PMID- 26454885 OWN - NLM STAT- MEDLINE DCOM- 20161102 LR - 20220129 IS - 1096-0929 (Electronic) IS - 1096-6080 (Print) IS - 1096-0929 (Linking) VI - 149 IP - 1 DP - 2016 Jan TI - Establishing the "Biological Relevance" of Dipentyl Phthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels. PG - 178-91 LID - 10.1093/toxsci/kfv224 [doi] AB - 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. CI - Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US. FAU - Gray, Leon Earl Jr AU - Gray LE Jr AD - *Reproductive Toxicology Branch, Toxicology Assessment Division, National Health and Environmental Effects Laboratory, Office of Research and Development, U.S. Environmental Protection Agency (US EPA), Research Triangle Park, North Carolina 27711; gray.earl@epa.gov. FAU - Furr, Johnathan AU - Furr J AD - *Reproductive Toxicology Branch, Toxicology Assessment Division, National Health and Environmental Effects Laboratory, Office of Research and Development, U.S. Environmental Protection Agency (US EPA), Research Triangle Park, North Carolina 27711; FAU - Tatum-Gibbs, Katoria R AU - Tatum-Gibbs KR AD - *Reproductive Toxicology Branch, Toxicology Assessment Division, National Health and Environmental Effects Laboratory, Office of Research and Development, U.S. Environmental Protection Agency (US EPA), Research Triangle Park, North Carolina 27711; FAU - Lambright, Christy AU - Lambright C AD - *Reproductive Toxicology Branch, Toxicology Assessment Division, National Health and Environmental Effects Laboratory, Office of Research and Development, U.S. Environmental Protection Agency (US EPA), Research Triangle Park, North Carolina 27711; FAU - Sampson, Hunter AU - Sampson H FAU - Hannas, Bethany R AU - Hannas BR AD - *Reproductive Toxicology Branch, Toxicology Assessment Division, National Health and Environmental Effects Laboratory, Office of Research and Development, U.S. Environmental Protection Agency (US EPA), Research Triangle Park, North Carolina 27711; FAU - Wilson, Vickie S AU - Wilson VS AD - *Reproductive Toxicology Branch, Toxicology Assessment Division, National Health and Environmental Effects Laboratory, Office of Research and Development, U.S. Environmental Protection Agency (US EPA), Research Triangle Park, North Carolina 27711; FAU - Hotchkiss, Andrew AU - Hotchkiss A AD - NCEA, ORD, USEPA, Washington, District of Columbia; and. FAU - Foster, Paul M D AU - Foster PM AD - National Toxicology Program, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina 27709. LA - eng GR - MR/K006584/1/MRC_/Medical Research Council/United Kingdom GR - RW7592285501-1/PHS HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20151009 PL - United States TA - Toxicol Sci JT - Toxicological sciences : an official journal of the Society of Toxicology JID - 9805461 RN - 0 (Esters) RN - 0 (Phthalic Acids) RN - 3XMK78S47O (Testosterone) SB - IM MH - Animals MH - Dose-Response Relationship, Drug MH - Esters/toxicity MH - Female MH - Fetus/*drug effects/metabolism MH - Male MH - Phthalic Acids/*toxicity MH - Pregnancy MH - Prenatal Exposure Delayed Effects MH - Rats MH - Rats, Sprague-Dawley MH - Reproduction/drug effects MH - Testis/chemistry/*drug effects/metabolism MH - Testosterone/analysis/*biosynthesis/blood PMC - PMC4715258 OTO - NOTNLM OT - anti-androgen OT - dipentyl phthalate OT - fetal male rat endocrine OT - risk assessment EDAT- 2015/10/12 06:00 MHDA- 2016/11/03 06:00 PMCR- 2017/01/01 CRDT- 2015/10/12 06:00 PHST- 2015/10/12 06:00 [entrez] PHST- 2015/10/12 06:00 [pubmed] PHST- 2016/11/03 06:00 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - kfv224 [pii] AID - 10.1093/toxsci/kfv224 [doi] PST - ppublish SO - Toxicol Sci. 2016 Jan;149(1):178-91. doi: 10.1093/toxsci/kfv224. Epub 2015 Oct 9.