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Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPAR?.

ABSTRACT: Perfluorooctanoate, a peroxisome proliferator-activated receptor alpha (PPAR?) agonist, has the potential to lower testosterone levels as a result of testicular toxicity. To elucidate the mechanism and impact of PPAR? 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 (mPPAR?), Ppar?-null and PPAR?-humanized (hPPAR?) mice for 6 weeks. Both low- and high-dose APFO significantly reduced plasma testosterone concentrations in mPPAR? and hPPAR? 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(17?) 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 Ppar?-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 mPPAR? and hPPAR? mice, which may, in part, be related to APFO-induced mitochondrial damage.

SUBMITTER: Li Y

PROVIDER: S-EPMC6661110 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARα.

Li Yufei Y Ramdhan Doni Hikmat DH Naito Hisao H Yamagishi Nozomi N Ito Yuki Y Hayashi Yumi Y Yanagiba Yukie Y Okamura Ai A Tamada Hazuki H Gonzalez Frank J FJ Nakajima Tamie T

Toxicology letters 20110625 3

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 re ...[more]

PMID: 21712084

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Project description:Phthalate esters (PEs) constitute a large class of compounds that are used for many consumer product applications. Many of the C2-C7 di-ortho PEs reduce fetal testicular hormone and gene expression levels in rats resulting in adverse effects seen later in life but it appears that relatively large reductions in fetal testosterone (T) levels and testis gene expression may be required to adversely affect reproductive development (Hannas, B. R., Lambright, C. S., Furr, J., Evans, N., Foster, P. M., Gray, E. L., and Wilson, V. S. (2012). Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: a targeted RT-PCR array approach for defining relative potency. Toxicol. Sci. 125, 544-557). The objectives of this study were (1) to model the relationships between changes in fetal male rat plasma testosterone (PT), T levels in the testis (TT), T production (PROD), and testis gene expression with the reproductive malformation rates, and (2) to quantify the "biologically relevant reductions" (BRRs) in fetal T necessary to induce adverse effects in the offspring. In the fetal experiment, Harlan Sprague-Dawley rats were dosed with dipentyl phthalate (DPeP) at 0, 11, 33, 100, and 300?mg/kg/day from gestational days (GD) 14-18 and fetal testicular T, PT levels, and T Prod and gene expression were assessed on GD 18. In the postnatal experiment, rats were dosed with DPeP from GD 8-18 and reproductive development was monitored through adulthood. The dose-response curves for TT levels (ED(50)?=?53?mg/kg) and T PROD (ED(50)?=?45?mg/kg) were similar, whereas PT was reduced at ED50 = 19?mg/kg. When the reductions in TPROD and Insl3 mRNA were compared with the postnatal effects of in utero DPeP, dose-related reproductive alterations were noted when T PROD and Insl3 mRNA were reduced by >45% and 42%, respectively. The determination of BRR levels may enable risk assessors to utilize fetal endocrine data to help establish points of departure for quantitative risk assessments.

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Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPAR?.

Publications

Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARα.

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