title: Disruption of rat testis development following combined in utero exposure to the phytoestrogen genistein and antiandrogenic plasticizer di-(2-ethylhexyl) phthalate.
abstract: Fetal exposure to environmental endocrine disruptors (EDs) is thought to contribute to reported idiopathic increases in adult male reproductive abnormalities. Although humans are exposed to myriad EDs from conception to adulthood, few studies have evaluated the effects of combined EDs on male reproduction. In the present study, we demonstrate that simultaneous gestational exposure to the phytoestrogen genistein and the antiandrogenic plasticizer di-(2-ethyhexyl) phthalate (DEHP) induces long-term alterations in testis development and function. Pregnant Sprague Dawley rats were gavaged from Gestational Day 14 to birth with corn oil, genistein, DEHP, or their mixture at 10 mg/kg/day, a dose selected from previous dose-response studies using single chemicals for its lack of long-term testicular effects. Hormonal and testicular end points were examined in adult male offspring. Serum testosterone levels were unchanged. However, significant increases were observed in testis weight and in the expression of mast cell markers in testes from adult rats exposed gestationally to combined compounds. The ED mixture also altered the mRNA expression of Sertoli cell makers Wt1 and Amh and germ cell markers cKit and Sox17, measured by quantitative real-time PCR (qPCR), suggesting long-term disruption in testis function and spermatogenesis. Alterations in germ cell markers might reflect direct effects on fetal gonocytes or indirect effects via primary targeting of somatic cells, as suggested by differentially regulated Leydig cell associated genes (Hsd3b, Anxa1, Foxa3, and Pdgfra), determined by gene expression array, qPCR, and protein analyses. The two chemicals, when given in combination, induced long-term reproductive toxicity at doses not previously reported to produce any conspicuous long-term effects. Our study therefore highlights a need for a more comprehensive evaluation of the effects of ED mixtures.
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Jones
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Boisvert
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Tam B
authors.initials: TB
authors.lastname: Duong
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Sade
authors.initials: S
authors.lastname: Francois
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Thrane
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada Department of Medicine, McGill University, Montreal, Quebec, Canada Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada martine.culty@mcgill.ca.
authors.forename: Martine
authors.initials: M
authors.lastname: Culty
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004357:Drug Synergism; D052244:Endocrine Disruptors / Q000633:toxicity; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D019833:Genistein / Q000633:toxicity*; D007248:Infertility, Male / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D057466:Nonsteroidal Anti-Androgens / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D048789:Phytoestrogens / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017207:Rats, Sprague-Dawley; D012708:Sertoli Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000097:blood
chemical_list: D015415:Biomarkers; D052244:Endocrine Disruptors; D057466:Nonsteroidal Anti-Androgens; D048789:Phytoestrogens; D013739:Testosterone; D004051:Diethylhexyl Phthalate; D019833:Genistein
keywords: Leydig; Sertoli; endocrine disruptor; genistein; germ cells; phthalate; testis; toxicology