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Putative adverse outcome pathway development based on physiological responses of female fathead minnows to model estrogen versus androgen receptor agonists
Citation:
Morshead, M., K. Jensen, G. Ankley, S. Vliet, C. LaLone, D. Villeneuve, A. Vidales Aller, AND K. Watanabe. Putative adverse outcome pathway development based on physiological responses of female fathead minnows to model estrogen versus androgen receptor agonists. AQUATIC TOXICOLOGY. Elsevier Science Ltd, New York, NY, 261:106607, (2023). https://doi.org/10.1016/j.aquatox.2023.106607
Impact/Purpose:
Per- and polyflourinated alkyl substances (PFAS) are a broad chemical class of high concern to the Agency. Molecular screening of over 140 PFAS suggests that certain PFAS may act as endocrine disrupting chemicals based on their ability to interact with and activate estrogen receptors. Estrogen receptor agonism has been linked to a variety of adverse effects in humans and wildlife, but to date the causal mechanisms underlying the adverse effects of estrogen receptor agonism have not been formally assembled and described. The current paper compares and contrasts the responses of a well known estrogen receptor agonist with those of a known androgen receptor agonist and considers the results in light of current understanding of fish reproductive physiology to hypothesize two adverse outcome pathways linking estrogen receptor agonism to reproductive impairment in female fish. Organizing and disseminating this knowledge through the AOP framework has potential to establish the relevance of the screening assays for predicting ecological and human health hazard, and can also provide the basis for developing higher tier confirmatory to verify the screening results where needed. Once further developed, these AOPs are expected to inform a tiered approach for testing PFAS for their hazards as potential endocrine disrupting chemicals.
Description:
Several adverse outcome pathways (AOPs) have linked molecular initiating events like aromatase inhibition, androgen receptor (AR) agonism, and estrogen receptor (ER) antagonism to reproductive impairment in adult fish. Estrogen receptor agonists can also cause adverse reproductive effects, however, the early key events (KEs) in an AOP leading to this are mostly unknown. The primary aim of this study was to develop hypotheses regarding the potential mechanisms through which exposure to ER agonists might lead to reproductive impairment in female fish. Mature fathead minnows were exposed to 1 or 10 ng 17α-ethynylestradiol (EE2)/L or 10 or 100 µg bisphenol A (BPA)/L for 14 d. The response to EE2 and BPA was contrasted with the effects of 500 ng/L of 17β-trenbolone (TRB), an AR agonist, as well as TRB combined with the low and high concentrations of EE2 or BPA tested individually. Exposure to 10 ng EE2/L, 100 µg BPA/L, TRB, or the various mixtures with TRB caused significant decreases in plasma concentrations of 17β-estradiol. Exposure to TRB alone caused a significant reduction in plasma vitellogenin (VTG), but VTG was unaffected or even increased in females exposed to EE2 or BPA alone or, in most cases, in mixtures with TRB. Over the course of the 14-d exposure, the only treatments that clearly did not affect egg production were 1 ng EE2/L and 10 µg BPA/L. Based on these results and knowledge of hypothalamic–pituitary–gonadal axis function, we hypothesize an AOP whereby decreased production of maturation-inducing steroid leading to impaired oocyte maturation and ovulation, possibly due to negative feedback or direct inhibitory effects of membrane ER activation, could be responsible for causing adverse reproductive impacts in female fish exposed to ER agonists.
URLs/Downloads:
DOI: Putative adverse outcome pathway development based on physiological responses of female fathead minnows to model estrogen versus androgen receptor agonists
https://pubmed.ncbi.nlm.nih.gov/37354817/