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Dose-response assessment of fetal testosterone production and gene expression levels in rat testes following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate and diisononyl phthalate
Citation:
Hannas, B., C. R. LAMBRIGHT, J. R. FURR, K. HOWDESHELL, L. E. GRAY, AND V. S. WILSON. Dose-response assessment of fetal testosterone production and gene expression levels in rat testes following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate and diisononyl phthalate. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 123(1):206-13, (2011).
Impact/Purpose:
The goal of the current study was to enhance understanding of this class of compounds in the Sprague Dawley (SD) fetal rat following exposure on gestational days (GD) 14-18 by determining the relative potency factors for several phthalates on fetal testes endpoints, the effects of a nine phthalate mixture on fetal testosterone (T) production, and differences in SD and Wistar (W) strain responses of fetal T production and testicular gene expression to di(2ethylhexyl) phthalate (DEHP).
Description:
Several phthalate esters have been linked to the Phthalate Syndrome, affecting male reproductive development when administered to pregnant rats during in utero sexual differentiation. The goal of the current study was to enhance understanding of this class of compounds in the Sprague Dawley (SD) fetal rat following exposure on gestational days (GD) 14-18 by determining the relative potency factors for several phthalates on fetal testes endpoints, the effects of a nine phthalate mixture on fetal testosterone (T) production, and differences in SD and Wistar (W) strain responses of fetal T production and testicular gene expression to di(2ethylhexyl) phthalate (DEHP). We determined that di-isobutyl phthalate (DIBP) and diisoheptyl phthalate (DIHP) reduced fetal testicular T production with similar potency to DEHP, while diisononyl phthalate (DINP) was 2.3 fold less potent. DINP was also less potent at reducing StAR and Cyp l la gene expression levels, whereas DIBP was slightly more potent than DEHP. We observed that administration of dilutions of a mixture of nine phthalates (DEHP, DIHP, DIBP, dibutyl-, benzyl butyl-, dicyclohexyl-, diheptyl-, dihexyl-and dipentyl phthalate) reduced fetal T production in a dose-dependent manner best predicted by dose addition. Finally, we found that the differential effects of in utero DEHP treatment on epididymal and gubemacular differentiation in male SD and W rats (0, 100, 300, 500, 625, 750 or 875 mg DEHP /kg/day) are likely due to tissue specific strain differences in the androgen and ins13 signaling pathways rather than differential effects of DEHP on fetal testis T and ins13 production.
