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Establishing the Biological Relevance of Dipentyl Phthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels
Citation:
Gray, E., J. Furr, K. Tatum-Gibbs, C. Lambright, H. Sampson, B. Hannas, V. Wilson, A. Hotchkiss, AND P. Foster. Establishing the Biological Relevance of Dipentyl Phthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 149(1):178-91, (2016).
Impact/Purpose:
The results of the current study define how quantitative alterations in key events in the fetal testis androgen signaling Adverse Outcome Pathway, induced by in utero exposure to a phthalate, can be used to predict adverse effects in F1 male rats throughout postnatal life. We are defining the biologically relevance of alterations in fetal testis endocrine function that can be used to determine points of departure in risk assessment. In addition, these data have been used by several regulatory bodies to establish NOAELS, BMDs for their risk assessment activities. For example, the raw data are being analyzed by scientists in the IRIS program, the Consumer Product Safety Commission used these data to recommend a ban on the use of the phthalate in children's toys and the data contributed significantly to the EPA's decision to issue a SNURR for dipentyl phthalate.
Description:
Phthalate esters (PEs) constitute a large class of compounds that are used for many consumer product applications. Many of the C2-C7 di-ortho PEs reduce fetal testicular hormone and gene expression levels in rats resulting in adverse effects seen later in life but it appears that relatively large reductions in fetal testosterone (T) levels and testis gene expression may be required to adversely affect reproductive development (Hannas, B. R., Lambright, C. S., Furr, J., Evans, N., Foster, P. M., Gray, E. L., and Wilson, V. S. (2012). Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: a targeted RT-PCR array approach for defining relative potency. Toxicol. Sci. 125, 544-557). The objectives of this study were (1) to model the relationships between changes in fetal male rat plasma testosterone (PT), T levels in the testis (TT), T production (PROD), and testis gene expression with the reproductive malformation rates, and (2) to quantify the "biologically relevant reductions" (BRRs) in fetal T necessary to induce adverse effects in the offspring. In the fetal experiment, Harlan Sprague-Dawley rats were dosed with dipentyl phthalate (DPeP) at 0, 11, 33, 100, and 300 mg/kg/day from gestational days (GD) 14-18 and fetal testicular T, PT levels, and T Prod and gene expresson were assessed on GD 18. In the postnatal experiment, rats were dosed with DPeP from GD 8-18 and reproductive development was monitored through adulhood.The dose-response curves for TT levels (ED50 = 53 mg/kg) and T PROD (ED50 = 45 mg/kg) were similar, whereas PT was reduced at ED50 = 19 mg/kg. When the reductions in TPROD and 1nsl3 mRNA were compared with the postnatal effects of in utero DPeP, dose-related reproductive alterations were noted when T PROD and lnsl3 mRNA were reduced by >45% and 42%, respectively. The determination of BRR levels mayenable risk assessors to utilize fetal endocrine data to help establish points of departure for auantitative risk assessments.
