Citation:

Conley, J., C. Lambright, N. Evans, V. Wilson, AND E. Gray. Mixtures that Target Male Reproductive Tract Development. Society of Toxicology, Baltimore, MD, March 10 - 14, 2019.

Impact/Purpose:

This abstract is for an invited presentation at the 2019 Society of Toxicology meeting in a Workshop titled "Applying Systems Biology Approaches to Understand the Joint Action of Chemical and Nonchemical Stressors" organized by Cynthia Rider (NIEHS/NTP). This presentation will highlight the "antiandrogen" Adverse Outcome Pathway network developed by Earl Gray and his current and former postdocs and the relevant mixtures studies that have been conducted at EPA. Multiple experiments in Dr. Gray's lab, and others internationally, have clearly demonstrated the cumulative effects of environmental chemicals on disruption of male reproductive tract development. The AOP network approach is a synthetic framework for organizing the variety of molecular mechanisms and key events that lead to adverse male reproductive development and are informative for researchers and risk assessors.

Description:

Two of the most commonly occurring human birth defects are hypospadias of the phallus and cryptorchidism of one or both testes. Further, reductions in adult sperm counts have been reported in multiple countries. Increases in the prevalence rates of these disorders over the past several decades have been reported and exposure to environmental chemicals has been suggested as a causal factor. A variety of environmental chemicals that operate via a range of molecular mechanisms have been shown to produce male reproductive tract disorders following in utero exposures in laboratory animal experiments. For example, androgen receptor (AR) antagonists (such as vinclozolin) and some phthalates, which decrease testicular testosterone but do not interfere with AR activity, have both been shown to elicit dose-dependent increases in male reproductive tract malformations. During the last 10-15 years we have used a systems biology approach to incorporate these diverse mechanisms of male reproductive tract disruption into an Adverse Outcome Pathway (AOP) network. The AOP network converges on adverse outcomes of the developing male reproductive tract and serves as a conceptual model for the design and evaluation of complex mixtures studies. An underlying hypothesis of these mixtures studies is that although the chemicals target different molecular initiating events, their convergence at critical key events will ultimately lead to dose additive adverse effects when exposure occurs as a complex mixture. Results indicate that, despite acting through disparate molecular mechanisms, chemicals impacting male reproductive development act cumulatively to produce adverse effects similar to those observed in human populations. Moving forward, AOP networks provide a mechanistically-based framework for grouping chemicals, addressing mixture hazards, and in conducting cumulative risk assessments. Abstract does not necessarily reflect USEPA policy.

Record Details: