Citation:

Gray, E., J. Furr, J. Conley, C. Lambright, N. Evans, M. Cardon, V. Wilson, P. Foster, AND P. Hartig. A Conflicted Tale of Two Novel AR Antagonists In vitro and In vivo: Pyrifluquinazon versus Bisphenol C. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, , 632-643, (2019). https://doi.org/10.1093/toxsci/kfz010

Impact/Purpose:

Predicting the effects from in vitro to in vivo adverse effects for endocrine disrupting chemical is a major goal of the EDSP, EPA and part of the effort to reduce, refine and replace animal use with new approach methodology. Herein, we examined some of the limitations of extrapolating from in vitro androgen receptor binding and gene expression assays to adverse effects in utero on the male rat reproductive tract. These results indicate that ADME analyses must be included in attempts to extrapolate from in vitro AR assays to in vivo adverse effects.

Description:

Chemicals that disrupt androgen receptor function during sexual differentiation in utero induce a cascade of adverse effects on F1 male reproductive development including reduced AGD, retained nipples, agenesis of androgen-dependent organs and reproductive tract malformations. Among the chemicals that act as androgen receptor (AR) antagonists are flutamide, vinclozolin, and procymidone. Efforts are underway to use in vitro AR antagonism data to predict the adverse effects of in vivo exposure; however, the value of this approach has only been examined with a limited number of carefully selected reference chemicals. The objective of the current study is to compare the in vitro and in vivo activity of two novel AR antagonists, bisphenol C (BPC) and pyrifluquinazon (PFQ). Our results, like those in the literature, demonstrate that BPC is as potent as hydroxyflutamide in vitro, both being orders of magnitude more potent than PFQ. However, the ability of BPC to disrupt androgen-signaling in vivo has not been described. PFQ has been reported to interact with the rat AR, but not human AR, at high concentrations and to reduce androgen dependent tissue weights in the rat Hershberger assay. The objective of this study was to compare the potency of BPC to PFQ in vitro and their effects in vivo on reproductive development in male rat offspring. BPC was about 380-fold more potent than PFQ in vitro, but it was only about 2.5% as potent as PFQ in reducing AGD at birth and in inducing male reproductive tract abnormalities. In the absence of ADME models, extrapolating the effects of AR antagonists from in vitro to in vivo is an uncertain process, at best.

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