Effects And Mechanism Of Perinatal BPA Exposure On Metabolic Syndrome In The Rat Offspring

The incidence of metabolic syndrome, characterized by obesity, insulin resitance or hyperlipdemia etc., is rising at epidemic rates over the last several decades. Although genetic predisposition, obesity, diet and lack of exercise are commonly accepted causes of metabolic syndrome, it is argued that these factors alone cannot fully explain this phenomenon. There is mounting evidence suggesting that the increased presence of environmental endocrine disrupting chemicals (EDDs) plays an important part in the prevalence of metabolic syndrome. Increasing toxicological research so far has expanded the notion of EDDs beyond its original primary focus on reproductive development, sex differentiation and cancer to potential effects on metabolic state.Bisphenol A (BPA), one of the typical EDDs, is mainly used as the monomer to manufacture polycarbonate plastic and resin. As plastic manufacture developed very rapid, BPA is extensively used in the manufacture of many daily products and represents serious threat to the health of the population of almost every country in the world. Based on analysis of data from the National Health and Nutrition Examination Survey, researchers report a significant relationship between urine concentrations of BPA and type 2 diabetes and cardiovascular disease in representative sample of the adult US population. Animal studies also confirm that administration of BPA in mice would impairβcells function and disrupt glucose homeostasis via recently discovered estrogen response pathway. Notably, it is proven that BPA can easily cross the placenta and enter breast milk, and then is rapidly absorbed by offspring, causing toxicity in developmental organism. In the present study, we used an animal model to address whether perinatal BPA exposure would contribute to the disruptions of glucose and lipid homeostasis in rat offspring, and determine whether adverse metabolic consequences of BPA would be accelerate exacerbate under high-fat feeding condition after weaning. In addition, we addressed the possible mechanism of BPA-induced metabolic syndrome at cellular and molecular levels.PartⅠ:Effects of Perinatal BPA Exposure on Lipid Metabolism in the Rat OffspringObjective:To study whether perinatal BPA exposure disrupts lipid homeostasis in the rat offspring. Methods:Pregnant Wistar rats were administered corn oil,50,250 and 1250μg/kg/day BPA by oral gavage from gestation day 0 (GDO) through the end of lactation (poatanal day 21, PND21). Pups were weaned on PND21.32 male and 32 female offspring were fed a normal diet or a high-fat diet after weaning. Body weight, food intake and parameters of lipid metabolism were determined during growth. Weight and histology of perigonadal adipose tissues were investigated at week 3 and 27. mRNA levels of PPARy, C/EBP-a, SREBP-1 and FAS in adipose tissues were determined in male pups at weaning. Results:Body weight was comparable between controls and BPA-exposed offspring during lactation. Although similar body fat percentage and size of adipocytes was observed among all treatment groups, expression of Lipogenic genes, PPARy, C/EBP-a, SREBP-1 and FAS, was increased in adipose tissue of 50μg/kg/day BPA exposed male offspring at weaning. After weaning, perinatal exposure to 50μg/kg/day BPA resulted in increased body weight in adult offspring fed a normal diet. Body fat percentage, size of adipocytes, serum TG and leptin were increased in adult males exposed to 50μg/kg/day BPA, whereas no difference was displayed in females. On a high-fat diet, such effects were accelerated and exacerbated. In addition to increased body weight in early adulthood,50μg/kg/day BPA exposed offspring exhibited elevated serum TC, TG, LDL and leptin, reduced serum HDL, as well as increased size of adipocytes and elevated body fat percentage at adulthood. No adverse effect of perinatal BPA exposure at 250 and 1250μg/kg/day was observed no matter fed a normal diet or a high-fat diet. Conclusion:Perinatal exposure to BPA at 50μg/kg/day alters early lipogenesis and adipocyte differentiation, and then gives rise to obesity and dyslipidaemia at adulthood in the rat offspring.Part II:Perinatal Exposure to Bisphenol A at Reference Dose Predisposes Offspring to Glucometabolic Disorders in Adult RatsObjective:In this study, we investigated the effects of early-life BPA exposure on metabolic syndrome in rat offspring fed a normal diet and a high-fat diet. Methods: Pregnant Wistar rats were exposed to BPA (50,250 or 1250μg/kg/day) or corn oil throughout gestation and lactation by oral gavage. Offspring were fed a normal diet or a high-fat diet post-weaning. Body weight, parameters of glucose and lipid metabolism was measured in offspring. Morphology of beta cells was examined by immunocytochemistry, and ultrastructural changes ofβcells were observed by transmission electron microscope. Function and mRNA expression ofβcells were determined by isolated islets in adult offspring. Results:On a normal diet, perinatal exposure to 50μg/kg/day BPA resulted in increased body weight, elevated serum insulin and impaired glucose tolerance in adult offspring. On a high-fat diet, such detrimental effects were accelerated and exacerbated. Furthermore, severe metabolic syndrome, as shown by obesity, dyslipidemia, hyperleptindemia, hyperglycemia, hyperinsulinemia and glucose intolerance, was observed in high-fat fed offspring perinatally exposed to 50μg/kg/day BPA. No adverse effect of perinatal BPA exposure at 250 and 1250μg/kg/day was observed no matter on a normal diet or a high-fat diet. Conclusion:Perinatal exposure to BPA at reference dose, but not at high dose, impairs glucose tolerance in adult rat offspring on a normal diet, and predisposes offspring to metabolic syndrome at adult on a high-fat diet. High-fat diet intake is a trigger that initiates adverse metabolic effects of BPA.PartⅢ:Perinatal BPA Exposure at Reference Dose Promotes Nonalcoholic Fatty Liver Disease in Adult Male Rat OffspringObjective:Nonalcoholic fatty liver disease is predicted to become one of the main cause of chronic liver disease in the next decades. This study examines whether perinatal BPA exposure predisposes rat offspring to nonalcoholic fatty liver disease. Methods:Pregnant Wistar rats were exposed to corn oil and 50μg/kg/day BPA dissolved in corn oil from gestation days 0 (GD 0) to postnatal days 21(PND 21). Male offspring were fed a normal diet or high-fat diet after weaning and were raised from PND 21 to the age of 27 week. At week 27, Liver mass, histology and lipid content were investigated. Parameters of lipid metabolism and liver function were determined. Moreover, mRN A levels of genes involved in lipogenesis and fatty acidβ-oxidation, and protein levels of PPARy, IL-6 and TNF-a were analyzed in hepatic tissue in male offspring. Results:On a normal diet, TC and FFA in serum and liver were elevated in BPA-exposed male offspring. Steatosis in liver was displayed, although no BPA-exposed male offspring on a normal diet exhibited abnormal liver function and signs of inflammation. On a high-fat diet, BPA-exposed male offspring displayed hyperlipidaemia, abnormal liver function with raised AST, ALT and GGT, profound liver damages with swelled hepatocellular, disordered hepatic cord and severe steatosis in morphological assessments. BPA-exposed male offspring also exhibited histological signs of inflammation with significantly changed expression of TNF-a and IL-6. In addition, expression of genes involved in fatty acid oxidation and metabolism was changed in BPA-exposed male offspring on both diets. Conclusion:Perinatal BPA exposure at reference dose contributes to the development of nonalcoholic fatty liver disease in adult offspring. High-fat diet promotes and exacerbates the detrimental effects of BPA. BPA exposed offspring weaned onto high-fat diet develop into severe nonalcoholic steatohepatitis (NASH) at adulthood.