Comparison of in utero phthalate exposure on fetal rat testis transcript and endocrine alterations with apical reproductive alterations in male rats

Abstract

In utero administration of some diortho phthalate esters (PEs) produces reproductive tract malformations in male and female rat offspring via unknown molecular initiating events. Although the molecular initiating event(s) for these effects are unknown, the PEs consistently alter several key endocrine and gene expression events in the fetal male rat providing a signature of in utero PE exposure. We compared the dose-related alterations of in utero PE exposure on gene expression levels, measured with targeted RT-qPCR custom arrays, and ex vivo testosterone production (T Prod) with the reproductive alterations seen in F1 male rats from three different PE studies. The PEs studied included dicyclohexyl (DCHP) and dipentyl phthalate (DPeP) and a mixture study with five phthalates (DCHP, diethylhexyl (DEHP), dibutyl (DBP), butyl benzyl (BBP), and diisobutyl phthalate (DiBP)). These results demonstrate that targeted testis gene expression and/or T Prod data from short-term prenatal studies conducted during a critical window of fetal masculinization can be used to determine points-of-departure (PODs) for PEs and that these PODs are several fold more protective than the apical effects in postnatal animals. The clear linkage of these gene transcript and testosterone changes to the adverse effects of in utero exposure can facilitate acceptance of the use of gene expression and endocrine data to determine PODs for risk assessment. Furthermore, the use of gene expression and endocrine data from short-term in vivo fetal studies in place of multigenerational reproductive studies for POD determination for PE and mixtures of PEs could increase the rate of POD development for risk assessment and reduce use of animals and other resources.