Cytochrome P450 3A1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.

<h4>Background</h4>2,2',4,4'-tetrabromodiphenyl ether (BDE47) is the dominant PBDE congener in humans, wildlife, and the environment. It has been reported to be metabolized by cytochrome P450 (CYP) enzymes. Still, the effects of BDE47 on spermatogenesis failure are attracting a...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Zhan Zhang, Xiaoming Zhang, Zhenzhen Sun, Huibin Dong, Lianglin Qiu, Jun Gu, Jingping Zhou, Xinru Wang, Shou-Lin Wang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bf2762ef527c48dbb20b9ad6c7130548
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:bf2762ef527c48dbb20b9ad6c7130548
record_format	dspace
spelling	oai:doaj.org-article:bf2762ef527c48dbb20b9ad6c71305482021-11-18T07:42:33ZCytochrome P450 3A1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.1932-620310.1371/journal.pone.0066301https://doaj.org/article/bf2762ef527c48dbb20b9ad6c71305482013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23762486/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>2,2',4,4'-tetrabromodiphenyl ether (BDE47) is the dominant PBDE congener in humans, wildlife, and the environment. It has been reported to be metabolized by cytochrome P450 (CYP) enzymes. Still, the effects of BDE47 on spermatogenesis failure are attracting an increasing amount of attention. However, it is unclear whether CYP-mediated metabolism contributes to BDE47-induced reproductive toxicity.<h4>Methodology and principal findings</h4>The role of cytochrome P450 3A1 (CYP3A1) in the formation of oxidative metabolites of BDE47 and its induced spermatogenesis failure was investigated in SD rats. BDE47 significantly increased the expression and activity of CYP3A1 in rat liver, and 3-OH-BDE47, the major oxidative metabolite of BDE47, dose-dependently increased in rat liver, serum, and testis, which was aggravated by dexamethasone (DEX), an inducer of CYP3A1. Additionally, testicular 3-OH-BDE47 and reactive oxygen species (ROS) in seminiferous tubules increased especially when BDE47 was administered in combination with DEX, which was confirmed in GC-1 and GC-2 cells that 3-OH-BDE47 induced more ROS production and cell apoptosis via the upregulation of FAS/FASL, p-p53 and caspase 3. As a result, daily sperm production dose-dependently decreased, consistent with histological observations in giant cells and vacuolar spaces and increase in TUNEL-positive apoptotic germ cells.<h4>Conclusion</h4>CYP3A1-mediated metabolic activation of BDE47 and the active metabolite 3-OH-BDE47 and consequent ROS played an important role in reduction of spermatogenesis by germ cell apoptosis. Our study helps provide new insights into the mechanism of reproductive toxicity of environmental chemicals.Zhan ZhangXiaoming ZhangZhenzhen SunHuibin DongLianglin QiuJun GuJingping ZhouXinru WangShou-Lin WangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e66301 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zhan Zhang Xiaoming Zhang Zhenzhen Sun Huibin Dong Lianglin Qiu Jun Gu Jingping Zhou Xinru Wang Shou-Lin Wang Cytochrome P450 3A1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.
description	<h4>Background</h4>2,2',4,4'-tetrabromodiphenyl ether (BDE47) is the dominant PBDE congener in humans, wildlife, and the environment. It has been reported to be metabolized by cytochrome P450 (CYP) enzymes. Still, the effects of BDE47 on spermatogenesis failure are attracting an increasing amount of attention. However, it is unclear whether CYP-mediated metabolism contributes to BDE47-induced reproductive toxicity.<h4>Methodology and principal findings</h4>The role of cytochrome P450 3A1 (CYP3A1) in the formation of oxidative metabolites of BDE47 and its induced spermatogenesis failure was investigated in SD rats. BDE47 significantly increased the expression and activity of CYP3A1 in rat liver, and 3-OH-BDE47, the major oxidative metabolite of BDE47, dose-dependently increased in rat liver, serum, and testis, which was aggravated by dexamethasone (DEX), an inducer of CYP3A1. Additionally, testicular 3-OH-BDE47 and reactive oxygen species (ROS) in seminiferous tubules increased especially when BDE47 was administered in combination with DEX, which was confirmed in GC-1 and GC-2 cells that 3-OH-BDE47 induced more ROS production and cell apoptosis via the upregulation of FAS/FASL, p-p53 and caspase 3. As a result, daily sperm production dose-dependently decreased, consistent with histological observations in giant cells and vacuolar spaces and increase in TUNEL-positive apoptotic germ cells.<h4>Conclusion</h4>CYP3A1-mediated metabolic activation of BDE47 and the active metabolite 3-OH-BDE47 and consequent ROS played an important role in reduction of spermatogenesis by germ cell apoptosis. Our study helps provide new insights into the mechanism of reproductive toxicity of environmental chemicals.
format	article
author	Zhan Zhang Xiaoming Zhang Zhenzhen Sun Huibin Dong Lianglin Qiu Jun Gu Jingping Zhou Xinru Wang Shou-Lin Wang
author_facet	Zhan Zhang Xiaoming Zhang Zhenzhen Sun Huibin Dong Lianglin Qiu Jun Gu Jingping Zhou Xinru Wang Shou-Lin Wang
author_sort	Zhan Zhang
title	Cytochrome P450 3A1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.
title_short	Cytochrome P450 3A1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.
title_full	Cytochrome P450 3A1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.
title_fullStr	Cytochrome P450 3A1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.
title_full_unstemmed	Cytochrome P450 3A1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.
title_sort	cytochrome p450 3a1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/bf2762ef527c48dbb20b9ad6c7130548
work_keys_str_mv	AT zhanzhang cytochromep4503a1mediates2244tetrabromodiphenyletherinducedreductionofspermatogenesisinadultrats AT xiaomingzhang cytochromep4503a1mediates2244tetrabromodiphenyletherinducedreductionofspermatogenesisinadultrats AT zhenzhensun cytochromep4503a1mediates2244tetrabromodiphenyletherinducedreductionofspermatogenesisinadultrats AT huibindong cytochromep4503a1mediates2244tetrabromodiphenyletherinducedreductionofspermatogenesisinadultrats AT lianglinqiu cytochromep4503a1mediates2244tetrabromodiphenyletherinducedreductionofspermatogenesisinadultrats AT jungu cytochromep4503a1mediates2244tetrabromodiphenyletherinducedreductionofspermatogenesisinadultrats AT jingpingzhou cytochromep4503a1mediates2244tetrabromodiphenyletherinducedreductionofspermatogenesisinadultrats AT xinruwang cytochromep4503a1mediates2244tetrabromodiphenyletherinducedreductionofspermatogenesisinadultrats AT shoulinwang cytochromep4503a1mediates2244tetrabromodiphenyletherinducedreductionofspermatogenesisinadultrats
_version_	1718423124613005312

Cytochrome P450 3A1 mediates 2,2',4,4'-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats.

Ejemplares similares