title: A mixture of five phthalate esters inhibits fetal testicular testosterone production in the sprague-dawley rat in a cumulative, dose-additive manner.
abstract: Phthalate diesters are chemicals to which humans are ubiquitously exposed. Exposure to certain phthalates during sexual differentiation causes reproductive tract malformations in male rats. In the fetal rat, exposure to the phthalates benzylbutyl phthalate (BBP), di(n)butyl phthalate (DBP), and diethylhexyl phthalate (DEHP) decreases testicular testosterone production and insulin-like 3 hormone mRNA levels. We characterized the dose-response effects of six individual phthalates (BBP, DBP, DEHP, diethyl phthalate [DEP], diisobutyl phthalate [DiBP], and dipentyl phthalate [DPP]) on gestation day (GD) 18 testicular testosterone production following exposure of Sprague-Dawley rats on GD 8-18. BBP, DBP, DEHP, and DiBP were equipotent (ED50 of 440 +/- 16 mg/kg/day), DPP was about threefold more potent (ED50 = 130 mg/kg/day) and DEP had no effect on fetal testosterone production. We hypothesized that coadministration of these five antiandrogenic phthalates would reduce testosterone production in a dose-additive fashion because they act via a common mode of toxicity. In a second study, dams were dosed at 100, 80, 60, 40, 20, 10, 5, or 0% of the mixture. The top dose contained 1300 mg of total phthalates/kg/day including BBP, DBP, DEHP, DiBP (300 mg/kg/day per chemical), and DPP (100 mg DPP/kg/day). This mixture ratio was selected such that each phthalate would contribute equally to the reduction in testosterone. As hypothesized, testosterone production was reduced in a dose-additive manner. Several of the individual phthalates and the mixture also induced fetal mortality, due to pregnancy loss. These data demonstrate that individual phthalates with a similar mechanism of action can elicit cumulative, dose additive effects on fetal testosterone production and pregnancy when administered as a mixture.
authors.affiliation: Reproductive Toxicology Division, NHEERL, ORD, United States Environmental Protection Agency (USEPA), Research Triangle Park, North Carolina 27711, USA.
authors.forename: Kembra L
authors.initials: KL
authors.lastname: Howdeshell
authors.forename: Vickie S
authors.initials: VS
authors.lastname: Wilson
authors.forename: Johnathan
authors.initials: J
authors.lastname: Furr
authors.forename: Christy R
authors.initials: CR
authors.lastname: Lambright
authors.forename: Cynthia V
authors.initials: CV
authors.lastname: Rider
authors.forename: Chad R
authors.initials: CR
authors.lastname: Blystone
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Hotchkiss
authors.forename: Leon Earl
authors.initials: LE
authors.lastname: Gray
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003993:Dibutyl Phthalate / Q000031:analogs & derivatives / Q000633:toxicity; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects*; D016015:Logistic Models; D008297:Male; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis*
chemical_list: D010795:Phthalic Acids; D003993:Dibutyl Phthalate; D013739:Testosterone; D004051:Diethylhexyl Phthalate; C025605:diisobutyl phthalate; C007379:diethyl phthalate; C027561:butylbenzyl phthalate