期刊
SYSTEMS BIOLOGY IN REPRODUCTIVE MEDICINE
卷 58, 期 1, 页码 57-62出版社
INFORMA HEALTHCARE
DOI: 10.3109/19396368.2011.648820
关键词
follicle; ovary; toxicology; VCD; VCH
资金
- NIEHS NIH HHS [R01 ES009246-10S1, R01 ES09246, R01 ES009246, T32 ES007091, ES007091, ES06694, P30 ES006694] Funding Source: Medline
The occupational chemical 4-vinylcyclohexene diepoxide (VCD) has been shown to cause selective destruction of ovarian small pre-antral (primordial and primary) follicles in rats and mice by accelerating the natural, apoptotic process of atresia. Chemicals that destroy primordial follicles are of concern to women because exposure can result in premature ovarian failure (early menopause). Initial studies using in vivo exposure of rats determined that VCD specifically targets primordial and primary (small pre-antral) follicles and that repeated dosing is required. Through a method of isolation of ovarian small follicles, biochemical and molecular studies determined that intracellular pro-apoptotic pathways are activated following VCD dosing in rats. Subsequently an in vitro system using cultured whole neonatal rat ovaries was developed to provide more mechanistic information. That approach was used to demonstrate that the cell survival c-kit/kit ligand signaling pathway is the direct target for VCD-induced ovotoxicity. Specifically, VCD directly interacts with the oocyte-associated c-kit receptor to inhibit its autophosphorylation, and thereby impair oocyte viability. The cellular and molecular approach developed to determine these findings is described in this article.
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