Use of genomic data in risk assessment case study: II. Evaluation of the dibutyl phthalate toxicogenomic data set

Toxicol Appl Pharmacol. 2013 Sep 15;271(3):349-62. doi: 10.1016/j.taap.2011.06.014. Epub 2011 Jun 30.


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, of the 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 the eight DBP toxicogenomic studies of the rat testis 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 of the testis effects observed in rats after in utero DBP exposure, other MOAs are likely to be operative. A reanalysis of one 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.

Keywords: AGD; BBP; DBP; DEG; DEHP; DEP; DMP; DOTP; DPP; Development; EST; FDR; GD; GO; IRIS; Insl3; Integrated Risk Information System; LC; LOAEL; LOEL; Leydig cells; MAQC; MOA; Male reproduction; NIEHS; NOAEL; NOEL; National Institute of Environmental Health Sciences; PCA; PPAR; Phthalate syndrome; Phthalates; REM; RT-PCR; Risk assessment; Rosetta error model; SD; SNR; STAR; Science to Achieve Results; Sprague–Dawley; T; Testicular dysgenesis syndrome; Testosterone; Toxicogenomic; U.S. Environmental Protection Agency; US EPA; WD; WOE; Wolffian duct; anogenital distance; benzyl butyl phthalate; di-(2-ethylhexyl) phthalate; dibutyl phthalate; diethyl phthalate; differentially-expressed gene; dimethyl phthalate; dioctyl tere-phthalate; dipentyl phthalate; expressed sequence tag; false discovery rate; gene ontology; gestation day; insulin-like 3; lowest observed adverse effect level; lowest observed effect level; microarray quality control project; mode of action; no observed adverse effect level; no observed effect level; peroxisome proliferator-activated receptor; principal component analysis; reverse transcription-polymerase chain reaction; signal-to-noise ratio; testosterone; weight-of-evidence.

MeSH terms

  • Animals
  • Dibutyl Phthalate / toxicity*
  • Environmental Pollutants / toxicity*
  • Gene Expression Regulation / drug effects*
  • Genomics
  • Male
  • Oligonucleotide Array Sequence Analysis
  • Plasticizers / toxicity*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Assessment
  • Testis / drug effects*
  • Testis / metabolism


  • Environmental Pollutants
  • Plasticizers
  • Dibutyl Phthalate