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Evaluation of genomic biomarkers and relative potency of phthalate-induced male reproductive developmental toxicity using a targeted rtPCR array approach**
Citation:
HANNAS, B. S., C. R. LAMBRIGHT, J. R. FURR, N. Evans, P. D. Foster, L. E. GRAY, AND V. S. WILSON. Evaluation of genomic biomarkers and relative potency of phthalate-induced male reproductive developmental toxicity using a targeted rtPCR array approach**. Presented at Society of Toxicology (SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
Exposure to certain phthalate esters (PEs) during sexual differentiation induces reproductive tract malformations in male rats due to reductions in fetal testicular testosterone (T) production and expression of steroidogenesis-and insl3-related genes. In the current study, we used a 96-well rtPCR array containing key target genes representing sexual determination and differentiation, steroldogenesls, gubernaculum development, and androgen signaling pathways to rank the relative potency of several PEs.
Description:
Exposure to certain phthalate esters (PEs) during sexual differentiation induces reproductive tract malformations in male rats due to reductions in fetal testicular testosterone (T) production and expression of steroidogenesis-and insl3-related genes. In the current study, we used a 96-well rtPCR array containing key target genes representing sexual determination and differentiation, steroldogenesls, gubernaculum development, and androgen signaling pathways to rank the relative potency of several PEs. We performed dose-response studies in which we dosed dams gestational day (GD) 14-18 with diisobutyl (DIBP) dipentyl (DPeP) dihexyl (DHP) diheptyl (DHeP), diisononyl (DINP), or diisodecyl phthalate (DIDP) and serial dilutions of a mixture of 9 phthalates. All phthalates, with the exception of DIDPJreduced fetal testicular T production. Several genes involved in cholesterol transport, androgen synthesis and insl3 were down-regulated in a dose responsive manner by DIBP, DPeP, DHP, DHeP, DINP, and the 9-PE mixture. Despite speculation about PPAR involvement in the effects of PEs on the fetal testis, the potent PPARα agonist WY-14643 did not induce PPAR-related genes or reduce fetal testicular T production or expression levels of related genes following GD 14-18 exposure, indicating that the anti-androgenic activity of PEs is not PPARα-mediated. The overall sensitivity of the fetal endpoints (gene expression or T production) for the six phthalates from most to least was: Cyp11b1>SR-B1>StAR>T production>Cyp11a1>Cyp17a1> insI3>HSD-3P >Cyp11b2. The overall potency of the individual phthalates was: DPeP>DHP> DHeP> DIBP> DINP. Finally, the observed mixture interaction was adequately modeled by the dose-addition model for most of the affected genes. These data advance our understanding of the collective reproductive toxicity of PE compounds. Disclaimer: This abstract does not necessarily reflect EPA policy.