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
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Administration of individual chemicals and mixtures during sexual differentiation that disrupt the androgen signaling pathway can induce reproductive abnormalities in male rats. In the current study, we co-administered the heptafluoroisopropyl pesticide pyrifluquinazon (PFQ, CAS 337458-27-2 , 1-Acetyl-6-(perfluoropropan-2-yl)-3-((pyridin-3-ylmethyl)amino)-3,4-dihydroquinazolin-2(1H)-one) and dibutyl phthalate (DBP, CAS 84-74-2) to pregnant rats during sexual differentiation of the reproductive tract. Both chemicals have been shown to disrupt male reproductive tract differentiation in a dose-related manner reducing male anogenital distance (AGD), permanently reducing androgen-dependent tissue weights and sperm counts, and inducing reproductive malformations in male rat offspring, albeit by different mechanisms of action that converge downstream in the androgen signaling pathway on a common key event. Rat dams were orally dosed from gestation days 14-18 with dilutions of a fixed ratio mixture 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 or response addition models, or whether significant interactions such as synergy or antagonism occurred. For each endpoint observed data were compared to dose addition and response addition model predictions. As hypothesized, the mixture reduced F1 male AGD, reproductive organ weights and sperm counts and induced hypospadias with dose addition consistently providing a better prediction of the observed effects than response addition. These results confirmed our hypothesis that chemicals that disrupt the androgen signaling pathway induce dose-additive male reproductive abnormalities regardless the specific mechanism of action.