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Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: A targeted rtPCR array approach for defining relative potency
Hannas, B., C. Lambright, J. Furr, N. Evans, P. Foster, E. Gray, AND V. Wilson. Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: A targeted rtPCR array approach for defining relative potency. Oxford (ed.), TOXICOLOGICAL SCIENCES 125(2):544-57, (2012).
Male rat fetuses exposed to certain phthalate esters (PEs) during sexual differentiation display reproductive tract malformations due to reductions in testosterone (T) production and the expression of steroidogenesis-and INSL3-related genes. In the current study} we used a 96well rtPCR array containing key target genes representing sexual determination and differentiation} steroidogenesis} gubernaculum development} and androgen signaling pathways to rank the relative potency of several PEs. We executed dose-response studies with diisobutyl (DIBPL dipentyl (DPePL dihexyl (DHPL diheptyl (DHePL diisononyl (DINPL or diisodecyl phthalate (DIDP) and serial dilutions of a mixture of 9 phthalates. All phthalates, with the exception of DIDP} reduced fetal testicular T production. Several genes involved in cholesterol transport} androgen synthesis and Ins/3 also were down-regulated in a dose responsive manner by DIBP} DPeP} DHP} DHeP} DINP} and the 9-PE mixture. Despite speculation of PPAR involvement in the effects of PEs on the fetal testis} no PPAR-related genes were affected in the fetal testes by exposure to any of the tested PEs. Furthermore} the potent PPARaagonist} WY14643 did not reduce fetal testicular T production following GD 14-18 exposure} suggesting that the anti-androgenic activity of PEs is not PPARa-mediated. The overall sensitivity of the fetal endpoints (gene expression or T production) for the six phthalates from most to least was: Cypllbl>Scarbl>Star >T production>Cypllal>Cyp17al> Ins/3>Hsd3b>Cypllb2. The overall potency of the individual phthalates was: DPeP>DHP> DHeP> DIBP> DINP. Finally} the observed mixture interaction was adequately modeled by the dose addition (DA) model for most of the affected genes. Together} these data advance our understanding of the collective reproductive toxicity of the PE compounds.
This paper provides dose response and mixture data related to individual phthalateinduced fetal endocrine disruption for dipentyl phthalate, diisononyl phthalate, dihexyl phthalate, diheptyl phthalate, diisodecyl phthalate and diisobutyl phthalate. Many of these phthalates are included on the NCEA IRIS and OCSPP agendas for risk assessment and therefore, this data may be useful in the risk assessment process, which may ultimately contribute to the protection of human health.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
TOXICOLOGY ASSESSMENT DIVISION
REPRODUCTIVE TOXICOLOGY BRANCH