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STRUCTURE ACTIVITY RELATIONSHIP OF PHTHALATE ESTERS TO INHIBITED FETAL TESTICULAR TESTOSTERONE PRODUCTION IN THE SPRAGUE DAWLEY RAT
Citation:
HOWDESHELL, K., J. R. FURR, C. R. LAMBRIGHT, V. S. WILSON, AND L. EARL GRAY. STRUCTURE ACTIVITY RELATIONSHIP OF PHTHALATE ESTERS TO INHIBITED FETAL TESTICULAR TESTOSTERONE PRODUCTION IN THE SPRAGUE DAWLEY RAT. Presented at Triangle Consortium for Reproductive Biology, Chapel Hill, NC, January 27, 2007.
Description:
Several of the phthalate esters (widely used as plasticizers of polyvinyl chloride and other applications) have been shown to inhibit fetal testicular testosterone (T) production and Insl3 mRNA in the laboratory rat. The current study was designed to define the dose response of 7 individual phthalates with respect to their impact on fetal T production. Time-pregnant Sprague Dawley female rats were administered oral doses from gestation day (GD) 8 through 18 with a broad dose range (25-900 mg/kg/d) of the following phthalates: benzyl butyl phthalate, BBP; dibutyl phthalate, DBP; diisobutyl phthalate, DiBP; diisoheptyl phthalate, DiHP; dipentyl phthalate, DPP; diethyl phthalate, DEP; and di-n-heptyl phthalate, DnHP. On GD18, fetal testes were collected and incubated ex vivo for fetal T production. We report that fetal T production was suppressed by phthalates with monoester metabolites of 4 to 6 carbons in the ortho position, whereas those with longer or shorter side chains (or in the para-position) were inactive. BBP, DBP and DiBP were of similar potency to the known reproductive toxicant diethylhexyl phthalate (DEHP). DiHP and DPP were 2-fold and 5-fold more potent than DEHP, respectively. As expected based on structure, a range of 100 to 900 mg/kg/d DEP and DnHP did not significantly reduce fetal T production. The same phthalates that inhibited fetal T production also caused mid-pregnancy fetal loss, albeit at higher dose levels. The fetal resorptions are consistent with previously reported phthalate-induced suppression of progesterone during pregnancy. In conclusion, the ability of phthalates to suppress fetal T production is determined by their monoester metabolite structure and the SAR of our study was the same as that reported in pubertal male rats. We plan to use the relative potency data of the bioactive phthalates to design mixture studies measuring the effects of phthalate mixtures on fetal T production and Insl3 gene expression.