Dynamic Nature of Alterations in the Endocrine System of Fathead Minnows Exposed to the Fungicide Prochloraz (original) (raw)
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Aquatic Toxicology, 2011
Prochloraz is a fungicide known to cause endocrine disruption through effects on the hypothalamicpituitary-gonadal (HPG) axis. To determine the short-term impacts of prochloraz on gene expression and steroid production, adult female fathead minnows (Pimephales promelas) were exposed to the chemical (0 or 300 g/L) for a time-course of 6, 12 and 24 h. Consistent with inhibition of cytochrome P450 17␣-hydroxylase/17,20-lyase (CYP17) and aromatase (CYP19), known molecular targets of prochloraz, plasma 17-estradiol (E2) was reduced within 6 h. Ex vivo E2 production was significantly reduced at all time-points, while ex vivo testosterone (T) production remained unchanged. Consistent with the decrease in E2 levels, plasma concentrations of the estrogen-responsive protein vitellogenin were significantly reduced at 24 h. Genes coding for CYP19, CYP17, and steroidogenic acute regulatory protein were up-regulated in a compensatory manner in ovaries of the prochloraz-treated fish. In addition to targeted quantitative real-time polymerase chain reaction analyses, a 15k feature fathead minnow microarray was used to determine gene expression profiles in ovaries. From time-point to time-point, the microarray results showed a relatively rapid change in the differentially expressed gene (DEG) profiles associated with the chemical exposure. Functional analysis of the DEGs indicated changes in expression of genes associated with cofactor and coenzyme binding (GO:0048037 and 0050662), fatty acid binding (GO:0005504) and organelle organization and biogenesis (GO:0006996). Overall, the results from this study are consistent with compensation of the fish HPG axis to inhibition of steroidogenesis by prochloraz, and provide further insights into relatively rapid, system-wide, effects of a model chemical stressor on fish.
Aquatic Toxicology, 2012
The objective of this study was to evaluate temporal effects of the model steroidogenesis inhibitor ketoconazole (KTC) on aspects of reproductive endocrine function controlled by the hypothalamicpituitary-gonadal (HPG) axis in the fathead minnow (Pimephales promelas). Ketoconazole inhibits the activity of two cytochrome P450s (CYPs) key to sex steroid production in vertebrates, CYP11a (cholesterol side chain cleavage) and CYP17 (c17␣-hydroxylase/17, 20-lyase). Sexually mature fish were exposed to water-borne KTC (30 or 300 g/L) in a flow-through system for up to 8 d, following which animals were allowed to recover in clean water. Fish were sampled after 1, 4 and 8 d of exposure, and after 1, 8 and 16 d of recovery. A shorter-term time-course experiment also was conducted in which females were sampled on seven occasions during a 12 h KTC exposure. Ketoconazole consistently depressed ex vivo gonadal synthesis of testosterone (T) in both sexes, and 17-estradiol (E2) in females during both exposure and recovery phases of the time-course studies. Effects on ex vivo steroidogenesis in females occurred within as little as 1 h of exposure. Plasma concentrations of T in males and E2 in females also were depressed by exposure to KTC, but these decreases did not persist to the same degree as observed for the ex vivo effects. In females, after decreases within 12 h, plasma E2 concentrations were similar to (or greater than) controls at 24 h of exposure, while in males, plasma T returned to levels comparable to controls within 1 d of cessation of KTC exposure. The discrepancy between the ex vivo and in vivo data at later stages in the test is consistent with some type of compensatory response to KTC in fish. However, we were unable to ascertain the mechanistic basis for such a response. For example, although a number of genes related to steroid synthesis (e.g., cyp11a, cyp17) were up-regulated in the gonads of both males and females during the exposure and early recovery phases of the experiment, this did not seem to account for the resurgence in plasma steroid concentrations in KTC-exposed fish. Further studies focused on metabolism and clearance of steroids might lend insights as to the effects of KTC on plasma steroid concentrations. Overall, our results demonstrate the complex, temporally dynamic nature of the vertebrate HPG system in response to chemical stressors.
Effect of Endocrine Disrupting Chemicals on HPG Axis: A Reproductive Endocrine Homeostasis
Hot Topics in Endocrinology and Metabolism, 2021
The hypothalamic–pituitary-gonadal (HPG) axis plays a crucial and integrative role in the mammalian endocrine regulation to maintain homeostasis. The HPG axis is primarily responsible for governing all the hormonal events related to reproductive activity. Endocrine-disrupting chemicals (EDCs) comprise a diverse group of naturally occurring and synthetic compounds that mimic and interfere with the endogenous chemical hormones. Epidemiological investigations have shown increasing evidence of altered development and detrimental effects on reproductive health during the past 50 years associated with endocrine disruptors affecting the HPG axis. The pleiotropic harmful effects of EDCs act through hormone-dependent downstream signaling pathways responsible for gonad development either through direct interaction with steroid hormone receptor or via epigenetic regulation. Hence, this chapter summarizes the biological plausibility of EDCs exposure and elucidates the mechanism of action underl...
Environmental Toxicology, 2014
A range of chemicals found in the aquatic environment have the potential to influence endocrine function and affect sexual development by mimicking or antagonizing the effects of hormones, or by altering the synthesis and metabolism of hormones. The aim of this study was to evaluate whether the effects of chemicals interfering with sex hormone synthesis may affect the regulation of early ovarian development via the modulation of sex steroid and insulin-like growth factor (IGF) systems. To this end, ex vivo ovary cultures of juvenile brown trout (Salmo trutta fario) were exposed for 2 days to either 1,4,6androstatriene-3,17-dione (ATD, a specific aromatase inhibitor), prochloraz (an imidazole fungicide), or tributyltin (TBT, a persistent organic pollutant). Further, juvenile female brown trout were exposed in vivo for 2 days to prochloraz or TBT. The ex vivo and in vivo ovarian gene expression of the aromatase (CYP19), responsible for estrogen production, and of IGF1 and 2 were compared. Moreover, 17b-estradiol (E2) and testosterone (T) production from ex vivo ovary cultures was assessed. Ex vivo exposure to ATD inhibited ovarian E2 synthesis, while T levels accumulated. However, ATD did not affect ex vivo expression of cyp19, igf1, or igf2. Ex vivo exposure to prochloraz inhibited ovarian E2 production, but did not affect T levels. Further prochloraz up-regulated igf1 expression in both ex vivo and in vivo exposures. TBT exposure did not modify ex vivo synthesis of either E2 or T. However, in vivo exposure to TBT down-regulated igf2 expression. The results indicate that ovarian inhibition of E2 production in juvenile brown trout might not directly affect cyp19 and igf gene expression. Thus, we suggest that the test chemicals may interfere with both sex steroid and IGF systems in an independent manner, and based on published literature, potentially lead to endocrine dysfunction and altered sexual development.
Environmental Science & Technology, 2010
Exposure to environmental estrogens such as 17R-ethinylestradiol (EE2) has been associated with feminization and a decline in fertility of male fish. To investigate the effect of estrogen exposure on steroid homeostasis, we exposed roach (Rutilus rutilus) to EE2 (1-29 ng/L) for 18 days and analyzed steroid profiles in bile and plasma using targeted analyses and in liver and gonadal tissues using mass spectrometry metabolite profiling techniques (metabolomics). Exposure to EE2 resulted in a concentration dependent reduction of estrogens and androgens in bile and plasma of both male and female fish. At 10 ngEE2/L, significant reductions in concentrations of hydroxyprogesterone, androstenedione, 11-hydroxyandrostenedione, and 11-ketotestosterone were detected in the testes metabolome, indicating disruption of steroid biosynthesis upstream of androgen metabolism. Estrogen exposure also resulted in increased biosynthesis of cortisol and cortisone in testes and ovaries, respectively, but did not alter glucocorticoid concentrations in the liver or plasma. This first report on the effect of EE2 exposure on the steroid metabolome in fish tissues suggests that both sex steroid and glucocorticoid pathways are one of the primary targets of estrogen exposure in fish gonads and provides further insights into the mode of action of this endocrine disrupting chemical.
Environmental Toxicology and Chemistry, 2011
Inhibition of enzymes involved in the synthesis of sex steroids can substantially impact developmental and reproductive processes controlled by the hypothalmic-pituitary-gonadal (HPG) axis. A key steroidogenic enzyme that has received little attention from a toxicological perspective is 3b-hydroxysteroid dehydrogenase (3b-HSD). In these studies, we exposed reproductively-active fathead minnows (Pimephales promelas) to the model 3b-HSD inhibitor trilostane at two test concentrations (300 and 1,500 mg/L) over a 16-d period that included both 8-d exposure and 8-d recovery phases. Plasma concentrations of 17b-estradiol (E2) in females were depressed within hours of exposure to the drug and remained decreased at the highest trilostane concentration throughout the 8-d exposure. Reductions in E2 were accompanied by decreases in plasma concentrations of the estrogen-responsive protein vitellogenin (VTG). During the recovery phase of the test, plasma E2 and VTG concentrations returned to levels comparable to those of controls, in the case of E2 within 1 d. Up-regulation of ovarian expression of gene products for follicle-stimulating hormone receptor (fshr) and aromatase (cyp19a1a) suggested active compensation in trilostane-exposed animals. Effects of trilostane on HPG-related endpoints in exposed males were less pronounced, although, as in females, up-regulation of gonadal fshr was seen. Data from these time-course studies provide insights as to direct impacts, compensatory responses, and recovery from effects associated with perturbation of a comparatively poorly characterized enzyme/pathway critical to sex steroid synthesis. This information is important to the design and interpretation of approaches for assessing the occurrence and effects of HPG-active chemicals in both the laboratory and the field.
Environmental Toxicology and Chemistry, 2000
Yellow perch were given a single intraperitoneal injection of polychlorinated biphenyl (PCB) 126 dissolved in corn oil at nominal concentrations of 0, 10, 100, and 500 g/kg body weight. Following the injection, the fish were held for four weeks under photothermal conditions characteristic for Ohio, USA, and fed a commercial fish food. Thereafter, they were sacrificed to examine the PCB 126 concentrations in the liver and to assess the contaminant effects on hepatic P4501A activity, reproductive hormones in plasma, and steroidogenic potential of gonads. The administered doses resulted in liver concentrations of 0.8 (corn oil control), 12.1, 38.9, and 174.5 g/kg wet tissue weight. Hepatic P4501A indices were differentially affected depending on both the PCB 126 dose and fish gender. In untreated fish, the P4501A protein and ethoxyresorufin-O-deethylase activity were several times lower in females than in males. In treated males, the hepatic P4501A was inhibited by all three PCB 126 doses. In females, a significant P4501A induction occurred in those dosed with 10 g/kg, while no changes were found in the two higher-dosed female groups in comparison to controls. A significant negative correlation was observed between hepatic P4501A indices and gonad somatic indexes values and plasma estradiol concentrations. The PCB 126 administration produced alterations in concentrations of plasma sex hormones in females but not in males. The in vitro steroidogenic potential of the female and male gonads was not affected by the in vivo PCB 126 treatment.
World, 2012
The aquatic ecosystem is one of the most exposed environments to pollutants. A lot of xenobiotics are known to disrupt the reproductive endocrine system. Fish are one of the primary risk organisms for Endocrine Disrupting Chemicals [EDCs]. In common with all vertebrates, reproduction in fish is controlled by the Hypothalamic-Pituitary-Gonad-Liver [HPGL] axis. The multitude of hormones controlling this axis and the complexity of hormones regulation, make from the HPGL axis a major target of EDCs. Variation of hormones synthesis levels, disturbance of genes expression, alteration of gonads structure and disruption of liver functions were noted. HPGL axis represents so one of the most important endpoints in the risk assessment of EDCs. In this review, we seek to extract from recent literature concepts regarding the effects of EDCs on the endocrine reproductive system in fish that might be of interest to explain some alterations in the wide populations of fish.