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Effects of maternal cigarette smoke exposure on the progression of nonalcoholic steatohepatitis in offspring mice

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Abstract

Cigarette smoke (CS) is a dominant carcinogenic agent in a variety of human cancers. CS exposure during pregnancy can adversely affect the fetus. Non-alcoholic fatty liver disease (NAFLD) is considered as a hepatic manifestation of a metabolic disorder, and ranges from simple steatosis to cirrhosis leading to hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is a more severe phase of NAFLD. Recently, there is increasing apprehension about the CS-related chronic liver diseases. Therefore, we examined whether maternal CS exposure could affect the pathogenesis of NASH in offspring. Mainstream CS (MSCS) was exposed to pregnant C57BL/6 mice via nose-only inhalation for 2 h/day, 5 days/week for 2 weeks from day 6 to 17 of gestation at 0, 300, or 600 μg/L. Three-week-old male offspring mice were fed methionine and choline-supplemented (MCS) diet or methionine and choline-deficient including high-fat (MCDHF) diet for 6 weeks to induce NASH. Maternal MSCS exposure increased the severity of NASH by increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic total cholesterol (TC) and triglyceride (TG) levels, pro-inflammation, fibrosis, and steatosis in offspring mice. Especially, maternal MSCS exposure significantly downregulated the phosphorylation of AMP-activated protein kinase (AMPK) in MCDHF diet-fed offspring mice. Subsequently, the protein levels of sterol regulatory element-binding protein (SREBP)-1c and stearoyl-CoA desaturase-1 (SCD1) were upregulated by maternal MSCS exposure. In conclusion, maternal MSCS exposure exacerbates the progression of NASH by modulating lipogenesis on offspring mice.

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Acknowledgements

This study was supported by grants (No. 21203MFDS318) from the Ministry of Food and Drug Safety, Republic of Korea and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) (HI20C0209) (J-W.K.) funded by the Ministry of Health & Welfare, Republic of Korea.

Funding

This study was supported by grants (No. 21203MFDS318) from the Ministry of Food and Drug Safety, Republic of Korea and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) (HI20C0209) (J-W.K.) funded by the Ministry of Health & Welfare, Republic of Korea.

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  1. Daram Yang and Jong Won Kim contributed equally to this work.

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  1. Biosafety Research Institute and Laboratory of Veterinary Pathology, College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-Ro, Iksan-Si, Jeollabuk-Do, 54596, Republic of Korea

    Daram Yang, Jong Won Kim, Hyuneui Jeong, Chae Woong Lim & Bumseok Kim

  2. Inhalation Toxicology Center, Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, 30, Baekak 1-Gil, Jeongeup, 56212, Republic of Korea

    Min Seok Kim & Kyuhong Lee

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Contributions

Conceptualization and investigation were performed by DY and JWK. DY and JWK contributed equally to this work. Data analysis was performed by DY and HJ. Material preparation was performed by MSK and KL. The first draft of the manuscript was written by DY and was edited by CWL and BK. Funding acquisition was managed by JWK and BK. All authors read and approved the final manuscript.

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Correspondence to Bumseok Kim.

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All animal experiments were carried out in accordance with the guidelines of the Animal Care and Ethics Committees of Korea Institute of Toxicology (KIT; Dae-Jeon, Republic of Korea). The animal facility at the KIT is fully authorized by the National Association of Laboratory Animal Care.

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Yang, D., Kim, J.W., Jeong, H. et al. Effects of maternal cigarette smoke exposure on the progression of nonalcoholic steatohepatitis in offspring mice. Toxicol Res. 39, 91–103 (2023). https://doi.org/10.1007/s43188-022-00153-1

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