Thyroid hormone induce a p53-dependent DNA damage through PI3K/Akt activation in sperm.
Accumulating evidences showed that thyroid hormone was participated in the functioning of the reproductive system, and an elevated level of thyroid hormones had a negative impact on reproductive system. However, the molecular basis for this observation still remains to be fully understood. Here, we show that l-Thyroxine significantly impaired human sperm motility. The molecular basis showed that thyroxine receptor stimulation triggers Phosphatidyl Inositol 3-kinase (PI3K)/Akt signaling activation leading to the E3 ligase MDM2 phosphorylation at serine 166, which directly interacted with p53 for degradation. p53 degradation caused a p53-dependent DNA damage checkpoint or repair dysfunction, which eventually results in DNA damage accumulation in sperm. Our results highlight that inhibition of PI3K/Akt pathway or p53 degradation is important in maintaining sperm motility in a thyroxine receptor (TR)-dependent manner.
Department of Reproduction and Infertility, Chengdu Women and Children's Central Hospital, Chengdu 610091, China. Electronic address: xianhong1206@163.com.
Hong
H
Xian
Department of Reproduction and Infertility, Chengdu Women and Children's Central Hospital, Chengdu 610091, China.
Fang
F
Wang
Department of Reproduction and Infertility, Chengdu Women and Children's Central Hospital, Chengdu 610091, China.
Wending
W
Teng
Department of Reproduction and Infertility, Chengdu Women and Children's Central Hospital, Chengdu 610091, China.
Dong
D
Yang
College of Animal Science & Technology, Sichuan Agricultural University, Chengdu 610000, China.
Ming
M
Zhang
D000328:Adult; D000638:Amiodarone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004249:DNA Damage; D000077764:Dronedarone; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D015398:Signal Transduction; D013081:Sperm Motility; D013094:Spermatozoa / Q000187:drug effects / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000638:Amiodarone; D002867:Chromones; D000077764:Dronedarone; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D011988:Receptors, Thyroid Hormone; D013974:Thyroxine; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C497206:MDM2 protein, human
DNA damage; PI3K/Akt; Sperm motility; l-Thyroxine; p53