Citation:

Gray, E., C. Lambright, N. Evans, V. Wilson, B. Hannas, P. Foster, AND J. Conley. Biological Relevance of Phthalate-Induced Disruption of Fetal Testis Hormones and Gene Expression: Key Events in a Novel AOP. Society of Toxicology - Virtual, NA, Virtual, March 12 - 26, 2021.

Impact/Purpose:

This research provides a method (NAM) using a short term in vivo fetal testis screen measuring testosterone production to accurately predict the doses that produce adverse effects on the development of the male rat reproductive tract

Description:

Previously, we demonstrated that exposure to some diortho-phthalate esters (PEs) during sexual differentiation disrupts fetal rat testis insl3 and testosterone production (T Prod) and testis gene expression in a dose related manner (Furr et al., 2015; Hannas et al., 2012). The objectives of the current project were to expand the number of PEs, PE alternatives, pesticides, and drugs and to relate these fetal testis alterations to adverse effects in the reproductive tract of the male offspring. The pesticides included those that are known or suspected to reduce T Prod and those that do not. We also included several PPAR agonists hexafluoropropylene oxide-dimer acid (GenX, Conley et al., 2019), pirixinic acid (WY 14643), clofibrate since it has been hypothesized that the PEs disrupt male sex differentiation via PPAR receptors and acetaminophen, which reportedly reduces fetal T Prod like the PEs. We found that PEs that disrupt T Prod also disrupted testis expression of about mRNA for about 35 genes related to sterol transport, T and insl3 hormone syntheses, and lipoprotein and cholesterol synthesis. PEs had little or no effect however on mRNA expression for genes in the PPAR pathway in the fetal liver whereas the three PPAR agonists induced the expression of mRNA for multiple PPAR pathway genes without reducing T Prod. Linuron, prochloraz, 4-methylimidazole, bisphenol C, reduced T Prod, whereas acetaminophen, vinclozolin, flutamide, DINCH, DPHP, hexaconazole had no effect on T Prod. Dexamethasone reduced T Prod but only at dosage levels that also induced maternal weight loss. The T Prod data were compared to the effects of PEs and mixtures of PEs to the reproductive abnormalities in male rat offspring to describe the biological relevance of these reductions using data from PEs studied in our laboratory and studies from the literature. We found that this relationship was nonlinear with the slope of the malformation rate increasing steeply as T Prod is reduced by more than 35 to 50% of control. In summary, PEs that disrupt T Prod act via a novel AOP includes down regulation of mRNA levels for genes involved in fetal endocrine function and cholesterol synthesis and metabolism. This profile was not displayed by PEs that did not reduce T Prod, PPAR agonists or the other chemicals. We also demonstrate that the reductions in fetal T Prod in utero can be used quantitatively to predict the doses that produce adverse reproductive tract effects in the male offspring. This abstract does not reflect EPA policy

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