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Effects of early-life bisphenol A exposure combined with post-weaning high-fat diet on glucose and lipid metabolism in mice and their mechanisms
CHEN Fubin, HUANG Haiyan, ZHANG Huihong, LIU Jianjun, ZHU Wei, XIE Yirong, LI Hongya, PI Shurong, ZHONG Jingyi, DING Shuren, ZHANG Ke, WU Fan, ZHANG Bo, HE Yun
Carcinogenesis, Teratogenesis & Mutagenesis
2024, 36 (6):
421-430.
DOI: 10.3969/j.issn.1004-616x.2024.06.001
OBJECTIVE： To investigate the effects of early-life Bisphenol A (BPA) exposure on glucose and lipid metabolism in post-weaning mice fed a high-fat diet. METHODS： Pregnant mice were exposed to BPA through drinking water at a concentration of 0.5 mg/(kg·d) from gestational day 6 until weaning of offspring. Twenty pregnant mice were divided equally into control and BPA groups. The weaned offspring were organized into，four groups：normal diet control，normal diet BPA，high-fat diet control，and high-fat diet BPA，with 10 mice per group，balanced by sex. Mice were sacrificed at postnatal day 21 (PND21) and postnatal day 91 (PND91) for the collection of blood and pancreas samples. Before sacrificing the PND91 mice，they were tested for glucose and insulin tolerance. Non-targeted lipidomics of the pancreas was analyzed using high-resolution liquid chromatography-mass spectrometry. qPCR was employed to measure mRNA expression levels of ceramide synthesis genes in the pancreas. Plasma insulin and pancreatic ceramide synthase activity were assessed using ELISA kits. Malondialdehyde (MDA) and superoxide dismutase (SOD) activities in the pancreas were measured using specific assay kits. RESULTS： At PND21，both male and female offspring in the BPA exposure group exhibited accelerated weight gain compared to the control group. At PND91，male mice in the high-fat diet BPA group showed increased body weight compared to the high-fat diet control group (P<0.05). Results of glucose tolerance and insulin tolerance tests at PND91 indicated that，compared to the high-fat diet control group，both male and female mice in the high-fat diet BPA group had significantly increased areas under the blood glucose curve (P<0.05). Calculating the insulin resistance index in mice，it was found that，male mice in the PND91 high-fat diet BPA group had an elevated insulin resistance index (P<0.05). Non-targeted lipidomics of the pancreas revealed that at PND21，compared to the control group，male and female mice in the BPA group had significantly increased ceramide (Cer) abundance (P<0.05). At PND91，compared to the high-fat diet control group，male mice in the high-fat diet BPA group had significantly increased ceramide abundance (P<0.05). Results from pancreatic qPCR showed that at PND21，compared to the control group，male mice in the BPA group had upregulated mRNA expression of the Cers4 and Cers6 genes，while female mice had upregulated Cers4 gene expression (P<0.05). At PND91，compared to the high-fat diet control group，male mice in the high-fat diet BPA group had upregulated mRNA expression of the Cers2，Cers4，and Cers6 genes (P<0.05). Analysis of ceramide synthase activity in the pancreas indicated that at PND21，compared to the control group，male mice in the BPA group had significantly enhanced Cers2，Cers4，and Cers6 activity (P<0.05). At PND91，compared to the high-fat diet control group，male mice in the high-fat diet BPA group had significantly enhanced Cers2 and Cers4 activity (P<0.05). Assessment of oxidative and antioxidative indicators showed that at PND91，compared to the high-fat diet control group，male mice in the high-fat diet BPA group had significantly increased pancreatic MDA content and significantly decreased SOD activity (P<0.05). Correlation analysis indicated a significantly positive correlation between ceramide abundance and the oxidative/antioxidative ratio in the pancreas of PND91 male mice (P<0.05). CONCLUSION： Early-life BPA exposure combined with post-weaning high-fat diet impaired glucose tolerance in offspring mice. It increased the de novo synthesis of pancreatic ceramide in male offspring mice in a sex-specific manner，which was closely related to the imbalance of oxidative and antioxidative status in the pancreas of male mice.
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