Non-alcoholic Fatty Liver Disease Induced by Perinatal Exposure to Bisphenol a Is Associated With Activated mTOR and TLR4/NF-κB Signaling Pathways in Offspring Rats

Abstract

Accumulating evidence suggests a role of bisphenol A (BPA) in non-alcoholic fatty liver disease (NAFLD), and its mechanism may be related to the up-regulation of lipogenic genes, but the mechanism of BPA induced lipogenic gene expression remains unknown. The aim of this study was to investigate the effects of perinatal exposure to BPA on NAFLD and its mechanisms. Pregnant Sprague-Dawley rats had access to drinking water containing 1 or 10 μg/ml BPA from gestational day 6 to post-natal day 21. For 5 weeks after weaning, offspring drank normal water without BPA. Body weight, lipid profile and the expression of genes or proteins involved in mTOR mediated lipid metabolism and autophagy, as well as inflammatory response were investigated in the 8-wk-old offspring of different genders. The results showed that body weight was increased only in females, however, males, and females from dams treated with BPA had significantly excess visceral adipose tissue, which was consistent with adipocyte hypertrophy. Elevated TG levels and up-regulation of lipogenic genes or proteins in liver, such as sterol regulatory element binding protein 1 (SREBP1), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FAS) were consistent with increased liver lipid droplets in offspring exposed to BPA. Compared with controls, the protein levels of InsR, p-IRS-1, IRS-1, TSC1, and TSC2 were decreased, p-PI3K, p-Akt (S473), p-Akt (T308), p-mTOR, and mTOR were increased, and the impaired autophagic degradation was evidenced by increased protein levels of p62, although the levels of p-ULK1, Beclin1, and LC3B proteins were increased in liver of BPA-exposed offspring. The levels of TLR4 and NF-κB proteins were also significantly increased, and ERα protein was significantly decreased in BPA-exposed offspring. Our findings indicate that perinatal exposure to BPA causes the development of NAFLD in both female and male offspring, which is associated with up-regulation of lipogenic genes, dysregulated autophagy and activated inflammatory response involving the PI3K/Akt/mTOR and TLR4/NF-κB pathways.

Bisphenol A and Type 2 Diabetes Mellitus: A Review of Epidemiologic, Functional, and Early Life Factors

“…In the liver, BPA stimulates lipid accumulation through the upregulation of lipogenic genes, such as sterol regulatory element binding protein 1 ( SREBP1 ) [ 140 , 141 ]. This evidence suggests that BPA contributes to the development of non-alcoholic fatty liver disease (NAFLD), a frequent metabolic disturbance in T2DM [ 142 , 143 ].…”

Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma

“…These findings suggested that hepatic steatosis progresses by factors other than anabolic synthesis such as inhibition of autophagy and lysosome dysfunction [38]. Perinatal exposure to bisphenol has also been associated with the development of NASH in mice offspring through the activation of the PI3K/AKT/mTOR pathway in a process that involves the overexpression of lipogenic genes, autophagy impairment and inflammatory response [45]. On the other hand, dysbiosis of the gut microbiota may play a key role in the development of NAFLD [44].…”

Toxicological Assessment of Oral Co-Exposure to Bisphenol A (BPA) and Bis(2-ethylhexyl) Phthalate (DEHP) in Juvenile Rats at Environmentally Relevant Dose Levels: Evaluation of the Synergic, Additive or Antagonistic Effects

“…Overall, metabolic data indicate that the two plasticizers, triggering different pathways, may determine overlapping or compensatory derangements. Indeed, both compounds are known to induce liver oxidative stress, but BPA seems to mainly induce non-alcoholic fatty liver disease [ 33 , 34 ] whereas DEHP, although similarly involved in lipid metabolism disorders, is a potential carcinogen through the activation of the peroxisome proliferating receptor gamma [ 35 ]. Concerning serum metabolic biomarkers, none of the mixtures tested apparently induced metabolic effects with similar pattern as recorded with DEHP individually administered [ 11 ] in both sexes, or at the highest dose of BPA, predominantly in males [ 10 ].…”