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A FETAL RAT TESTIS ENDOCRINE AND GENOMIC "SIGNATURE"ACCURATELY PREDICTS THE PHTHALATE SYNDROME OF MALFORMATIONS.
Citation:
GRAY, L. E., B. S. HANNAS, J. R. FURR, C. R. LAMBRIGHT, N. Evans, V. S. WILSON, AND P. Foster. A FETAL RAT TESTIS ENDOCRINE AND GENOMIC "SIGNATURE"ACCURATELY PREDICTS THE PHTHALATE SYNDROME OF MALFORMATIONS. Presented at Society of Toxicology(SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
Phthalate esters (PE) vary greatly in their potency to induce malformations during sexual differentiation in the male rat. Since in vitro assay batteries are currently unable to generate useful information on the potential of chemicals within this class to disrupt reproductive development, we evaluated these chemicals in a short term in vivo protocol (called the fetal phthalate screen: FPS) that relies upon testosterone production (T) and testis gene expression to discriminate "active" from "inactive" PEs
Description:
ABSTRACT BODY: Phthalate esters (PE) vary greatly in their potency to induce malformations during sexual differentiation in the male rat. Since in vitro assay batteries are currently unable to generate useful information on the potential of chemicals within this class to disrupt reproductive development, we evaluated these chemicals in a short term in vivo protocol (called the fetal phthalate screen: FPS) that relies upon testosterone production (T) and testis gene expression to discriminate "active" from "inactive" PEs. "Active" PEs are further evaluated in full dose response studies using the FPS protocol and relative potency factors are calculated. To date, approximately twenty PEs and alternatives have been evaluated at a single dosage level and about ten of these have been examined in dose response studies. These results demonstrate that "active" PEs produce a consistent "Signature" including reduced Tand cyp11b1, StAR, cyp17a1, SCARB, cyp11a1, HSD-313 and Insl3 gene expression (Hannas et ai, 2011). Comparison of the ED50s of the FPS Signatures, with the ED50s of the postnatal Phthalate Syndrome (pPS) reveals that this FPS Signature can be used to predict the potency of a PE to induce reproductive tract malformations. For example, in the FPS and in postnatal studies the relative potencies in mg/kg (ED50s for FPS:pPS) are dipentyl phthalate (50:132) >DBP (296:567) >DINP (846)1500)>>DIDP (no effectno effect). In addition, the relative potency factors for the FPS Signature can be used to predict the effects of mixtures of PEs in the fetal testis and on postnatal reproductive development. Although the current FPS protocol does not eliminate animal use it represents a considerable reduction in resources as it uses relatively small numbers of animals per dose group (3-5 litters) and only 5 days of dosing are required prior to necropsy. This abstract does not necessarily reflect EPA or NTP policy. NTP, NIEHS/EPA IA HHS Y1-ES8014- 01; EPA RW75922