A growing body of evidence suggests that environmental pollutants, such as polychlorinated biphenyls (PCBs), bisphenol-A, phthalates and arsenic, may play an important role in the pathophysiology of type-2 diabetes mellitus (T2DM), obesity, and metabolic syndrome (MetS). While the evidence supports the role of environmental pollutants as potential risk factors for metabolic diseases, several important challenges remain to establish causality in human populations: 1) there have been few prospective longitudinal cohort studies, raising concerns related to causal inferences and problems of reverse causality; 2) data on emerging pollutants widespread in our environment such as brominated flame retardants and antibacterial agents and preservatives is lacking; 3) data on underlying mechanisms in human populations is lacking; and 4) data on combined effects of multiple pollutants in relation to metabolic diseases is lacking due to statistical challenges. Although women become more susceptible to cardio-metabolic disorders during the menopausal transition due to the hormonal changes, little is known about the role of environmental pollutants in metabolic diseases during this critical window of susceptibility. This new epidemiologic study in a multi-ethnic cohort of women seeks to address these research gaps and improve our understanding of how exposure to multiple pollutants affects the risks of developing T2DM, obesity and MetS. We propose 1) to identify potential environmental pollutants associated with incident T2DM, obesity and MetS; 2) to assess the associations of environmental pollutants with longitudinal changes in intermediate metabolic traits including blood pressure, body composition (e.g., fat mass and percent body fat), lipid profiles, insulin resistance and C-reactive protein, and with cross-sectional associations with adipokines (e.g., leptin and adiponectin); and 3) to examine the combined effects of multiple pollutants on T2DM, obesity and MetS evaluated simultaneously and construct an Environmental Risk Score. We will also explore potential pollutant-pollutant interactions in relation to metabolic outcomes. We will conduct a case-cohort study (n=950; 382 new cases of T2DM, obesity and/or MetS occurred between 1999 and 2010 and a random subcohort of 753 women (185 overlap with new cases)) in the Study of Women's Health Across the Nation (SWAN), a multi-site, multi-ethnic cohort of midlife women who are at increased metabolic risk, evaluated annually or bi-annually for more than 10 years. We will evaluate more than 120 environmental pollutants such as PCBs, organochlorine pesticides, flame retardants, organophosphate pesticides and metabolites, heavy metals, phthalates, bisphenol-A, and other phenolic compounds assessed in either serum or urine samples. This project addresses strategic priorities of the National Institute of Environmental Health Sciences (NIEHS), including identifying common biological pathways and understanding disease pathogenesis by combined environmental exposures. We will address these issues using innovative analytic approaches likely to yield new insights on the study of multiple pollutants and human health.