The female gonad is detrimentally affected by a variety of environmental exposures including polycyclic aromatic hydrocarbons, anti-cancer therapies, pesticides, plasticizers and persistent organic pollutants. Mechanisms of ovotoxicity include hyperactivation of primordial follicle growth, somatic and germ cell DNA damage, impaired folliculogenesis and steroidogenesis. The ovary can respond to ovotoxicants by chemical biotransformation and DNA damage. Despite this, ovotoxicant exposures can result in endocrine disruption and early onset of menopause. We have discovered a physiological status x exposure paradigm of ovotoxicity, such that altered systemic metabolism can influence ovotoxicity. Specifically, the ovary of an obese female has blunted chemical biotransformation and DNA repair responses to ovotoxicant exposures. Perfluorooctanoic acid (PFOA) is a persistent environmental pollutant with a half-life of years in humans. To explore the hypothesis that altered systemic physiology during obesity would affect the ovarian response to PFOA exposure, female wild type (KK.Cg-a/a; lean) or KK.Cg-Ay/J mice (obese) received saline (CT) or PFOA (2.5 mg/Kg) per os for 15 days beginning at 7 weeks of age with water and food ad libitum. There were no treatment effects on food intake, final body weight, steroid hormone level, length spent at different stages of the estrous cycle, uterus, heart, kidney, or spleen weight (P > 0.05). Liver weight was increased (P < 0.05) by PFOA exposure in both lean and obese mice. Ovary weight was decreased in the lean but not obese mice exposed to PFOA (P < 0.05). Relative to vehicle control, exposure to PFOA altered 22 and 28 proteins in lean and obese mice, respectively, as quantified by LC-MS/MS. Cellular pathways targeted by PFOA included cancer, estrogen signaling, PI3K-AKT signaling, progesterone-mediated oocyte maturation, metabolic, xenobiotic metabolism, DNA damage and reproduction. Taken together, ovotoxicants negatively affect fertility through several modes of action and alterations to systemic metabolism contribute to ovotoxicity.