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PUTATIVE ADVERSE OUTCOME PATHWAY FOR INHIBITON OF BRAIN AROMATASE IN FISH LEADING TO REPRODUCTIVE IMPAIRMENT
Citation:
Mills, L., T. Johnston, AND S. Laws. PUTATIVE ADVERSE OUTCOME PATHWAY FOR INHIBITON OF BRAIN AROMATASE IN FISH LEADING TO REPRODUCTIVE IMPAIRMENT. Society of Toxicology 56th Annual Meeting, Baltimore, Maryland, March 12 - 16, 2017.
Impact/Purpose:
The purpose of this abstract is to describe the contents of a poster to be prepared for the 56th annual meeting of the Society of Toxicology. The poster will show a putative adverse outcome pathway for inhibition of brain aromatase in fish leading to reproductive impairment.
Description:
The adverse outcome pathway (AOP) provides a framework for organizing knowledge to define links between a molecular initiating event (MIE) and an adverse outcome (AO) occurring at a higher level of biological organization, such as the individual or population. The AOP framework proceeds from a general (e.g., not chemical specific) molecular mode of action, designated as a MIE, through stepwise changes in biological status, defined as key events (KEs), to a final AO that can be used in risk assessment. Because aromatase-inhibiting pharmaceuticals are widely used to treat breast cancer patients, we explored the unintended consequences that might occur in fish exposed to these chemicals through wastewater discharge into the aquatic environment. Unlike mammals, fish have two isoforms of aromatase, one that predominates in the ovary (cyp19a1a) and a second (cyp19a1b) that prevails in the brain. Aromatase activity in fish brain can be 100 to 1000 times that in mammals and is associated with reproduction. We have developed a putative AOP for inhibition of brain aromatase in fish leading to reproductive dysfunction based on review of relevant literature and reproductive experiments with the marine fish cunner (Tautogolabrus adspersus) exposed to aromatase-inhibiting pharmaceuticals in the laboratory. The first KE in this AOP is a decrease in brain aromatase activity due to exposure to an aromatase inhibitor. KEs then progress through subsequent steps including decreased production of estradiol by aromatase-containing radial glial cells, reduced release of gonadotropin releasing hormone by the hypothalamus, decreased release of luteinizing hormone by the pituitary, lowered production of maturation inducing hormone in ovary or testis, and decreased gamete production. These KEs lead to the final AO of reproductive impairment at the level of the individual. Biological plausibility and empirical evidence for each KE are summarized and essentiality of the proposed KEs is considered in the context of the entire AOP.