title: Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARα.
abstract: Perfluorooctanoate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, has the potential to lower testosterone levels as a result of testicular toxicity. To elucidate the mechanism and impact of PPARα on this reproductive toxicity, ammonium perfluorooctanoate (APFO) at doses of 0, 1.0 (low) mg/kg/day, or 5.0 (high) mg/kg/day was orally given daily to 129/sv wild-type (mPPARα), Pparα-null and PPARα-humanized (hPPARα) mice for 6 weeks. Both low- and high-dose APFO significantly reduced plasma testosterone concentrations in mPPARα and hPPARα mice, respectively. These decreases may, in part, be associated with decreased expression of mitochondrial cytochrome P450 side-chain cleavage enzyme, steroidogenic acute regulatory protein or peripheral benzodiazepine receptor as well as microsomal cytochrome P450(17α) involved in the steroidogenesis. Additionally, both doses increased abnormalities in sperm morphology and vacuolated cells in the seminiferous tubules of both mouse lines. In contrast, APFO caused only a marginal effect either on the testosterone synthesis system or sperm and testis morphology in Pparα-null mice. These results suggest that APFO may disrupt testosterone biosynthesis by lowering the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone and androstandione in the testis of mPPARα and hPPARα mice, which may, in part, be related to APFO-induced mitochondrial damage.
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University, Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Li
authors.forename: Doni Hikmat
authors.initials: DH
authors.lastname: Ramdhan
authors.forename: Hisao
authors.initials: H
authors.lastname: Naito
authors.forename: Nozomi
authors.initials: N
authors.lastname: Yamagishi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yanagiba
authors.forename: Ai
authors.initials: A
authors.lastname: Okamura
authors.forename: Hazuki
authors.initials: H
authors.lastname: Tamada
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D002210:Caprylates / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D005466:Fluorocarbons / Q000008:administration & dosage / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D013081:Sperm Motility / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000097:blood*; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C463819:Bzrp protein, mouse; D002210:Caprylates; D004785:Environmental Pollutants; D005466:Fluorocarbons; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D010750:Phosphoproteins; D012333:RNA, Messenger; D018079:Receptors, GABA; D000098682:Steroidogenic Acute Regulatory Protein; D013739:Testosterone; C023036:perfluorooctanoic acid; D013250:Steroid Hydroxylases