Investigating obesity-induced altered ovarian intracellular signaling

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Project summary: Obesity is a global public health issue. A number of chemicals precipitate amenorrhea, premature menopause and infertility in females. Affected women experience chronic, permanent health effects since the proportion of their life spent post-menopause is lengthened, thereby increasing the likelihood of associated health complication development (including coronary heart disease, obesity, type II diabetes, osteoporosis and depression). Reproductive dysfunction also results from obesity and we have published a number of studies demonstrating that the ovary of an obese female has heightened sensitivity to chemical exposures that induce ovarian damage and infertility. This increased sensitivity arises from altered abundance of chemical metabolism proteins within the ovary and raises concern about increased risk to obese women of environmental chemical exposures that target the ovary. Our strong published and preliminary data support that the ovary of obese females have altered chemical metabolism in addition to a blunted DNA repair response when exposed to chemicals that cause DNA damage. This is concerning since DNA damage can lead to loss of fertility in females or represent a risk to offspring health should this damage be improperly repaired. Indeed, offspring of obese women have increased rates of birth defects. We have demonstrated our findings in adult post-pubertal mice, however, whether these impacts are also noted in females who experience an obese environment during gestation or pre-pubertally remains unclear but represents a major concern for female public health. In light of our strong and worrying evidence for a heightened sensitivity of the obese female ovary to chemical-induced damage, we will mechanistically investigate our central hypothesis that obesity potentiates ovotoxicity through reduced repair of DNA damage, altered ovarian chemical biotransformation, and induction of oxidative stress. We will utilize the alkylating agent, dimethylbenz[a]anthracene (DMBA) to induce ovarian DNA damage at three stages of importance in ovarian development; during gestation, pre-puberty and post-puberty. We will investigate our hypothesis through completion of three specific aims: Aim 1 will investigate obesity effects on DNA repair response to DMBA exposure; Aim 2 will examine obesity-induced impacts on DMBA chemical metabolism; and Aim 3 will determine effects of DMBA exposure and obesity on induction of ovarian oxidative stress. This work is applicable to general female health, ovarian toxicity, infertility and even extends to carcinogenesis. The data has basic and translational importance and is relevant to the NIEHS mission. This proposal is pioneering, innovative, and couples the additive effect of altered physiological and metabolic status on ovarian toxicity that occurs as a consequence of environmental chemical exposures.