In Utero Exposure to a Mixture of the Perfluoroalkyl-Isopropyl Pesticide Pyrifluquinazon With Dibutyl Phthalate Cumulatively Disrupts Male Rat Reproductive Development via Different Mechanisms of Action

Abstract

Abstract Administration of individual chemicals and mixtures during sexual differentiation that disrupt the androgen signaling pathway can induce reproductive abnormalities in male rats. In this study, we coadministered the heptafluoroisopropyl pesticide pyrifluquinazon (PFQ), and dibutyl phthalate (DBP) to pregnant rats during sexual differentiation of the reproductive tract. Both chemicals have been shown to disrupt reproductive tract differentiation in a dose-related manner reducing male anogenital distance, permanently reducing androgen-dependent tissue weights and sperm counts, and inducing reproductive malformations in male offspring, albeit by different mechanisms of action that converge downstream in the androgen signaling pathway on a common key event. Rats were orally dosed from gestation days 14–18 with dilutions of PFQ and DBP at 0%, 12.5%, 25%, 50%, 75%, and 100% of the top dose (100 mg/kg PFQ and 750 mg/kg DBP). The mixture ratio was selected such that each chemical would contribute equally to multiple effects on the male offspring reproductive tract and the dose range was designed to determine if the mixture produced additive effects predicted by dose addition (DA) or response addition (RA) models, or whether significant interactions occurred. Observed data were compared with DA and RA model predictions. As hypothesized, the mixture reduced F1 male anogenital distance, reproductive organ weights and sperm counts and induced hypospadias with DA consistently providing a better prediction of the observed effects than RA. These results support our hypothesis that chemicals that disrupt the androgen signaling pathway induce dose-additive male reproductive abnormalities regardless of the specific mechanism of action.