EPA Science Inventory

Use of Genomic Data in Risk Assessment Caes Study: II. Evaluation of the Dibutyl Phthalate Toxicogenomic Dataset

Citation:

EULING, S., L. D. WHITE, A. S. Kim, B. Sen, V. S. WILSON, C. KESHAVA, N. KESHAVA, S. D. HESTER, M. Ovacik, M. Ierepetritou, A. Ioannis, AND K. W. Gaido. Use of Genomic Data in Risk Assessment Caes Study: II. Evaluation of the Dibutyl Phthalate Toxicogenomic Dataset. TOXICOLOGICAL AND APPLIED PHARMICOLOGY. Elsevier Science BV, Amsterdam, Netherlands, doi:10.1016(j.taap.2011):1-14, (2011).

Description:

An evaluation of the toxicogenomic data set for dibutyl phthalate (DBP) and male reproductive developmental effects was performed as part of a larger case study to test an approach for incorporating genomic data in risk assessment. The DBP toxicogenomic data set is composed of nine in vivo studies from the published literature that exposed rats to DBP during gestation and evaluated gene expression changes in testes or Wolffian ducts of male fetuses. The exercise focused on qualitative evaluation, based on a lack of available dose-response data, ofthe DBP toxicogenomic data set to postulate modes and mechanisms of action for the male reproductive developmental outcomes, which occur in the lower dose range. A weight-of evidence evaluation was performed on DBP testis toxicogenomic studies across all eight studies at the gene and pathway levels. The results showed relatively strong evidence of DBP-induced downregulation of genes in the steroidogenesis pathway and lipid/sterol/cholesterol transport pathway as well as effects on immediate early gene/growth/differentiation, transcription, peroxisome proliferator-activated receptor signaling and apoptosis pathways in the testis. Since two established modes of action (MOAs), reduced fetal testicular testosterone production and Insl3 gene expression, explain some but not all ofthe testis effects observed in rats after in utero DBP exposure, other MOAs are likely to be operative. A reanalysis ofone DBP microarray study identified additional pathways within cell signaling, metabolism, hormone, disease, and cell adhesion biological processes. These putative new pathways may be associated with DBP effects on the testes that are currently unexplained. This case study on DBP identified data gaps and research needs for the use of toxicogenomic data in risk assessment. Furthermore, this study demonstrated an approach for evaluating toxicogenomic data in human health risk assessment that could be applied to future chemicals.

Purpose/Objective:

This case study on DBP identified data gaps and research needs for the use of toxicogenomic data in risk assessment

URLs/Downloads:

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Start Date: 06/30/2011
Completion Date: 06/30/2011
Record Last Revised: 01/25/2013
Record Created: 12/30/2010
Record Released: 12/30/2010
OMB Category: Other
Record ID: 232223

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

INTEGRATED SYSTEMS TOXICOLOGY DIVISION

SYSTEMS BIOLOGY BRANCH