Does perinatal exposure to Bisphenol A contribute to adult obesity

Tufts University Boston, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Obesity is one of the most common health problems in the US. The rapid increase in the prevalence of obesity in the U.S. suggests that primary causes may be environmental. Although changes in diet and physical activity have long been considered the major culprit in this regard, there is novel information that points to environmental endocrine disrupters as potential causative agents. While performing experiments aimed at understanding the effects of perinatal exposure to environmentally relevant levels of the estrogen bisphenol-A (BPA) we observed a substantial increase in body weight that persisted throughout the adult life of these animals. Further exploration revealed adiposity, hyperphagia and glucosuria. The nature of the metabolic aberrations underlying this type of obesity is unknown, but its persistence long after cessation of exposure suggests that BPA exerts early, irreversible effects on metabolic programming. Our working hypothesis is that exposure to BPA during fetal and neonatal life disrupts the development of key metabolic regulatory networks (in systemic organs and/or in the CNS), leading to sustained alterations in expression of genes involved in regulation of food intake, triglyceride anabolism and catabolism, and/or glucose utilization. Specific Aim 1 will assess the nature of the weight gain in the offspring of pregnant mice exposed to BPA from gestational day 9 through lactation. The following parameters will be measured postnatally and at two later ages: body size; mass and linear growth rates and composition, food consumption, tissue mass and adipose cell number, size of individual adipose depots; fasting levels of metabolically relevant plasma metabolites and hormones. Specific Aim 2 will explore the expression pattern of genes encoding metabolically relevant genes as indicators of the relative activity levels and state of regulation of major anabolic and catabolic pathways in tissues involved in the control of energy balance. They include C/EBP-alpha, PPAR-gamma, FAS, Glut-4, HSL, and leptin in white adipose tissue, UCP1 in brown adipose tissue, and POMC and NPY in the hypothalamus. These parameters will be investigated using real-time RT-PCR; mRNA levels will be measured during the period of BPA exposure, and at two later points at the same ages and doses examined in Aim 1. These studies will indicate the extent of obesity and whether there is differential involvement of specific adipose depots or increases in adipocyte numbers following perinatal BPA treatment. They also will provide indicators of the major candidate pathways involved, and will guide the development of hypotheses about the mechanisms underlying this phenomenon, including dysregulation and interactions of CNS and peripheral pathways. It is expected that these results, in turn, may generate a better understanding of the obesity problem, and provide elements to help devise a sound policy addressing this serious public health problem.