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Cross-Species Conservation of Endocrine Pathways: A Critical Analysis of Tier 1 Fish and Rat Screening Assays with 12 Model Chemicals
Citation:
Ankley, G. AND E. Gray. Cross-Species Conservation of Endocrine Pathways: A Critical Analysis of Tier 1 Fish and Rat Screening Assays with 12 Model Chemicals. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 32(5):1084-1087, (2013).
Impact/Purpose:
Many structural and functional aspects of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis are known to be highly conserved, but the full significance of this from a toxicological perspective has received comparatively little attention. High-quality data generated through development and validation of Tier 1 tests for the USEPA Endocrine Disruptor Screening Program (EDSP) offer a unique opportunity to compare responses of mammals versus fish to chemicals that may affect shared pathways within the HPG axis. Our current analysis focuses on data generated with 12 model chemicals tested in the EDSP 21-d fathead minnow test and in one or more of the four in vivo rat Tier 1 screens (Uterorophic, Hershberger, male and female pubertal assays). There was high concordance between the fish and rat assays with respect to identifying chemicals that impacted specific endocrine pathways of concern. The fish assay identified all 12 chemicals as endocrine-active, while one or more of the rat tests produced positive results for 11 of the 12 chemicals. Our results are significant both to the cross-species extrapolation of toxicity of HPG-active substances, and the optimization of screening/testing frameworks for endocrine-disrupting chemicals.
Description:
Many structural and functional aspects of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis are known to be highly conserved, but the full significance of this from a toxicological perspective has received comparatively little attention. High-quality data generated through development and validation of Tier 1 tests for the USEPA Endocrine Disruptor Screening Program (EDSP) offer a unique opportunity to compare responses of mammals versus fish to chemicals that may affect shared pathways within the HPG axis. Our current analysis focuses on data generated with model chemicals that act (primarily) as estrogen receptor agonists (17á-ethynylestradiol, methoxychlor, bisphenol A), androgen receptor agonists (methyltestosterone, 17â-trenbolone), androgen receptor antagonists (flutamide, vincolozolin, p,p’-DDE) or inhibitors of different steroidogenic enzymes (ketoconazole, fadrozole, fenarimol, prochloraz). All 12 chemicals had been tested in the EDSP 21-d fathead minnow test and in one or more of the four in vivo rat Tier 1 screens (Uterorophic, Hershberger, male and female pubertal assays). There was high concordance between the fish and rat assays with respect to identifying chemicals that impacted specific endocrine pathways of concern. The fish assay identified all 12 chemicals as endocrine-active, while one or more of the rat tests produced positive results for 11 of the 12 chemicals. Our results are significant both to the cross-species extrapolation of toxicity of HPG-active substances, and the optimization of screening/testing frameworks for endocrine-disrupting chemicals.
