| Obesity is now a worldwide epidemic, with increased risk of cardiovascular disease, diabetes and metabolic syndrome. Lipid metabolic disorder is the main cause of obesity. The visceral fat, hyperlipidemia, insulin resistance and hypertension are common performances of lipid metabolic disorder. Liver is a critical organism to maintain a homeostasis of lipid, protein and glucose. Once the abnormal hepatocytic lipid metabolism occured, followed by mass fatty accumulation in hepatocytes, resulted in severe dyslipidemia, insulin resistance and hepatic steatosis. Extensive laboratory studies had found that sex hormones and sex hormone receptors play an important role in the body to maintain lipid metabolic balance. Epidemiological studies also observed that the epidemiological characteristics of lipid metabolic disorder-related diseases are associated with age and gender. Postmenopausal women and older men are more likely to develop diabetes, high cholesterol and other metabolic diseases, which emphasized the importance of sex hormones on lipid metabolism.Polybrominated diphenyl ethers (polyrominated diphenyl ethers, PBDEs) are a class of brominated flameretardant chemicals widely used in textiles, furniture, electronics and electrical products. Over the past several decades, PBDEs were concerned a lot because of the significant increased levels in the environment and in humans.2,2’,4,4’-tetrabromodiphenyl ether (BDE47) is the dominant PBDE congener in humans, wildlife, and the environment. BDE47 has estrogenic activity, which could bind to the androgen receptor and estrogen receptor competitively. Studies have shown that BDE47 could induce the lipid metabolic disorders and its mechanism may be related to sex hormone receptors in the liver.In this study, we conducted epidemiological studies and animal models exposure to BDE7 with estrogen (E2) and estrogen receptor inhibitors (ICI182,780) as tools for drug, evaluating the BDE47-induced sexual differences of hepatic lipid metabolism and attempting to reveal the related molecular mechanism of sex hormones receptors. The results will provide new perspectives and technical support on toxicological studies of chemicals, and also provide important references for risk assessment, hazard control and prevention of environmental contaminants-induced metabolic disease,PartⅠ:Effect of sex hormone receptors on BDE47-induced sexual differences of hepatic lipid metabolismObjective:To compare the prevalence of dyslipidemia between different genders and ages, and evaluate the association between prevalence of dyslipidemia and serum exposure levels of BDE47.Methods:Carry out a community-based cross-sectional study, enrolling a total of 884 participants with 391 men and 493 women from 2010 to 2012 in China. All the participants received a questionnaire, health examination, and the detection of 7 PBDE congeners in serum. Using logistic regression analysis to found related risk factors of dyslipidemia and using GC-MS/MS to measure BDE47 concentration in serum, further to analyze the relationship between their exposure levels and the incidence of dyslipidemia.Results:The cross-sectional study found that the educational level of male was significantly higher than females’(P<0.05). Smoking, alcohol consumption, family income, type of diet were statistically significant between male and female (P<0.05). Biochemical index detection show that the female group has a significant dyslipidemia (P<0.05). Unvariate and multivariate logistic regression analysis were carried out to find risk factors of dyslipidemia. Results showed that visceral obesity and age are major risk factors for dyslipidemia. Serum BDE47 detect results show that the detection rate between male and female was a significant difference (P<0.05). There was a positive correlation between serum BDE-47 and the incidence of dyslipidemia in male or female group (P<0.05, OR> 1). Compared with reference group, male patients in the low and high BDE47 exposure groups increased the risk of diabetes by fold (adjusted OR=1.308,95%CI:1.103,1.919) and fold (adjusted OR=1.316,95%CI:1.124,1.803) respectively, and with increasing levels of BDE47 exposure, the risk of dyslipidemia showed a significant increase (adjusted Ptrend= 0.022). Compared with reference group, female patients in the low and high BDE47 exposure groups increased the risk of diabetes by fold (adjusted OR=1.405, 95%CI:1.206,1.793) and fold (adjusted OR=1.417,95%CI:1.195,1.891) respectively, and with increasing levels of BDE47 exposure, the risk of dyslipidemia showed a significant increase (adjusted Ptrend= 0.011).Conclusion:In this study population, the prevalence of dyslipidemia in female was significantly higher than that in male. Likely, the prevalence of dyslipidemia was significantly increased after the menopause. Age and visceral obesity are major risk factors for population dyslipidemia. There is a positive correlation between the serum BDE-47 concentration and the incidence of dyslipidemia, and women are more susceptible than men.Part Ⅱ:Effect of sex hormone receptors on BDE47-induced sexual differences of mouse hepatic lipid metabolismObjective:To analyze and evaluate the effect of BDE47 on male and female mouse hepatic lipid metabolism and primarily investigate the sex hormone and their receptor pathways’mechanisms of action.Methods:Briefly, forty adult male and fifty female C57BL/6 mouse (g) were randomly divided into four groups and five groups. They were administered BDE47, E2, ICI182,780 according to study design. The control mice received a same volume of corn oil only. Then biochemical index, the level of serum E2 and serum T, and pathological changes of the liver were detected. Using immunohistochemistry of hepatocystic AR/ESR1 expression, and explore the sex hormones receptor pathway’s molecular mechanisms of action.Results:Compared with the control group, BDE47 induced elevated blood lipids, hepatocytic fatty degeneration of the liver cells, but had no effect on the AR’s and ER’s expression and localization. E2 is able of inducing the expression of ESR1 in hepatocyte and then low down the serum lipid levels in mice, followed in reducing the degree of hepatic steatosis. Further studies showed that, BDE47 significantly induced transcriptional activation of SCD-1 and FASN, while inhibiting the transcriptional activation of the SHP thereby increasing SREBP-lc transcription; E2 has the opposite effect to BDE47.Conclusion:The present study suggests that:BDE47 could lead to male and female mice hepatocytic lipid metabolic disorders. E2 might regulate lipid metabolism in the liver. The possible mechanisms in male mice involve that; (1) BDE47 interferences the hepatocytic lipid metabolism by reducing the levels of testosterone; (2) BDE47 antagonizes AR, which suppresses the activation of AR by testosterone, and then inhibites the hepatocytic lipid metabolism pathway; (3) BDE47 antagonizes ESER1, followed by raising hepatic lipid synthesis gene SCD-1, FASN and inhibiting SHP, then increasing SREBP-lc, eventually leads to hepatocytic lipid synthesis. Mechanism of female mice is mainly involved in the inhibition of ESR1, interfering the transcriptional activation of lipid metabolism related genes. |
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