Citation:

Ankley, G., K. Santana Rodriguez, K. Jensen, D. Miller, AND D. Villeneuve. AOP Report: Adverse Outcome Pathways for Aromatase Inhibition or Androgen Receptor Agonism Leading to Male-Biased Sex Ratio and Population Decline in Fish. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 42(4):747-756, (2023). https://doi.org/10.1002/etc.5581

Impact/Purpose:

Endocrine disrupting chemicals (EDCs) have been and continue to be of concern to EPA in terms of their potential to adversely affect human health and the environment. Given the large number of varied compounds (pesticides, drugs, some industrial products) that need to be assessed as possible EDCs, innovative approaches are needed to determine those chemicals of most concern. These approaches include rapid, cost-effective in vitro and in vivo measures that detect perturbation of endocrine pathways. However, to be useful for regulatory decision making, these measures of perturbation need to be translated into apical responses meaningful to risk assessment, such as changes in development or reproduction. The adverse outcome pathway (AOP) framework has been used to make the linkage between rapid measures of endocrine system changes and apical responses in a formalized manner. This subproduct describes two novel AOPs relating changes in the metabolism of sex steroids or activation of the androgen receptor to occurrence of male-biased fish populations, which is expected to directly affect long-term viability of the population. Consequently, these AOPs directly support the efforts of EPA, specifically OCSPP, to assess EDCs. This journal article summarizes a large amount of information concerning the two AOPs that is described in detail in a publicly accessible AOP-wiki.

Description:

Screening and testing of potential endocrine-disrupting chemicals for ecological effects are examples of risk assessment/regulatory activities that can employ adverse outcome pathways (AOPs) to establish linkages between readily measured alterations in endocrine function and whole organism– and population-level responses. Of particular concern are processes controlled by the hypothalamic–pituitary–gonadal/thyroidal (HPG/T) axes. However, the availability of AOPs suitable to meet this need is currently limited in terms of species and life-stage representation relative to the diversity of endpoints influenced by HPG/T function. In our report we describe two novel AOPs that comprise a simple AOP network focused on the effects of chemicals on sex differentiation during early development in fish. The first AOP (346) documents events starting with inhibition of cytochrome P450 aromatase (CYP19), resulting in decreased availability of 17β-estradiol during gonad differentiation, which increases the occurrence of testis formation, resulting in a male-biased sex ratio and consequent population-level declines. The second AOP (376) is initiated by activation of the androgen receptor (AR), also during sexual differentiation, again resulting in a male-biased sex ratio and population-level effects. Both AOPs are strongly supported by existing physiological and toxicological evidence, including numerous fish studies with model CYP19 inhibitors and AR agonists. Accordingly, AOPs 346 and 376 provide a basis for more focused screening and testing of chemicals with the potential to affect HPG function in fish during early development.

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