In utero exposure to a mixture of the perfluoroalkylisopropyl pesticide pyrifluquinazon with dibutyl phthalatecumulatively disrupts male rat reproductive development via different mechanisms of action
Administration of individual of 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 heptafluoro-isopropyl 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 on from day 14 to 18 via oral gavage. 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 toxicity that converge downstream in the androgen signaling pathway on a common key event. The experiment is a fixed ratio dilution study and rats were dosed with 0, 12.5, 25, 50, 75 and 100% of the top dose (100 mg/kg PFQ and 750 mg/kg DBP). These two chemicals disrupt the development of many of the same tissues and this mixture ratio was selected such that each chemical would contribute to multiple effects on the reproductive tract and the dose range was designed to determine if the mixture interacted in a synergistic, antagonistic, or additive manner as compared to the dose addition prediction for each endpoint.
As hypothesized, the mixture reduced AGD, reduced reproductive organ weights and sperm counts and induced reproductive malformations in males in an additive manner with dose addition providing as good or better prediction of the observed effects. These results confirmed our hypothesis that chemicals that disrupt the androgen signaling pathway induce dose-additive male reproductive abnormalities regardless the mechanism of toxicity.