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Perinatal testosterone exposure potentiates vascular dysfunction by ER? suppression in endothelial progenitor cells.

ABSTRACT: Recent clinical cohort study shows that testosterone therapy increases cardiovascular diseases in men with low testosterone levels, excessive circulating androgen levels may play a detrimental role in the vascular system, while the potential mechanism and effect of testosterone exposure on the vascular function in offspring is still unknown. Our preliminary results showed that perinatal testosterone exposure in mice induces estrogen receptor ? (ER?) suppression in endothelial progenitor cells (EPCs) in offspring but not mothers, while estradiol (E2) had no effect. Further investigation showed that ER? suppression is due to perinatal testosterone exposure-induced epigenetic changes with altered DNA methylation on the ER? promoter. During aging, EPCs with ER? suppression mobilize to the vascular wall, differentiate into ER?-suppressed mouse endothelial cells (MECs) with downregulated expression of SOD2 (mitochondrial superoxide dismutase) and ERR? (estrogen-related receptor ?). This results in reactive oxygen species (ROS) generation and DNA damage, and the dysfunction of mitochondria and fatty acid metabolism, subsequently potentiating vascular dysfunction. Bone marrow transplantation of EPCs that overexpressed with either ER? or a SIRT1 single mutant SIRT1-C152(D) that could modulate SIRT1 phosphorylation significantly ameliorated vascular dysfunction, while ER? knockdown worsened the problem. We conclude that perinatal testosterone exposure potentiates vascular dysfunction through ER? suppression in EPCs.

SUBMITTER: Xie W

PROVIDER: S-EPMC5557363 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Perinatal testosterone exposure potentiates vascular dysfunction by ERβ suppression in endothelial progenitor cells.

Xie Weiguo W Ren Mingming M Li Ling L Zhu Yin Y Chu Zhigang Z Zhu Zhigang Z Ruan Qiongfang Q Lou Wenting W Zhang Haimou H Han Zhen Z Huang Xiaodong X Xiang Wei W Wang Tao T Yao Paul P

PloS one 20170815 8

Recent clinical cohort study shows that testosterone therapy increases cardiovascular diseases in men with low testosterone levels, excessive circulating androgen levels may play a detrimental role in the vascular system, while the potential mechanism and effect of testosterone exposure on the vascular function in offspring is still unknown. Our preliminary results showed that perinatal testosterone exposure in mice induces estrogen receptor β (ERβ) suppression in endothelial progenitor cells (E ...[more]

PMID: 28809938

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Project description:BACKGROUND:Autism spectrum disorder (ASD) is characterized by impairments in social communication and restricted or repetitive behaviors or interests. ASD is now diagnosed in more than one out of 100 children and is biased towards males by a ratio of at least 4:1. Many possible explanations and potential causative factors have been reported, such as genetics, sex, and environmental factors, although the detailed mechanisms of ASD remain unclear. METHODS:The dams were exposed through oral contraceptives to either vehicle control (VEH) alone, levonorgestrel (LNG) alone, ethinyl estradiol (EE) alone, or a combination of LNG/EE for 21 days during their pregnancy. The subsequent 10-week-old offspring were used for autism-like behavior testing, and the limbic tissues were isolated for analysis. In another experimental group, 8-week-old male offspring were treated by infusion of ERβ overexpression/knockdown lentivirus in the amygdala, and the offspring were analyzed after 2 weeks. RESULTS:We show that prenatal exposure of either LNG alone or a LNG/EE combination, but not EE alone, results in suppression of ERβ (estrogen receptor β) and its target genes in the amygdala with autism-like behavior in male offspring, while there is a much smaller effect on female offspring. However, we find that there is no effect on the hippocampus and hypothalamus. Further investigation shows that ERβ suppression is due to LNG-mediated altered methylation on the ERβ promoter and results in tissue damage with oxidative stress and the dysfunction of mitochondria and fatty acid metabolism, which subsequently triggers autism-like behavior. Overexpression of ERβ in the amygdala completely restores LNG-induced ERβ suppression and autism-like behaviors in offspring, while ERβ knockdown mimics this effect, indicating that ERβ expression in the amygdala plays an important role in autism-like behavior development. CONCLUSIONS:We conclude that prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERβ suppression in the amygdala. To our knowledge, this is the first time the potential effect of oral contraceptives on the contribution of autism-like behavior in offspring has been discovered.

Project description:Background: Both supraphysiological and subphysiological testosterone levels are associated with increased cardiovascular risk. Testosterone consumption at supraphysiological doses has been linked to increased blood pressure, left ventricular hypertrophy, vascular dysfunction, and increased levels of inflammatory markers. Activation of the NLRP3 inflammasome contributes to the production of proinflammatory cytokines, leading to cardiovascular dysfunction. We hypothesized that supraphysiological levels of testosterone, via generation of mitochondrial reactive oxygen species (mROS), activates the NLRP3 inflammasome and promotes vascular dysfunction. Methods: Male, 12 week-old C57Bl/6J (WT) and NLRP3 knockout (NLRP3-/-) mice were used. Mice were treated with testosterone propionate [TP (10 mg/kg) in vivo] or vehicle for 30 days. In addition, vessels were incubated with testosterone [Testo (10-6 M, 2 h) in vitro]. Testosterone levels, blood pressure, vascular function (thoracic aortic rings), pro-caspase-1/caspase-1 and interleukin-1? (IL-1?) expression, and generation of reactive oxygen species were determined. Results: Testosterone increased contractile responses and reduced endothelium-dependent vasodilation, both in vivo and in vitro. These effects were not observed in arteries from NLRP3-/- mice. Aortas of TP-treated WT mice (in vivo), as well as aortas from WT mice incubated with testo (in vitro), exhibited increased mROS levels and increased caspase-1 and IL-1? expression. These effects were not observed in arteries from NLRP3-/- mice. Flutamide [Flu, 10-5 M, androgen receptor (AR) antagonist], carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 10-6 M, mitochondrial uncoupler) and MCC950 (MCC950, 10-6 M, a NLRP3 receptor inhibitor) prevented testosterone-induced mROS generation. Conclusion: Supraphysiological levels of testosterone induce vascular dysfunction via mROS generation and NLRP3 inflammasome activation. These events may contribute to increased cardiovascular risk.

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Perinatal testosterone exposure potentiates vascular dysfunction by ER? suppression in endothelial progenitor cells.

Publications

Perinatal testosterone exposure potentiates vascular dysfunction by ERβ suppression in endothelial progenitor cells.

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