title: Prepubertal mouse testis growth and maturation and androgen production are acutely sensitive to di-n-butyl phthalate.
abstract: Phthalates are plasticizers with widespread industrial, domestic, and medical applications. Epidemiological data indicating increased incidence of testicular dysgenesis in boys exposed to phthalates in utero are reinforced by studies demonstrating that phthalates impair fetal rodent testis development. Because humans are exposed to phthalates continuously from gestation through adulthood, it is imperative to understand what threat phthalates pose at other life stages. To determine the impact during prepuberty, we assessed the consequences of oral administration of 1 to 500 mg di-n-butyl phthalate (DBP)/kg/d in corn oil to wild-type (C57BL/6J) male mice from 4 to 14 days of age. Dose-dependent effects on testis growth correlated with reduced Sertoli cell proliferation. Histological and immunohistochemical analyses identified delayed spermatogenesis and impaired Sertoli cell maturation after exposure to 10 to 500 mg DBP/kg/d. Interference with the hypothalamic-pituitary-gonadal axis was indicated in mice fed 500 mg DBP/kg/d, which had elevated circulating inhibin but no change in serum FSH. Increased immunohistochemical staining for inhibin-α was apparent at doses of 10 to 500 mg DBP/kg/d. Serum testosterone and testicular androgen activity were lower in the 500 mg DBP/kg/d group; however, reduced anogenital distance in all DBP-treated mice suggested impaired androgen action at earlier time points. Long-term effects were evident, with smaller anogenital distance and indications of disrupted spermatogenesis in adult mice exposed prepubertally to doses from 1 mg DBP/kg/d. These data demonstrate the acute sensitivity of the prepubertal mouse testis to DBP at doses 50- to 500-fold lower than those used in rat and identify the upregulation of inhibin as a potential mechanism of DBP action.
authors.affiliation: Department of Anatomy, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Moody
authors.forename: Hoey
authors.initials: H
authors.lastname: Goh
authors.forename: Amanda
authors.initials: A
authors.lastname: Bielanowicz
authors.forename: Paul
authors.initials: P
authors.lastname: Rippon
authors.forename: Kate L
authors.initials: KL
authors.lastname: Loveland
authors.forename: Catherine
authors.initials: C
authors.lastname: Itman
mesh_terms: D000728:Androgens / Q000097:blood / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003993:Dibutyl Phthalate / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000633:toxicity*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007265:Inhibins / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010968:Plasticizers / Q000008:administration & dosage / Q000633:toxicity*; D011897:Random Allocation; D012708:Sertoli Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D046468:Sexual Development / Q000187:drug effects*; D012741:Sexual Maturation / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects; D013733:Testicular Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000097:blood
chemical_list: D000728:Androgens; D052244:Endocrine Disruptors; D010968:Plasticizers; C422362:inhibin A; D003993:Dibutyl Phthalate; D013739:Testosterone; D007265:Inhibins