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Identifying potential key events linking xenoestrogen exposures in female fathead minnows to reproductive impairment
Citation:
Morshead, M., K. Jensen, N. Garcia-Reyero, E. Perkins, G. Ankley, S. Vliet, C. LaLone, AND Dan Villeneuve. Identifying potential key events linking xenoestrogen exposures in female fathead minnows to reproductive impairment. SETAC North America 42nd Annual meeting, Portland, OR, November 14 - 18, 2021. https://doi.org/10.23645/epacomptox.16983511
Impact/Purpose:
Considerable weight of evidence has accumulated in the literature that exposure to chemicals that can bind to and activate vertebrate estrogen receptors can cause endocrine disruption that has been associated with adverse reproductive outcomes. However, to date relatively little emphasis has been placed on describing the mechanistic pathways through which estrogens cause those effects and or effect thresholds that can provide an early warning signal that a particular concentration or duration of exposure will likely produce the adverse effect. The present study aims to identify of the key biological markers of progression to an adverse estrogenic effect in fish. The study compares the responses to a strong androgen, for which an adverse outcome pathway (AOP) has been well defined, to that of an estrogen and additionally considers global gene expression in fish ovaries. Results are being used to hypothesize potential key events for inclusion in an AOP. Results of these studies are intended to aid in the identification of response thresholds and/or tiered testing approaches that can more readily differentiate estrogenic exposures of concern from those that are likely too weak to cause adverse effects on reproduction. The results should aid multiple program offices involved in the ecological risk assessment of endocrine active chemicals.
Description:
Several adverse outcome pathways (AOPs) have linked endocrine related molecular initiating events like aromatase inhibition, androgen receptor (AR) agonism, and estrogen receptor (ER) antagonism, to reproductive impairment in adult (AOP25, AOP23, AOP30; aopwiki.com). It has been demonstrated that ER agonists can also lead to reproductive impairment in mature fish, however, the early key events (KEs) leading to this are mostly unknown. The aim of this study is to develop some hypotheses regarding the potential mechanisms through which exposure to exogenous ER agonists might lead to reproductive impairment in female fish. We exposed reproductively mature fathead minnows to low (1 ppt) and high (10 ppt) concentrations of 17α-ethinylestradiol (EE2), a strong ER agonist that is a common environmental pollutant, for 14 days. The response to EE2 was contrasted with that observed following a 14-day exposure to 17β-trenbolone (TRB) (500 ppt), a well-known AR agonist. Exposure to either high EE2 or TRB caused a decrease in plasma concentration of 17β-estradiol (E2) and ex vivo ovarian testosterone (T) production (albeit not significant in the case of high EE2). Exposure to high EE2 also caused a significant increase in plasma VTG and decrease in ex vivo ovarian E2 production. The cumulative eggs spawned/female over the experiment also decreased in both high EE2 and TRB treatments with a larger decrease in the TRB exposure. Based on these results and understanding of the hypothalamic–pituitary–gonadal axis (HPG axis), we hypothesize that ER agonism by EE2 causes negative feedback that results in decreased production of maturation inducing steroid leading to impaired oocyte maturation and ovulation, eventually resulting in a reduction in cumulative fecundity. Ovarian transcriptomic data from the experiment are being analyzed to evaluate consistency with our working hypothesis and/or provide insights into other potential key events based on Gene Set Enrichment Analysis and DAVID pathway enrichment analysis. The contents this abstract neither constitute nor necessarily reflect US EPA policy.
URLs/Downloads:
DOI: Identifying potential key events linking xenoestrogen exposures in female fathead minnows to reproductive impairment
MACKENZIE MORSHEAD SETAC POSTER_V4-M.PDF (PDF, NA pp, 480.998 KB, about PDF)