Metronidazole enhances steatosis-related early-stage hepatocarcinogenesis in high fat diet-fed rats through DNA double-strand breaks and modulation of autophagy

• Published in: Environmental science and pollution research international 2022-01, Vol.29 (1), p.779-789
• Main Authors: Eguchi, Ayumi, Mizukami, Sayaka, Nakamura, Misato, Masuda, Sousuke, Murayama, Hirotada, Kawashima, Masashi, Inohana, Mari, Nagahara, Rei, Kobayashi, Mio, Yamashita, Risako, Uomoto, Suzuka, Makino, Emi, Ohtsuka, Ryoichi, Takahashi, Naofumi, Hayashi, Shim-Mo, Maronpot, Robert R., Shibutani, Makoto, Yoshida, Toshinori
• Format: Article
• Language: English
• Subjects: Anaerobic bacteria; Anaerobic treatment; Animals; Antiinfectives and antibacterials; Antimicrobial agents; Aquatic Pollution; Atmospheric Protection/Air Quality Control/Air Pollution; Autophagy; Deoxyribonucleic acid; Diet; Diet, High-Fat - adverse effects; Diethylnitrosamine; DNA; DNA - metabolism; DNA damage; Earth and Environmental Science; Ecotoxicology; Environment; Environmental Chemistry; Environmental Health; Environmental science; Fatty liver; Gene expression; Genes; Hepatectomy; Hepatitis; Hepatocytes; High fat diet; Humans; Intestinal parasites; Lipid Metabolism; Lipids; Liver; Liver - metabolism; Liver diseases; Male; Metabolism; Metronidazole; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - metabolism; Nuclear transport; Parasites; Peroxisome proliferator-activated receptors; Rats; Research Article; Rodents; Steatosis; Translocation; Tumors; Waste Water Technology; Water Management; Water Pollution Control
• ISSN: 0944-1344; 1614-7499
• DOI: 10.1007/s11356-021-15689-2

Nonalcoholic fatty liver disease is a hepatic disorder with deposition of fat droplets and has a high risk of progression to steatosis-related hepatitis and irreversible hepatic cancer. Metronidazole (MNZ) is an antiprotozoal and antimicrobial agent widely used to treat patients infected with anaerobic bacteria and intestinal parasites; however, MNZ has also been shown to induce liver tumors in rodents. To investigate the effects of MNZ on steatosis-related early-stage hepatocarcinogenesis, male rats treated with N-nitrosodiethylamine following 2/3 hepatectomy at week 3 were received a control basal diet, high fat diet (HFD), or HFD containing 0.5% MNZ. The HFD induced obesity and steatosis in the liver, accompanied by altered expression of Pparg and Fasn , genes related to lipid metabolism. MNZ increased nuclear translocation of lipid metabolism-related transcription factor peroxisome proliferator-activated receptor gamma in hepatocytes, together with altered liver expression of lipid metabolism genes ( Srebf1 , Srebf2 , Pnpla2 ). Furthermore, MNZ significantly increased the number of preneoplastic liver foci, accompanied by DNA double-strand breaks and late-stage autophagy inhibition, as reflected by increased levels of γ-H2AX, LC3, and p62. Therefore, MNZ could induce steatosis-related hepatocarcinogenesis by inducing DNA double-strand breaks and modulating autophagy in HFD-fed rats.