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Effects of trenbolone, flutamide and a mix of both in fathead minnow ovaries

ABSTRACT: Trenbolone and flutamide are prototypical model compounds for respectively androgen and anti-androgen modes of action. Trenbolone is an anabolic steroid used in cattle industry to increase weight gain and feed efficiency, and flutamide is a pharmaceutical used to treat prostate cancer. Androgens exert profound effects on the organization, development, and function of the male reproductive system through activation of androgen receptors (ARs). Flutamide, as an antiandrogen, was expected to temper the effects of trenbolone on androgen receptor (AR)-mediated gene expression. Female fathead minnows (Pimephales promelas) were exposed via the water to 0.05, 0.5 or 5 µg 17β-trenbolone/L; 50, 150 or 500 µg flutamide/L; or to a mixture of 0.5 μg/L trenbolone and 500 μg/L flutamide. After a 48 hr constant exposure gene expression in gonads was analyzed using a fathead minnow-specific 22,000-gene microarray. Trenbolone significantly changed the expression (P < 0.05) of roughly 750 different genes, while flutamide changed the expression of 1420 genes. Most of the genes that were regulated were distinct for the two chemicals. However, 70 genes were reciprocally regulated by the two treatments. Myelocytomatosis viral oncogene homolog (Myc), Yin Yang 1 (YY1) and interferon regulator factor 1 (IRF1) were among the important transcription factors reciprocally regulated by trenbolone and flutamide, suggesting they may be specifically regulated by the AR. These regulatory molecules, in conjunction with other reciprocally regulated transcription factors, may function as early molecular switches to control phenotypic changes in gonad tissue architecture and function.

ORGANISM(S): Pimephales promelas

PROVIDER: GSE14100 | GEO | 2008/12/23

SECONDARY ACCESSION(S): PRJNA111185

REPOSITORIES: GEO

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Project description:Triclocarban (TCC) is a widely used antimicrobial agent that is routinely detected in surface waters. The present study was designed to examine TCC’s efficacy and mode of action as a reproductive toxicant in fish. Reproductively mature Pimephales promelas were continuously exposed to either 1 or 5 μg TCC/L, 0.5 μg 17β-trenbolone (TRB)/L or a mixture (MIX) of 5 μg TCC and 0.5 μg TRB/L for 22 d and a variety of reproductive and endocrine-related endpoints were examined. The data were evaluated to answer several key questions: first, whether exposure to TCC could be linked with an ecologically-relevant adverse outcome, i.e., impaired reproduction; second, whether the present study provided additional support for augmentation of androgen action as an endocrine-disrupting mode of action for TCC; and third, whether there were any novel and/or plausible linkages between changes in the ovarian transcriptome and the apical responses observed in females that could support adverse outcome pathway development and/or further hypothesis-driven testing. Fathead minnows were randomly paired (one male, one female) and placed in tanks at a density of two pairs per tank with six replicate tanks per treatment. Pairs were separated by a water permeable mesh divider and each pair had its own breeding substrate. The fish were held in the test system, receiving UV-treated, filtered Lake Superior (control) water only, for a 21 d acclimation period during which the fecundity and fertility of each pair were assessed daily. After 21 d, exposures were initiated with pairs that had spawned successfully during acclimation. Fish were exposed continuously to target test concentrations of 0 (Lake Superior control), TCC (1 and 5 µg/L), TRB (0.5 μg/L), or a mixture of the two chemicals (5 μg TCC and 0.5 μg TRB/L) for 22 d. Water concentrations of TCC and TRB were determined in stock solutions and all exposure tanks every two to three days. General water quality characteristics (mean ± SD) measured regularly over the course of the Experiment were: temperature, 24.8 ± 0.7 oC; pH, 7.87 ± 0.04; dissolved oxygen, 6.8 ± 0.35 mg/L. Ovary RNA samples from twenty four fish (n=5 for all treatments except TRB alone; n=4) were selected for microarray analysis.

Project description:Metformin, along with its biotransformation product guanylurea, are commonly observed in municipal wastewaters and subsequent surface waters. Previous studies in fish have identified metformin as a potential endocrine active compound but there are inconsistencies in the literature with regard to effects. To further investigate the potential reproductive toxicity of metformin and guanylurea to fish, a series of experiments were performed with reproductively mature fathead minnows (Pimephales promelas). First, explants of mature fathead minnow ovary tissue were exposed to 0.001-100 µM metformin or guanylurea to investigate whether they can directly perturb steroidogenesis. Second, spawning pairs of fathead minnows were exposed to metformin (0.41, 4.1, 41 µg/L) or guanylurea (1.0, 10, 100 µg/L) for 23 d to assess impacts on reproduction. Lastly, male fathead minnows were exposed to 41 µg/L metformin, 100 µg/L guanylurea, or a mixture of both compounds, with samples collected over a 96 h time course to investigate potential impacts to the hepatic transcriptome or metabolome. Neither metformin or guanylurea effected estradiol or testosterone by ovary tissue exposed in vitro. In the 23 d exposure, neither compound significantly impacted transcription of endocrine-related genes in male liver or gonad, circulating steroid concentrations in male or female fish, or fecundity of spawning pairs. In the 96 h time course, 100 µg guanylurea/L elicited more differential gene expression than 41 µg metformin/L , and showed the greatest impacts after 96 h. A number of DEGs up-regulated after 24 h were subsequently down-regulated after 96 h, demonstrating time-dependent impacts of guanylurea on the liver. Overall, metformin and guanylurea did not elicit effects consistent with reproductive toxicity in adult fathead minnows at environmentally relevant concentrations. Where effects were identified using ‘omics approaches, guanylurea induced greater impacts than metformin.

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Effects of trenbolone, flutamide and a mix of both in fathead minnow ovaries

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