidence of a crosstalk between the thyroid and HPG axes in several vertebrates (e.g., mammals, amphibians, fish) (206). ...
Article
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In all vertebrates, the thyroid axis is an endocrine feedback system that affects growth, differentiation, and reproduction, by sensing and translating central and peripheral signals to maintain homeostasis and a proper thyroidal set-point. Fish, the most diverse group of vertebrates, rely on this system for somatic growth, metamorphosis, reproductive events, and the ability to tolerate changing environments. The vast majority of the research on the thyroid axis pertains to mammals, in particular rodents, and although some progress has been made to understand the role of this endocrine axis in non-mammalian vertebrates, including amphibians and teleost fish, major gaps in our knowledge remain regarding other groups, such as elasmobranchs and cyclostomes. In this review, we discuss the roles of the thyroid axis in fish and its contributions to growth and development, metamorphosis, reproduction, osmoregulation, as well as feeding and nutrient metabolism. We also discuss how thyroid hormones have been/can be used in aquaculture, and potential threats to the thyroid system in this regard.
... Our results suggest an absence of such long-term programming effects of the HPT-axis in our study system-however it must be noted that circulating TH levels are highly variable in response to internal and external (food, temperature, circadian) variations 4,49 , which could mask potential organizing effects. Effects of maternal THs might also appear in the interactions with other endocrine axis, such as glucocorticoids 52,53 or gonads [54][55][56] . Experimental challenges with thyrotropin-releasing hormones (TRH) or thyriod-stimulating hormone (TSH) are now needed to test for the effects of prenatal THs on the sensitivity of the HPT-axis in birds. ...
Article
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Maternal effects via hormonal transfer from the mother to the offspring provide a tool to translate environmental cues to the offspring. Experimental manipulations of maternally transferred hormones have yielded increasingly contradictory results, which may be explained by differential effects of hormones under different environmental contexts. Yet context-dependent effects have rarely been experimentally tested. We therefore studied whether maternally transferred thyroid hormones (THs) exert context-dependent effects on offspring survival and physiology by manipulating both egg TH levels and post-hatching nest temperature in wild pied flycatchers (Ficedula hypoleuca) using a full factorial design. We found no clear evidence for context-dependent effects of prenatal THs related to postnatal temperature on growth, survival and potential underlying physiological responses (plasma TH levels, oxidative stress and mitochondrial density). We conclude that future studies should test for other key environmental conditions, such as food availability, to understand potential context-dependent effects of maternally transmitted hormones on offspring, and their role in adapting to changing environments.
... circuits, and the modulation of synaptic plasticity and neuroprotection, particularly in the hippocampus are frequently determined through the actions of gonadal steroid hormones (Fester et al., 2011;Haimov-Kochman and Berger, 2014). Crosstalk and interaction of sex hormones and thyroid hormones have been suggested (Duarte-Guterman et al., 2014). Estrogen and thyroid hormones play pivotal functions in a wide range of physiological processes including cell differentiation and proliferation, cellular metabolism, and brain function (Brent, 2012). ...
Article
Transient thyroid function abnormalities at birth exhibit intellectual developmental and cognitive disorders in adulthood. Given the well-known effects of physical activity and sex hormones on cognitive functions and brain-derived neurotrophic factor (BDNF), the present study examined the effects of treadmill exercise, sex hormones, and the combined treatment on learning and memory and hippocampal BDNF levels in transient congenital hypothyroid rats. To induce hypothyroidism, 6-propyl-2-thiouracil was added to the drinking water from the 6th day of gestation to the 21st postnatal day (PND). From PNDs 28 to 47, female and male pup rats received 17β-estradiol and testosterone, respectively, and about 30 min later, they were forced to run on the treadmill for 30 min once a day. On PNDs 48-55, spatial learning and memory of all rats tested in the water maze, which followed by measurement of BDNF in the hippocampus. Results showed that developmental hypothyroidism induced significant deficits in spatial learning and memory and hippocampal BDNF in both male and female rats. In both male and female hypothyroid rats, exercise and exercise plus sex hormones, but not sex hormones alone alleviated learning and memory deficits and all treatments (exercise, sex hormones, and the combined treatment) increased hippocampal BDNF. These disconnects in the effects of exercise, sex hormones and the combined treatment on behavioral and neurochemical outcomes suggest that a neurochemical mechanism other than hippocampal BDNF might contribute in the ameliorating effects of exercise on learning and memory deficits induced by developmental thyroid hormone insufficiency.
... Regarding the deiodinases, the available data showed that Dio2 is more expressed than Dio1 whereas there are no data for Dio3 (Figure 1, C). Since expressing the ensemble of transporters, enzymes and receptors involved in the peripheral TH signalling, rodents have been pivotal in unravelling the mechanisms regulating TH availability and activity in the development of ovarian dysfunctions [60]. ...
Article
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Thyroid hormones (THs) exert pleiotropic effects in different mammalian organs, including gonads. Genetic and non-genetic factors, such as ageing and environmental stressors (e.g., low-iodine intake, exposure to endocrine disruptors, etc.), can alter T4/T3 synthesis by the thyroid. In any case, peripheral T3, controlled by tissue-specific enzymes (deiodinases), receptors and transporters, ensures organ homeostasis. Conflicting reports suggest that both hypothyroidism and hyperthyroidism, assessed by mean of circulating T4, T3 and Thyroid-Stimulating Hormone (TSH), could affect the functionality of the ovarian reserve determining infertility. The relationship between ovarian T3 level and functional ovarian reserve (FOR) is poorly understood despite that the modifications of local T3 metabolism and signalling have been associated with dysfunctions of several organs. Here, we will summarize the current knowledge on the role of TH signalling and its crosstalk with other pathways in controlling the physiological and premature ovarian ageing and, finally, in preserving FOR. We will consider separately the reports describing the effects of circulating and local THs on the ovarian health to elucidate their role in ovarian dysfunctions.
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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.
Article
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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.
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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.
Preprint
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.
Article
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.
Article
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.
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1. 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. 2. Given the essential functions of maternal THs in development and metabolism, THs may be a mediator of life‐history variation across species. 3. 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 co‐vary with migratory status, developmental mode, and traits related to pace‐of‐life (e.g. basal metabolic rate, maximum lifespan). 4. We collected un‐incubated eggs (n = 1‐21 eggs per species, median = 7) from 34 wild and captive bird species across 17 families and 6 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. 5. 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 lifespan. 6. 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.
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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.
Preprint
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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.
Article
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.
Article
Thyroid-stimulating hormone (TSH) is an important glycoprotein in hypothalamic-pituitary-thyroid axis, which plays a crucial role in the synthesis and release of thyroid hormones in vertebrates. Rice field eel, Monopterus albus, a protogynous hermaphroditic fish, which undergoes sex reversal from a functional female to a male, is an ideal model to investigate the regulation of sex differentiation. In this study, we obtained the cDNA sequence of thyroid-stimulating hormone β subunit (tshβ) from rice field eel, which contained a complete open reading frame and encoded a putative protein of 151 amino acids. Multiple alignment of protein sequences showed that tshβ was highly conserved in teleost. The tissue distribution indicated that tshβ showed high expression in the pituitary, moderate expression in the brain region, gonad, intestine and liver, and low expression in other peripheral tissues. During natural sex reversal, the expression of tshβ had no significant difference in the pituitary. Compared to that in the ovary, the expression of tshβ increased significantly in the gonad at late intersexual and male stages. After treatment by different doses of triiodothyronine (T3) (1 μg/g, 10 μg/g and 100 μg/g body weight), serum T3 and free triiodothyronine (FT3) increased sharply, while the expression of tshβ were inhibited significantly in the pituitary. Although T3 had no significant effect on the levels of serum E2, it stimulated the release of serum 11-KT at high-dose group. We also detected the effects of T3 on the expression of gonadal differentiation-related genes in rice field eel. T3 treatment inhibited the expression of foxl2, cyp19a1a and dax1, while stimulated the expression of sox9a1. These results indicate that TSH may be involved in sex differentiation, and THs may play roles in the regulation of male development and sex reversal in rice field eel.
Article
Progestins and estrogens are widespread in various aquatic environments and their potential endocrine disruption effects to aquatic organisms have drawn growing concern. However, their combined effects in aquatic organisms remain elusive. The aim of the present study was to assess the effects of the binary mixtures of gestodene (GES) and 17α-ethinylestradiol (EE2) on the hypothalamic–pituitary–thyroid (HPT) axis of zebrafish (Danio rerio) using the eleuthero-embryos. Embryos were exposed to GES and EE2 alone or in combination at concentrations ranging from 41 to 5329 ng L⁻¹ (nominal ones from 50 to 5000 ng L⁻¹) for 48 h, 96 h and 144 h post fertilization (hpf). The results showed that the transcripts of the genes along the HPT axis displayed pronounced alterations. There was no clear pattern in the change of the transcripts of these genes over time and with concentrations. However, in general, the transcripts of the genes were inversely affected by EE2 (increase 0.5 to 4.2-folds) and GES (inhibition 0.4 to 4.9-folds), and their mixtures showed interactive effects in embryonic zebrafish. In addition, physiological data (mortality, malformation, body length and heart rate etc.) denoted higher toxicity of the two chemicals in combination than alone based on the developmental toxicity and neurotoxicity (locomotor behavior). These results indicated that the interactive effects of these two chemicals might be different between at the transcriptional level and at the whole organismal level. In summary, GES and EE2 affect the HPT axis (related genes expression and thyroid hormones (THs) levels) and exhibit developmental toxicity and neurotoxicity.
Article
Brominated flame retardant chemicals, such as 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EHTBB) (CAS #: 183658–27-7) and bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) (CAS #: 26040–51-7), have been detected in avian tissues and eggs from remote regions. Exposure to EHTBB and TBPH has been shown to cause oxidative stress and altered thyroid function in rodents and fish, yet no controlled studies have examined potential adverse effects of exposure in birds. Because flame retardants have been detected in wild raptors, we used American kestrels (Falco sparverius) as a model raptor to determine whether in ovo exposure to EHTBB or TBPH affected growth, hatching success, oxidative stress, or thyroid function. We exposed kestrel embryos to nominal concentrations (10, 50, or 100 ng g⁻¹ egg weight) of EHTBB and TBPH via egg-injection on embryonic day 5. Embryonic exposure (~23 d) to EHTBB increased thyroid gland mass, reduced glandular colloid and total thyroxine (T4) in hatchling males and females, whereas deiodinase enzyme activity increased in males but decreased in females. Hatchlings exposed to TBPH in ovo exhibited reduced colloid and increased oxidative stress. Although exposure to EHTBB and TBPH caused several physiological effects (e.g., heart and brain mass), only exposure to 50 ng g⁻¹ EHTBB appeared to reduce hatching success. Our results suggest these flame retardants may be hazardous for predatory birds. Future research should evaluate long-term survival and fitness consequences in birds exposed to these chemicals.
Article
The goal of this study was to characterize morphological and molecular effects in rainbow trout alevins after waterborne exposures to 17β-estradiol (E2; 0.0008 to 0.5 μg/L), triiodothyronine (T3; 0.52 to 65 μg/L), and various co-treatments for 21 to 23 days. Interestingly, there was no consistent evidence that E2 alone influenced growth, development or deformity rates, however, 65 μg/L T3 alone expedited development, and both 13 μg/L and 65 μg/L alone caused a unique opercular deformity not previously reported. In addition, some potentiation between E2 and T3 at lower concentrations suggests some cross-talk between these two hormonal pathways may also contribute to the development of this opercular deformity. Gene expression changes were observed, including induction of vtg in rainbow trout alevins at 0.02 μg/L concentration of E2, which is the lowest concentration reported to induce vtg in rainbow trout alevins. These data suggest low-level E2 does not negate abnormal growth and development caused by hyperthyroidism, and examining more time points is likely required to demonstrate a stronger response profile for individual hormones and endocrine axes cross-talk.
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Present study was conducted to characterize the testicular changes in the peripubertal period in Tenyi-vo, a miniature size pig of North-eastern Himalayan (NEH) region of India. A total of twenty-four male pigs were randomly selected and categorised for castration at different age groups, G1 (Days 30-45), G2 (Days 60-65), G3 (Days 80-100) and G4 (Days 150-160), n=6 each category. Paired testes and epididymis were used for the assessment of biometry, cauda epididymal spermiogram, testicular histology and relative expression of the androgen receptor (AR), estrogen receptors (ERα and ERβ), aromatase (CYP19A1), and insulin like growth factor-1β receptor (IGF-1R) in qPCR. Plasma testosterone (T), estradiol (E 2 ), tri-iodothyronine (T 3 ), thyroxine (T 4 ), and cortisol concentrations were estimated on the day of castration in each group of male using commercial ELISA kits. In pigs of G2, a greater testicular weight, volume, epididymis weight was observed relative to G1. The presence of live spermatozoa at 1240.9±304.2×10 ⁶ /mLconcentration with 0.65% proximal droplets was recorded as early as day 60. The concentration of T increased steadily over the age of G1 to G4 and a significantly higher concentration was observed in G4 relative to the other categories. Among the transcripts analysed in the testis, the relative fold change of AR was 10.8 fold in G2, which was subsequently reduced in G3 and then down-regulated in G4. CYP19A1 was abundantly expressed in the testis and the fold change ranged from 41-54 fold, although it did not differ significantly from 60-150 days of age. Further, the presence of well-developed seminiferous tubules was evident in the Tenyi-vo male from day 60 onward with a body weight as low as 4.28 kg. The study concluded that the male of Tenyi-vo pig attained puberty at the earliest age of 60 days.
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Observations on the ontogeny and diversity of salamanders provided some of the earliest evidence that shifts in developmental trajectories have made a substantial contribution to the evolution of animal forms. Since the dawn of evo‐devo there have been major advances in understanding developmental mechanisms, phylogenetic relationships, evolutionary models, and an appreciation for the impact of ecology on patterns of development (eco‐evo‐devo). Molecular phylogenetic analyses have converged on strong support for the majority of branches in the Salamander Tree of Life, which includes 764 described species. Ancestral reconstructions reveal repeated transitions between life cycle modes and ecologies. The salamander fossil record is scant, but key Mesozoic species support the antiquity of life cycle transitions in some families. Colonization of diverse habitats has promoted phenotypic diversification and sometimes convergence when similar environments have been independently invaded. However, unrelated lineages may follow different developmental pathways to arrive at convergent phenotypes. This article summarizes ecological and endocrine based causes of life cycle transitions in salamanders, as well as consequences to body size, genome size, and skeletal structure. Salamanders offer a rich source of comparisons for understanding how the evolution of developmental patterns has led to phenotypic diversification following shifts to new adaptive zones. This article is protected by copyright. All rights reserved.
Article
Metabolic disorders induced by endocrine disruptors (ED) may contribute to amphibian population declines but no transgenerational studies have evaluated this hypothesis. Here we show that Xenopus tropicalis, exposed from the tadpole stage, to the ED benzo[a]pyrene (BaP, 50 ng.L⁻¹) produced F2 progeny with delayed metamorphosis and sexual maturity. At the adult stage, F2–BaP females displayed fatty liver with inflammation, tissue disorganization and metabolomic and transcriptomic signatures typical of nonalcoholic steato-hepatitis (NASH). This phenotype, similar to that observed in F0 and F1 females, was accompanied by a pancreatic insulin secretory defect. Metabolic disrupted F2–BaP females laid eggs with metabolite contents significantly different from the control and these eggs did not produce viable progeny. This study demonstrated that an ED can induce transgenerational disruption of metabolism and population collapse in amphibians under laboratory conditions. These results show that ED benzo[a]pyrene can impact metabolism over multiple generations and support epidemiological studies implicating environmental EDs in metabolic diseases in humans.
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Reproductive physiology and behavior is mainly regulated by the hypothalamus-pituitary-gonad (HPG) axis, although abnormal thyroid hormone (TH) levels alter HPG axis activity. Seasonally breeding animals, such as green anole lizards (Anolis carolinensis), undergo drastic hormonal and behavioral changes between breeding and non-breeding seasons, with increased sex steroid hormones, larger gonads and increased reproductive behaviors during the breeding compared to non-breeding seasons. Relatively less is known regarding the regulation of gonadal TH in seasonal reproduction. We examined whether the gonadal expression of enzymes involved in TH activation are altered in concert with seasonal reproduction. Type 2 deiodinase (Dio2) mRNA, the TH activating enzyme, was upregulated in breeding compared to non-breeding testes, while type 3 deiodinase (Dio3) mRNA, the TH deactivating enzyme, was upregulated in breeding ovaries. To study the association between the HPG axis and local activation of TH, we manipulated the HPG axis during the non-breeding season by subcutaneously injecting luteinizing hormone (LH) and follicle stimulating hormone (FSH) in male lizards. We found that acute LH and FSH injections induced many aspects of breeding, with increased testes size and testosterone levels. Surprisingly, Dio3 was upregulated in the testes after LH and FSH injections, while Dio2 mRNA levels were unchanged. These results suggest that there might be different roles for local TH activation in developing and maintaining fully mature and functional gonads. Our findings continue to support the role for TH in regulating reproduction.
Conference Paper
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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.
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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.
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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.
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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.
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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
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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.
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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.