4 Recent epidemiological studies showed an association between urinary levels of BPA and the prevalence of diabetes, cardiovascular diseases, and elevated markers of liver toxicity.5, 6 These studies pointed to metabolic disorders as a potential impact of exposure to low doses of BPA. In agreement with this hypothesis, experimental evidence has accumulated that BPA can alter several aspects of metabolic functions in rodents. Animal studies

showed an increased body weight in offspring of mothers exposed to BPA during gestation and/or lactation period.7 The increase in body weight was more pronounced and persistent in females than males and the effects were stronger at low compared with high doses of exposure. Such nonmonotonic dose-response relationship have been reported for many actions of BPA.8-11 How perinatal BPA exposure may exert these effects remains EX 527 datasheet to be determined, but potential target tissues of BPA action including adipose tissue and pancreas have been studied. Gestational exposure to BPA was shown to increase adipose tissue mass at weaning associated with adipocyte hypertrophy and overexpression of lipogenic genes.9, 10, 12 Low BPA doses were also shown to increase leptin and to decrease adiponectin secretion.9,

13In vitro studies documented learn more an increased lipid accumulation and adipocyte differentiation after exposure of 3T3L1 preadipocytes Interleukin-3 receptor to BPA and other endocrine-disrupting chemicals.14-16 Nadal and colleagues showed that BPA increases insulin synthesis and secretion with concurrent impacts on glucose homeostasis.17, 18In vivo injection of 1, 10, or 100 μg/kg/day of BPA to adult male mice resulted in a significant dose-dependent decrease in glycemia in parallel to an increase in insulin from 30 minutes after injection.19 Isolated islets

of pancreatic β-cells exposed to a range of BPA doses showed increased insulin content following an inverted U-shape dose-response curve.20 The same group recently reported on similar effects in pregnant mice and their offspring exposed to 10 or 100 μg/kg/day of BPA.21 Thus, both the adipose tissue and the pancreas have emerged as important targets of low BPA doses. Despite the important roles of the liver in whole body energy homeostasis, little is known about the hepatic impacts of exposure to environmentally relevant doses of BPA. Here we evaluated the effects of oral exposure to 50 μg/kg/day (TDI) or 5,000 μg/kg/day (NOAEL) of BPA on mouse liver transcriptome. Initial genome-wide microarray screenings evidenced a predominant impact of low BPA doses on lipid biosynthesis pathways. Using a wide range of doses, we showed that these effects are specific to low, environmentally relevant doses of BPA and correlate with an increased hepatic accumulation of neutral lipids.