One of the major public health challenges facing society in the 21st century is the increasing prevalence of metabolic diseases. Importantly, the incidence of obesity is rising dramatically leading to an epidemic of diabetes and an increased risk of developing metabolic syndrome and nonalcoholic fatty liver disease (NAFLD), which is the accumulation of triglyceride (TG) in the liver. Bisphenol A (BPA) is a ubiquitous chemical toxin in our environment and has been detected in the urine of greater than 90% of a cross section of the US population. This endocrine disruptor has been implicated in the development of hyperinsulinemia, increased adiposity, diabetes and clinically abnormal serum levels of liver enzymes. At the present time, we have limited knowledge of the effects of BPA exposure on hepatic gene expression, metabolism, and steatosis. This proposal seeks funds to test the hypothesis that perinatal and/or lifelong BPA exposure promotes the hepatic lipogenic program leading to NAFLD. The proposed research will take advantage of a unique opportunity- i.e., a planned good laboratory practice (GLP) study of BPA effects in Sprague Dawley rats that will be conducted at the FDA National Center for Toxicological Research (NCTR), where two separate cohorts exposed to several different doses of BPA by daily gavage will be generated. Gavage will begin in the pregnant mothers on gestational day 6 and continue through the day of birth. After birth, the pups will be gavaged directly beginning on postnatal day 1 (PND 1) continuing through PND21 (Cohort 1). In additional animals (Cohort 2), the oral gavage of BPA will continue daily throughout life.
The specific aim i s to determine the dose(s) of perinatal and lifelong BPA exposure that alters hepatic gene expression and promotes hepatic lipid accumulation. We will determine the chronology and progression of hepatic alterations in gene expression and lipid metabolism in the two cohorts at 6 and 12 months of age. We propose to determine relevant gene and protein expression that promote hepatic alterations in lipid metabolism. Additionally, we will obtain frozen and fixed liver tissues that will be used for histological studies to determine the presence of steatosis and inflammatory foci as well as studies to measure markers of lipid peroxidation and hepatic lipid accumulation. These data will be viewed in relation to the serum measurements of glucose and insulin that our laboratory has already obtained from a funded FDA/NCTR animal study, as well as data from studies by other already funded researchers, to determine adipose tissue weights, adipokines, and serum fatty acids, triglyceride, and cholesterol levels.

Public Health Relevance

Bisphenol A (BPA) is an ubiquitous chemical toxin in our environment and has been detected in the urine of greater than 90% of a cross section of the US population. The goal of the proposed study is to determine whether rats ingesting BPA while pregnant and/or continuously during life alters how the liver functions. In particular, we will investigate if BPA exposure causes livers in rats to produce and store more fat and cholesterol.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Small Research Grants (R03)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Heindel, Jerrold
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Tufts University
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United States
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Mashek, Douglas G; Greenberg, Andrew S (2014) Serum TAG analysis differentiates between genetic and obesity-associated NAFLD. Diabetes 63:42-4