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

Yufei Li, Doni Hikmat Ramdhan, Hisao Naito, Nozomi Yamagishi, Yuki Ito, Yumi Hayashi, Yukie Yanagiba, Ai Okamura, Hazuki Tamada, Frank J. Gonzalez, Tamie Nakajima

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 P45017α 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.

Original languageEnglish
Pages (from-to)265-272
Number of pages8
JournalToxicology Letters
Volume205
Issue number3
DOIs
Publication statusPublished - 10-09-2011

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perfluorooctanoic acid
PPAR alpha
Testosterone
Testis
Toxicity
Spermatozoa
Cholesterol
Pregnenolone
Seminiferous Tubules
Mitochondria
Biosynthesis
GABA-A Receptors
Cytochromes
Cytochrome P-450 Enzyme System

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Li, Yufei ; Ramdhan, Doni Hikmat ; Naito, Hisao ; Yamagishi, Nozomi ; Ito, Yuki ; Hayashi, Yumi ; Yanagiba, Yukie ; Okamura, Ai ; Tamada, Hazuki ; Gonzalez, Frank J. ; Nakajima, Tamie. / Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARα. In: Toxicology Letters. 2011 ; Vol. 205, No. 3. pp. 265-272.
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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 P45017α 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.",
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Li, Y, Ramdhan, DH, Naito, H, Yamagishi, N, Ito, Y, Hayashi, Y, Yanagiba, Y, Okamura, A, Tamada, H, Gonzalez, FJ & Nakajima, T 2011, 'Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARα', Toxicology Letters, vol. 205, no. 3, pp. 265-272. https://doi.org/10.1016/j.toxlet.2011.06.015

Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARα. / Li, Yufei; Ramdhan, Doni Hikmat; Naito, Hisao; Yamagishi, Nozomi; Ito, Yuki; Hayashi, Yumi; Yanagiba, Yukie; Okamura, Ai; Tamada, Hazuki; Gonzalez, Frank J.; Nakajima, Tamie.

In: Toxicology Letters, Vol. 205, No. 3, 10.09.2011, p. 265-272.

Research output: Contribution to journalArticle

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T1 - Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARα

AU - Li, Yufei

AU - Ramdhan, Doni Hikmat

AU - Naito, Hisao

AU - Yamagishi, Nozomi

AU - Ito, Yuki

AU - Hayashi, Yumi

AU - Yanagiba, Yukie

AU - Okamura, Ai

AU - Tamada, Hazuki

AU - Gonzalez, Frank J.

AU - Nakajima, Tamie

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N2 - 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 P45017α 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.

AB - 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 P45017α 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.

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