Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes.
Exposure to plasticizers di(n-butyl) phthalate (DBP) and diethylhexyl phthalate (DEHP) during sexual differentiation causes male reproductive tract malformations in rats and rabbits. In the fetal male rat, these two phthalate esters decrease testosterone (T) production and insulin-like peptide 3 (insl3) gene expression, a hormone critical for gubernacular ligament development. We hypothesized that coadministered DBP and DEHP would act in a cumulative dose-additive fashion to induce reproductive malformations, inhibit fetal steroid hormone production, and suppress the expression of insl3 and genes responsible for steroid production. Pregnant Sprague Dawley rats were gavaged on gestation days (GD) 14-18 with vehicle control, 500 mg/kg DBP, 500 mg/kg DEHP, or a combination of DBP and DEHP (500 mg/kg each chemical; DBP+DEHP); the dose of each individual phthalate was one-half of the effective dose predicted to cause a 50% incidence of epididymal agenesis. In experiment one, adult male offspring were necropsied, and reproductive malformations and androgen-dependent organ weights were recorded. In experiment two, GD18 testes were incubated for T production and processed for gene expression by quantitative real-time PCR. The DBP+DEHP dose increased the incidence of many reproductive malformations by >or=50%, including epididymal agenesis, and reduced androgen-dependent organ weights in cumulative, dose-additive manner. Fetal T and expression of insl3 and cyp11a were cumulatively decreased by the DBP+DEHP dose. These data indicate that individual phthalates with a similar mechanism of action, but with different active metabolites (monobutyl phthalate versus monoethylhexyl phthalate), can elicit dose-additive effects when administered as a mixture.
Howdeshell
Kembra L
KL
North Carolina State University, Department of Molecular Biomedical Sciences, Raleigh, North Carolina 27606, USA.
Furr
Johnathan
J
Lambright
Christy R
CR
Rider
Cynthia V
CV
Wilson
Vickie S
VS
Gray
L Earl
LE
D000818:Animals; D000831:Animals, Newborn; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D003993:Dibutyl Phthalate / Q000633:toxicity*; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005837:Genitalia, Male / Q000002:abnormalities / Q000187:drug effects* / Q000196:embryology; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D009929:Organ Size / Q000187:drug effects; D038081:Organogenesis / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
D007328:Insulin; C084797:Leydig insulin-like protein; D011506:Proteins; D012333:RNA, Messenger; D003993:Dibutyl Phthalate; D013739:Testosterone; D004051:Diethylhexyl Phthalate; D002786:Cholesterol Side-Chain Cleavage Enzyme