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Assessment of fetal testis function and postnatal development of the male rat following in utero exposure to diethylhexyl phthalate, dipentyl phthalate, diisobutyl phthalate, diisoheptyl phthalate and diisononyl phthalate
Hannas, B., J. R. FURR, C. R. LAMBRIGHT, V. S. WILSON, AND L. E. GRAY. Assessment of fetal testis function and postnatal development of the male rat following in utero exposure to diethylhexyl phthalate, dipentyl phthalate, diisobutyl phthalate, diisoheptyl phthalate and diisononyl phthalate. Presented at North Carolina Society of Toxicology (NC SOT), President's Award for Research Competition (PARC), RTP, NC, October 07, 2010.
The current study examined the effects of DPeP, DIBP, DIHP and DINP on fetal testis endocrinology and compared the results to the well studied phthalate diethylhexyl phthalate (DEHP).
Phthalate esters are a large class of plasticizer compounds widely used in many consumer product applications. Some phthalates induce male fetal endocrine toxicity and reproductive malformations through disruption of hormone production during sexual differentiation. Regulatory agencies require dose response and potency data to facilitate risk assessment of these compounds. Although some phthalates have been extensively studied, insufficient dose-response data are available for several phthalates including: dipentyl phthalate (DPeP), diisobutyl phthalate (DIBP), diisoheptyl phthalate (DIHP) and diisononyl phthalate (DINP). The current study examined the effects of DPeP, DIBP, DIHP and DINP on fetal testis endocrinology and compared the results to the well studied phthalate diethylhexyl phthalate (DEHP). In this study, we hypothesize that: (1) DPeP reduces fetal testicular testosterone (T) production and expression levels of hormone production-related genes and induces postnatal male reproductive malformations with greater potency than DEHP, and (2) DIHP and DIBP are equally potent to and DINP is less potent than DEHP for reducing fetal T production. To test these hypotheses, we dosed maternal rats on gestational day (GD) 14-18 with 0, 11,33, 100,300 mg/kg/d DPeP and subsequently evaluated fetal ex vivo testicular testosterone (T) production or testes gene expression changes for the hormone synthesis related genes StAR, Cypl l a, and Ins13 at GDI8. In addition we administered the same doses of DPeP to pregnant rats on GD 8-18 and evaluated the early postnatal endpoints of decreased anogenital distance (AGD) at postnatal day (PND) 2 and nipple retention at PND 13 in male offspring. We conducted similar dose response experiments to compare the effects of di-isoheptyl phthalate (DIHP), di-isobutyl phthalate (DIBP) and diisononyl-phthalate (DINP) to DEHP (administered GDI4-I8) on fetal testes T production on GDI8. Relative potency of phthalates was determined using ED50 values derived from regression analysis of the dose response data for each phthalate and the respective endpoints. As hypothesized, comparison of ED50s for these phthalates indicates that DIBP and DIHP reduced fetal testicular T production with similar potency to DEHP (p>0.3), whereas DINP was 2.3-fold less potent than DEHP (Fig 1). DPeP was approximately 8-fold more potent in reducing fetal T production relative to DEHP' DffiP and DIHP (Fig. 1), approximately 6-fold more potent in reducing StAR and Ins13 expression (Fig. 2a, b) and 3-fold more potent in reducing Cyp l l a expression relative to DEHP (Fig. 2c), making DPeP a good model phthalate for performing future mechanistic studies that require robust responses. Examination of the effects of the tested phthalates on neonatal male rat anogenital distance and nipple retention indicates that the relative potency of these compounds seen in utero is predictive oftheir potency to disrupt postnatal development of androgen-dependent tissues. Overall, the current study provides novel fetal endocrine dose response data on the effects of DPeP, DIHP, DIBP and DINP that should be useful to regulators conducting individual and cumulative risk assessments on the phthalates. This abstract does not necessarily reflect EPA policy.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
TOXICOLOGY ASSESSMENT DIVISION
REPRODUCTIVE TOXICOLOGY BRANCH