title: Establishing the "Biological Relevance" of Dipentyl Phthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels.
abstract: 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.
authors.affiliation: *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.
authors.forename: Leon Earl
authors.initials: LE
authors.lastname: Gray
authors.affiliation: *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;
authors.forename: Johnathan
authors.initials: J
authors.lastname: Furr
authors.affiliation: *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;
authors.forename: Katoria R
authors.initials: KR
authors.lastname: Tatum-Gibbs
authors.affiliation: *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;
authors.forename: Christy
authors.initials: C
authors.lastname: Lambright
authors.forename: Hunter
authors.initials: H
authors.lastname: Sampson
authors.affiliation: *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;
authors.forename: Bethany R
authors.initials: BR
authors.lastname: Hannas
authors.affiliation: *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;
authors.forename: Vickie S
authors.initials: VS
authors.lastname: Wilson
authors.affiliation: NCEA, ORD, USEPA, Washington, District of Columbia; and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hotchkiss
authors.affiliation: National Toxicology Program, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina 27709.
authors.forename: Paul M D
authors.initials: PM
authors.lastname: Foster
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000633:toxicity; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D013737:Testis / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood
chemical_list: D004952:Esters; D010795:Phthalic Acids; D013739:Testosterone
keywords: anti-androgen; dipentyl phthalate; fetal male rat endocrine; risk assessment