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Biol Reprod. 2016 Feb;94(2):31. doi: 10.1095/biolreprod.115.131656. Epub 2015 Nov 25.

Nicotine Induced Murine Spermatozoa Apoptosis via Up-Regulation of Deubiquitinated RIP1 by Trim27 Promoter Hypomethylation.

Author information

1
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
2
Department of Urology, Shanghai 6th People's Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
3
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, People's Republic of China zhaoxiaw@sjtu.edu.cn.
4
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, People's Republic of China zdqiao@sjtu.edu.cn.

Abstract

Nicotine significantly promoted apoptosis in stages I, VII, VIII, and XI spermatogonia, stages I, VII, VIII, X, and XI spermatocytes, and stages I-V, VII, and VIII elongating spermatids. To explore the underlying molecular mechanisms, sperm mRNA next-generation sequencing of nicotine-treated mice was conducted. Out of the 86 genes related to apoptosis, Tnf (tumor necrosis factor alpha) was screened to be the most significant varied transcript, and the Onto-pathway analysis indicated that the TNF apoptotic pathway was especially activated by nicotine exposure. The TNF pathway was further studied at the gene and protein levels. The results showed that RIP1, the key component in the TNF apoptotic pathway, was up-expressed in its deubiquitinated form in nicotine-treated mice testis. TRIM27, an E3 ubiquitin ligase that activated TNF apoptotic pathway through up-regulating deubiquitinated RIP1, was also overexpressed in nicotine-treated spermatocytes; moreover, four consecutive CpG sites near the Trim27 transcription start site were less frequently methylated. Finally, in vitro experiments of Trim27 overexpression and RNA interference in GC-1 spermatogonial cells confirmed that the RIP1 deubiquitination and TRIM27 hyopmethylation were both positively correlated with spermatocyte apoptosis. In summary, our study suggests that nicotine may induce murine spermatozoal apoptosis via the TNF apoptotic pathway through up-regulation of deubiquitinated RIP1 by Trim27 promoter hypomethylation.

KEYWORDS:

RIP1 deubiquitination; Trim27 hypomethylation; apoptosis; nicotine; spermatozoa

PMID:
26607717
DOI:
10.1095/biolreprod.115.131656
[Indexed for MEDLINE]

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