title: Fetal mouse phthalate exposure shows that Gonocyte multinucleation is not associated with decreased testicular testosterone.
abstract: The rat has been explored in detail for its in utero susceptibility to male reproductive tract malformation following phthalate exposure. Few other species have been studied in detail, and it is important for both mechanistic and risk assessment purposes to understand the species specificity of this response. We investigated the response of the fetal mouse testis to phthalate exposure and compared these results with those previously obtained from the rat. Initial experiments using a variety of phthalate congeners (monobutyl phthalate, di-(n-butyl) phthalate, or mono (2-ethylhexyl) phthalate) and exposure paradigms did not reduce fetal mouse testis testosterone levels. Pharmacokinetic data after a single 500 mg/kg di-(n-butyl)-phthalate (DBP) exposure on mouse gestation day (gd) 18 demonstrated that the concentrations and kinetics of the active metabolite monobutyl phthalate (MBP) in fetal and maternal plasma were similar to the rat. After a single 500 mg/kg or multiple day 250 mg/kg fetal mouse DBP exposure, rapid and dynamic changes in testis gene expression were observed, including induction of immediate early genes. Unlike the rat, expression of genes involved in cholesterol homeostasis and steroidogenesis were not decreased and were increased in a few cases. Similar to the rat, however, a 250- or 500-mg DBP/kg/day mouse exposure from gd 16 through 18 significantly increased seminiferous cord diameter, the number of multinucleated gonocytes per cord, and the number of nuclei per multinucleated gonocyte. Together, these results demonstrate that fetal mouse and rat phthalate exposure both induce immediate early gene expression and disrupt seminiferous cord and gonocyte development. This response in the mouse occurs without a measurable decrease in testicular testosterone, suggesting that altered seminiferous cord formation and gonocyte multinucleation may not be mechanistically linked to lowered testosterone.
authors.affiliation: The Hamner Institutes for Health Sciences Centers for Health Research, Research Triangle Park, NC 27709, USA. gaido@thechamner.org
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gaido
authors.forename: Janan B
authors.initials: JB
authors.lastname: Hensley
authors.forename: Delong
authors.initials: D
authors.lastname: Liu
authors.forename: Duncan G
authors.initials: DG
authors.lastname: Wallace
authors.forename: Susan
authors.initials: S
authors.lastname: Borghoff
authors.forename: Kamin J
authors.initials: KJ
authors.lastname: Johnson
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hall
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D003864:Depression, Chemical; D003993:Dibutyl Phthalate / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D010795:Phthalic Acids / Q000493:pharmacokinetics / Q000633:toxicity*; D011247:Pregnancy; D011863:Radioimmunoassay; D012671:Seminiferous Tubules / Q000187:drug effects / Q000648:ultrastructure; D013737:Testis / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D013739:Testosterone / Q000096:biosynthesis*
chemical_list: D009153:Mutagens; D010795:Phthalic Acids; D003993:Dibutyl Phthalate; D013739:Testosterone