The objective of this application is to determine the doses and mechanism(s) by which early-life exposure to the ubiquitous industrial chemical, bisphenol A (BPA), promotes insulin resistance (IR) and type2 diabetes (T2DM) in adults. Prior studies and preliminary data from this investigative team suggest that early-life (perinatal) exposure to BPA promotes IR and T2DM by increasing adiposity, altering pancreatic insulin secretion, and in females, promoting a phenotype similar to human polycystic ovarian syndrome (PCOS), which typically includes obesity and IR. The rationale for the proposed studies is that public health policy regarding the prevention of insulin resistance and T2DM will be significantly enhanced by definitive, mechanistic studies of BPA's role in promoting obesity and/or dysregulating glucose and insulin homeostasis. Accordingly, this project will investigate the effects of early BPA exposure (gestation through postnatal day 21) on the development of IR, T2DM and obesity in male and female rats and potential ovarian dysfunction in female rats. Glucose homeostasis, adiposity and adiposity-related biohumoral and tissue read-outs will be monitored at 4, 8, 12 and 18 months in male and female rats exposed to vehicle and 4 different doses of BPA. Blood and tissues (white and brown adipose depots, pancreas, liver, skeletal muscle and ovaries) will be collected for various biohumoral, histological, biochemical, gene expression and epigenetic analyses.
Specific Aim 1 will determine the dose(s) of perinatal BPA exposure that dysregulate glucose/insulin homeostasis in adult rats and will determine the chronology and progression of this dysregulation.
Specific Aim 2 will test the hypothesis that BPA-induced IR reflects the metabolic and inflammatory impacts of obesity and/or hormonal dysregulation in females.
Specific Aim 3 will identify BPA-induced transcriptional and epigenetic changes (DNA and histone methylation) in both white and brown adipose tissue that are associated with the development of IR and/or obesity. Completion of Aims 1-3 and integration of their results will provide an indepth assessment of the effects of early-life BPA exposure on the development of impaired glucose homeostasis, IR and T2DM in the adult and the associated BPA-induced adipose, pancreatic and ovarian changes that may promote this metabolic dysregulation. The significance of the proposed studies lies in their ability to identify the multiple effects of BPA exposure on gene expression, metabolism, body composition and hormones that may be contributing to societal increases in obesity, IR and T2DM.

Public Health Relevance

Although overnutrition and a sedentary lifestyle are considered the primary reason for the worldwide increase in obesity and diabetes, there is evidence to suggest that the unprecedented increase in chemicals in our environment may play a role in the decline in metabolic health. In vivo and in vitro studies suggest that BPA, a ubiquitous environmental endocrine disrupter, can promote fat accumulation and exert effects on the pancreas to increase insulin secretion, leading to insulin resistance and diabetes. As a consequence, this research is relevant to NIH's mission to reduce obesity-related health problems, especially diabetes and the related health-care costs.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZES1-JAB-J (BP))
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Heindel, Jerrold
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Tufts University
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