title: Dose-response assessment of fetal testosterone production and gene expression levels in rat testes following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate, and diisononyl phthalate.
abstract: Several phthalate esters have been linked to the Phthalate Syndrome, affecting male reproductive development when administered to pregnant rats during in utero sexual differentiation. The goal of the current study was to enhance understanding of this class of compounds in the Sprague Dawley (SD) fetal rat following exposure on gestational days (GDs) 14-18 by determining the relative potency factors for several phthalates on fetal testes endpoints, the effects of a nine phthalate mixture on fetal testosterone (T) production, and differences in SD and Wistar (W) strain responses of fetal T production and testicular gene expression to di(2-ethylhexyl) phthalate (DEHP). We determined that diisobutyl phthalate (DIBP) and diisoheptyl phthalate (DIHP) reduced fetal testicular T production with similar potency to DEHP, whereas diisononyl phthalate (DINP) was 2.3-fold less potent. DINP was also less potent at reducing StAR and Cyp11a gene expression levels, whereas DIBP was slightly more potent than DEHP. We observed that administration of dilutions of a mixture of nine phthalates (DEHP, DIHP, DIBP, dibutyl-, benzyl butyl-, dicyclohexyl-, diheptyl-, dihexyl-, and dipentyl phthalate) reduced fetal T production in a dose-dependent manner best predicted by dose addition. Finally, we found that the differential effects of in utero DEHP treatment on epididymal and gubernacular differentiation in male SD and W rats (0, 100, 300, 500, 625, 750, or 875 mg DEHP/kg/day) are likely due to tissue-specific strain differences in the androgen and insl3 signaling pathways rather than differential effects of DEHP on fetal testis T and insl3 production.
authors.affiliation: Toxicology Assessment Division, Reproductive Toxicology Branch, U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Research Triangle Park, North Carolina 27711, USA.
authors.forename: Bethany R
authors.initials: BR
authors.lastname: Hannas
authors.forename: Christy S
authors.initials: CS
authors.lastname: Lambright
authors.forename: Johnathan
authors.initials: J
authors.lastname: Furr
authors.forename: Kembra L
authors.initials: KL
authors.lastname: Howdeshell
authors.forename: Vickie S
authors.initials: VS
authors.lastname: Wilson
authors.forename: Leon E
authors.initials: LE
authors.lastname: Gray
mesh_terms: D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D003993:Dibutyl Phthalate / Q000031:analogs & derivatives / Q000633:toxicity; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D026901:Membrane Transport Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010795:Phthalic Acids / Q000633:toxicity*; D010968:Plasticizers / Q000633:toxicity*; D011247:Pregnancy; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity; D013737:Testis / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D007328:Insulin; C084797:Leydig insulin-like protein; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D010795:Phthalic Acids; D010968:Plasticizers; D011506:Proteins; D000098682:Steroidogenic Acute Regulatory Protein; D003993:Dibutyl Phthalate; D013739:Testosterone; C012125:diisononyl phthalate; D004051:Diethylhexyl Phthalate; D019363:Cytochrome P-450 CYP1A1; C025605:diisobutyl phthalate