期刊
REPRODUCTIVE TOXICOLOGY
卷 109, 期 -, 页码 121-134出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.reprotox.2022.03.007
关键词
Ovary; Chromium-VI; Germ cell; Somatic cells; Apoptosis; Sirtuin-1; EX-527; P53
资金
- United States National Insti-tute of Environmental Health Sciences (NIEHS) [1R01ES025234-01]
- Texas A&M Center for Environmental Health Research (TiCER) [P30-ES029067]
- United States National Institute of Environmental Health Sciences (NIEHS) [1R01ES025234-01]
- Texas A&M Center for Environmental Health Research (TiCER) [P30-ES029067]
This study reveals a novel mechanism for hexavalent chromium-induced apoptosis in the ovary, mediated through the p53-SIRT1 network. The findings suggest that targeting the p53 pathway may be an ideal approach to rescue ovaries from hexavalent chromium-induced apoptosis.
Environmental contamination with hexavalent chromium, Cr(VI), has been increasing in the United States as well as in developing countries. Exposure to Cr(VI) predisposes the human population to various diseases, including cancer, infertility, and developmental problems in children. Previous findings from our laboratory reported that prenatal exposure to Cr(VI) caused premature ovarian failure through p53-mediated mechanisms. Sirtuin 1 (SIRT1) is an NAD+-dependent histone deacetylase class III. SIRT1 deacetylates several histones and non-histone proteins such as p53 and NFkB. The current study determines a role for the SIRT1-p53 network in apoptosis induced by Cr(VI) in the ovary and establishes physical interaction between SIRT1 and p53. Adult pregnant dams were given regular drinking water or Cr(VI) (10 ppm potassium dichromate in drinking water, ad libitum), and treated with SIRT1 inhibitor, EX-527 (50 mg/kg body weight, i.p.,), during 9.5 14.5 days postcoitum. On postnatal day-1, ovaries from F1 offspring were collected for various analyses. Results indicated that Cr(VI) increased germ cell and somatic cell apoptosis, upregulated acetyl-p53, activated the apoptotic pathway, and inhibited cell survival pathways. Cr(VI) decreased acetyl-p53-SIRT1 co-localization in the ovary. In an immortalized rat granulosa cell line SIGC, Cr(VI) inhibited the physical interaction between SIRT1 and acetyl p53 by altering the p53:SIRT1 ratio. EX-527 exacerbated Cr(VI)-induced mechanisms. The current study shows a novel mechanism for Cr(VI)-induced apoptosis in the ovary, mediated through the p53-SIRT1 network, suggesting that targeting the p53 pathway may be an ideal approach to rescue ovaries from Cr(VI)-induced apoptosis.
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