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A short-term in vivo screen using fetal testosterone production, a key event in the phthalate adverse outcome pathway, to predict disruption of sexual differentiation.

ABSTRACT: This study was designed to develop and validate a short-term in vivo protocol termed the Fetal Phthalate Screen (FPS) to detect phthalate esters (PEs) and other chemicals that disrupt fetal testosterone synthesis and testis gene expression in rats. We propose that the FPS can be used to screen chemicals that produce adverse developmental outcomes via disruption of the androgen synthesis pathway more rapidly and efficiently, and with fewer animals than a postnatal one-generation study. Pregnant rats were dosed from gestational day (GD) 14 to 18 at one dose level with one of 27 chemicals including PEs, PE alternatives, pesticides known to inhibit steroidogenesis, an estrogen and a potent PPAR? agonist and ex vivo testis testosterone production (T Prod) was measured on GD 18. We also included some chemicals with "unknown" activity including DMEP, DHeP, DHEH, DPHCH, DAP, TOTM, tetrabromo-diethyl hexyl phthalate (BrDEHP), and a relatively potent environmental estrogen BPAF. Dose-response studies also were conducted with this protocol with 11 of the above chemicals to determine their relative potencies. CD-1 mice also were exposed to varying dose levels of DPeP from GD 13 to 17 to determine if DPeP reduced T Prod in this species since there is a discrepancy among the results of in utero studies of PEs in mice. Compared to the known male reproductive effects of the PEs in rats the FPS correctly identified all known "positives" and "negatives" tested. Seven of eight "unknowns" tested were "negatives", they did not reduce T Prod, whereas DAP produced an "equivocal" response. Finally, a dose-response study with DPeP in CD-1 mice revealed that fetal T Prod can be inhibited by exposure to a PE in utero in this species, but at a higher dose level than required in rats.Key words. Phthalate Syndrome, Fetal endocrine biomarkers, Phthalate adverse outcome pathway, testosterone production, fetal rat testis.

SUBMITTER: Furr JR

PROVIDER: S-EPMC4471440 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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A short-term in vivo screen using fetal testosterone production, a key event in the phthalate adverse outcome pathway, to predict disruption of sexual differentiation.

Furr Johnathan R JR Lambright Christy S CS Wilson Vickie S VS Foster Paul M PM Gray Leon E LE

Toxicological sciences : an official journal of the Society of Toxicology 20140505 2

This study was designed to develop and validate a short-term in vivo protocol termed the Fetal Phthalate Screen (FPS) to detect phthalate esters (PEs) and other chemicals that disrupt fetal testosterone synthesis and testis gene expression in rats. We propose that the FPS can be used to screen chemicals that produce adverse developmental outcomes via disruption of the androgen synthesis pathway more rapidly and efficiently, and with fewer animals than a postnatal one-generation study. Pregnant r ...[more]

PMID: 24798384

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Project 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 expression were assessed on GD 18. In the postnatal experiment, rats were dosed with DPeP from GD 8-18 and reproductive development was monitored through adulthood. The dose-response curves for TT levels (ED(50)?=?53?mg/kg) and T PROD (ED(50)?=?45?mg/kg) were similar, whereas PT was reduced at ED50 = 19?mg/kg. When the reductions in TPROD and Insl3 mRNA were compared with the postnatal effects of in utero DPeP, dose-related reproductive alterations were noted when T PROD and Insl3 mRNA were reduced by >45% and 42%, respectively. The determination of BRR levels may enable risk assessors to utilize fetal endocrine data to help establish points of departure for quantitative risk assessments.

Dataset Information

A short-term in vivo screen using fetal testosterone production, a key event in the phthalate adverse outcome pathway, to predict disruption of sexual differentiation.

Publications

A short-term in vivo screen using fetal testosterone production, a key event in the phthalate adverse outcome pathway, to predict disruption of sexual differentiation.

Similar Datasets

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