Copper-induced diurnal hepatic toxicity is associated with Cry2 and Per1 in mice
Background: This study aimed to investigate diurnal variations in copper-induced hepatic toxicity and the molecular mechanisms underlying this chronotoxicity. Methods: Male C57BL/6J mice were intraperitoneally injected with copper chloride (CuCl2) at zeitgeber time 2 (ZT2) or 14 (ZT14), twice per we...
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| Format: | Article |
| Language: | English |
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Komiyama Printing Co. Ltd
2023-12-01
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| Series: | Environmental Health and Preventive Medicine |
| Subjects: | |
| Online Access: | https://www.jstage.jst.go.jp/article/ehpm/28/0/28_23-00205/_html/-char/en |
| _version_ | 1797374982045564928 |
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| author | Sarah Tominaga Hiroki Yoshioka Satoshi Yokota Yosuke Tsukiboshi Masumi Suzui Makoto Nagai Hirokazu Hara Tohru Maeda Nobuhiko Miura |
| author_facet | Sarah Tominaga Hiroki Yoshioka Satoshi Yokota Yosuke Tsukiboshi Masumi Suzui Makoto Nagai Hirokazu Hara Tohru Maeda Nobuhiko Miura |
| author_sort | Sarah Tominaga |
| collection | DOAJ |
| description | Background: This study aimed to investigate diurnal variations in copper-induced hepatic toxicity and the molecular mechanisms underlying this chronotoxicity. Methods: Male C57BL/6J mice were intraperitoneally injected with copper chloride (CuCl2) at zeitgeber time 2 (ZT2) or 14 (ZT14), twice per week for 5 or 8 weeks. Seventy-two hours after the final CuCl2 injection, the mice were euthanized, and plasma samples were collected. The livers and kidneys were collected and weighed. In vitro experiments were performed to assess cell viability and fluctuations in clock gene expression levels in Hepa1-6 cells after CuCl2 treatment. We examined copper homeostasis- and apoptosis-related genes under clock genes overexpression. Results: Repeated CuCl2 administration for 8 weeks resulted in more severe toxicity at ZT14 compared to ZT2. CuCl2 administration at ZT14 elevated plasma aspartate aminotransferase, hepatic tumor necrosis factor-α, and interleukin-6 for 5 weeks, whereas the toxic effects of CuCl2 administration at ZT2 were weaker. Moreover, CuCl2 treatment inhibited Hepa1-6 cell viability in a dose-dependent manner. We observed increased expression of three clock genes (Ciart, Cry2, and Per1) after CuCl2 treatment. Among them, overexpression of Cry2 and Per1 accelerated CuCl2-induced inhibition of Hepa1-6 cell viability. Moreover, we found that the overexpression of Cry2 and Per1 regulates cleaved caspase-3 by modulating the copper transporter genes ATP7B and CTR1. Conclusion: These results suggest that CuCl2-induced diurnal toxicity is associated with Cry2 and Per1 expression through the regulation of copper transporter genes in mice. |
| first_indexed | 2024-03-08T19:13:39Z |
| format | Article |
| id | doaj.art-81fc2733836b4a2ab71abf9d4b515b48 |
| institution | Directory Open Access Journal |
| issn | 1342-078X 1347-4715 |
| language | English |
| last_indexed | 2024-03-08T19:13:39Z |
| publishDate | 2023-12-01 |
| publisher | Komiyama Printing Co. Ltd |
| record_format | Article |
| series | Environmental Health and Preventive Medicine |
| spelling | doaj.art-81fc2733836b4a2ab71abf9d4b515b482023-12-27T08:10:03ZengKomiyama Printing Co. LtdEnvironmental Health and Preventive Medicine1342-078X1347-47152023-12-0128787810.1265/ehpm.23-00205ehpmCopper-induced diurnal hepatic toxicity is associated with Cry2 and Per1 in miceSarah Tominaga0Hiroki Yoshioka1https://orcid.org/0000-0002-0977-434XSatoshi Yokota2Yosuke Tsukiboshi3Masumi Suzui4Makoto Nagai5Hirokazu Hara6Tohru Maeda7Nobuhiko Miura8College of Pharmacy, Kinjo Gakuin UniversityFaculty of Pharmacy, Gifu University of Medical ScienceDivision of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health SciencesFaculty of Pharmacy, Gifu University of Medical ScienceDepartment of Neurotoxicology, Nagoya City University Graduate School of Medical SciencesGraduate School of Health and Medicine, Gifu University of Medical ScienceLaboratory of Clinical Pharmaceutics, Gifu Pharmaceutical UniversityCollege of Pharmacy, Kinjo Gakuin UniversityDepartment of Health Science, Yokohama University of PharmacyBackground: This study aimed to investigate diurnal variations in copper-induced hepatic toxicity and the molecular mechanisms underlying this chronotoxicity. Methods: Male C57BL/6J mice were intraperitoneally injected with copper chloride (CuCl2) at zeitgeber time 2 (ZT2) or 14 (ZT14), twice per week for 5 or 8 weeks. Seventy-two hours after the final CuCl2 injection, the mice were euthanized, and plasma samples were collected. The livers and kidneys were collected and weighed. In vitro experiments were performed to assess cell viability and fluctuations in clock gene expression levels in Hepa1-6 cells after CuCl2 treatment. We examined copper homeostasis- and apoptosis-related genes under clock genes overexpression. Results: Repeated CuCl2 administration for 8 weeks resulted in more severe toxicity at ZT14 compared to ZT2. CuCl2 administration at ZT14 elevated plasma aspartate aminotransferase, hepatic tumor necrosis factor-α, and interleukin-6 for 5 weeks, whereas the toxic effects of CuCl2 administration at ZT2 were weaker. Moreover, CuCl2 treatment inhibited Hepa1-6 cell viability in a dose-dependent manner. We observed increased expression of three clock genes (Ciart, Cry2, and Per1) after CuCl2 treatment. Among them, overexpression of Cry2 and Per1 accelerated CuCl2-induced inhibition of Hepa1-6 cell viability. Moreover, we found that the overexpression of Cry2 and Per1 regulates cleaved caspase-3 by modulating the copper transporter genes ATP7B and CTR1. Conclusion: These results suggest that CuCl2-induced diurnal toxicity is associated with Cry2 and Per1 expression through the regulation of copper transporter genes in mice.https://www.jstage.jst.go.jp/article/ehpm/28/0/28_23-00205/_html/-char/encopperchronotoxicityhepatotoxicity |
| spellingShingle | Sarah Tominaga Hiroki Yoshioka Satoshi Yokota Yosuke Tsukiboshi Masumi Suzui Makoto Nagai Hirokazu Hara Tohru Maeda Nobuhiko Miura Copper-induced diurnal hepatic toxicity is associated with Cry2 and Per1 in mice Environmental Health and Preventive Medicine copper chronotoxicity hepatotoxicity |
| title | Copper-induced diurnal hepatic toxicity is associated with Cry2 and Per1 in mice |
| title_full | Copper-induced diurnal hepatic toxicity is associated with Cry2 and Per1 in mice |
| title_fullStr | Copper-induced diurnal hepatic toxicity is associated with Cry2 and Per1 in mice |
| title_full_unstemmed | Copper-induced diurnal hepatic toxicity is associated with Cry2 and Per1 in mice |
| title_short | Copper-induced diurnal hepatic toxicity is associated with Cry2 and Per1 in mice |
| title_sort | copper induced diurnal hepatic toxicity is associated with cry2 and per1 in mice |
| topic | copper chronotoxicity hepatotoxicity |
| url | https://www.jstage.jst.go.jp/article/ehpm/28/0/28_23-00205/_html/-char/en |
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