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Are anti-androgenic effects of phthalates on the fetal testis mediated via a peroxisome proliferator activated receptor-α (PPAR-α) associated molecular initiating event?
Citation:
Wilson, V., C. Lambright, N. Evans, J. Furr, J. Conley, M. Cardon, AND E. Gray. Are anti-androgenic effects of phthalates on the fetal testis mediated via a peroxisome proliferator activated receptor-α (PPAR-α) associated molecular initiating event? SOT, San Antonio, TX, March 11 - 15, 2018.
Impact/Purpose:
The molecular initiating event (MIE) leading to phthalate induced fetal male reproductive toxicity is unknown. It has been proposed , however, to be PPAR-alpha mediated. This evaluated that hypothesis and the results support that the MIE for phthalate mediated male toxicity in the fetal testis in not through activation of PPAR alpha.
Description:
In utero exposure to certain phthalate esters (PE) during the critical window of male sex differentiation reduces both fetal testis testosterone (T) production and expression of steroid transport and synthesis genes, resulting in reproductive tract malformations in adult male rodents. While the molecular initiating event (MIE) leading to this phthalate induced fetal male reproductive toxicity is unknown, it has been proposed to be PPAR-alpha mediated. To evaluate this hypothesis, we conducted multiple studies comparing effects of a potent PE and 2 PPAR-α agonists on T production and gene expression in fetal testes and liver. Sprague Dawley dams were dosed from GD 14-18 with corn oil vehicle or dipentyl phthalate (DPeP; 11 – 300 mg/kg/day), PPAR-alpha agonists WY14643 (WY; 100 – 400 mg/kg/day) or clofibrate (100 – 400 mg/kg/day). On GD18, ex vivo fetal testis T production and gene expression in fetal testes and livers were assessed using 2 Qrt-PCR arrays (1. Custom gene set e.g. steroid transport and synthesis, sex determination, testis differentiation, androgen and PPAR signaling, etc; 2. PPAR pathway specific genes (Qaigen PARN-149ZD)). In the fetal livers, the PPAR- agonists WY and clofibrate had pronounced effects on PPAR pathway genes (e.g. Ehhadh, Fabp1, Angptl4) while DPeP was significantly less potent and activated few PPAR specific genes. In the fetal testis, DPeP significantly altered genes associated with steroid transport and steroidogenesis on the custom array but WY and clofibrate did not. PPAR genes were much less impacted by WY in the testes than in the liver and PE did not consistently affect PPAR related genes in the testis. Further, fetal testis T production was significantly reduced by DPeP but not by WY or clofibrate. Taken together, these results support the hypothesis that activation of the PPAR-α pathway is not the MIE in phthalate-mediated male reproductive toxicity in the fetal rat testis. Disclaimer: This abstract does not necessarily reflect USEPA policy.