Epigenetic dysregulation of H19/IGF2 in hepatic cells exposed to toxic metal mixtures in vitro
Abstract Exposure to mixtures of toxic metals is known to cause adverse health effects through epigenetic alterations. Here we aimed to examine the unexplored area of aberrant DNA methylation in the H19/IGF2 domain following combined toxic metal exposure. An in vitro epigenotoxicity assay using the...
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Nature Portfolio
2024-11-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-80142-6 |
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| author | Yehoon Jo Eugene Lim Jihye Park Keunsoo Kang Mi-Yeon Shin Jeong Weon Choi Sungkyoon Kim Jaehyouk Lee |
| author_facet | Yehoon Jo Eugene Lim Jihye Park Keunsoo Kang Mi-Yeon Shin Jeong Weon Choi Sungkyoon Kim Jaehyouk Lee |
| author_sort | Yehoon Jo |
| collection | DOAJ |
| description | Abstract Exposure to mixtures of toxic metals is known to cause adverse health effects through epigenetic alterations. Here we aimed to examine the unexplored area of aberrant DNA methylation in the H19/IGF2 domain following combined toxic metal exposure. An in vitro epigenotoxicity assay using the human normal liver epithelial cell line THLE-3 was conducted. When THLE-3 cells were exposed to specific concentrations of either organic arsenic or MeHgCl, an increase in the H19 lncRNA levels and a marked reduction in the IGF2 mRNA levels were observed. In contrast, combined exposures coupled with CdCl2 resulted in the transcriptional repression of H19 and transcriptional activation of IGF2. It should be noted that the correlation between the dysregulated expression of H19/IGF2 and the hypermethylated CpG sites within the H19 differentially methylated region (DMR) was statistically significant. Furthermore, we performed transcriptomic analysis of the hepatocytes exposed to toxic metal combinations indicating enrichment of pro-inflammatory and anti-proliferative pathways compared to the unexposed cells. Our results suggest that hazardous metal mixtures may trigger epigenetic aberrations at the H19/IGF2 locus. We propose that altered CpG methylation in the H19 DMR could be a candidate biomarker for hepatic epigenotoxicity, in part, due to environmental exposure. |
| format | Article |
| id | doaj-art-604889e188ff4f2ab02f54e1bf17b12c |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-604889e188ff4f2ab02f54e1bf17b12c2025-08-20T02:49:17ZengNature PortfolioScientific Reports2045-23222024-11-0114111210.1038/s41598-024-80142-6Epigenetic dysregulation of H19/IGF2 in hepatic cells exposed to toxic metal mixtures in vitroYehoon Jo0Eugene Lim1Jihye Park2Keunsoo Kang3Mi-Yeon Shin4Jeong Weon Choi5Sungkyoon Kim6Jaehyouk Lee7Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National UniversityInstitute of Health and Environment, Graduate School of Public Health, Seoul National UniversityDepartment of Microbiology, College of Science & Technology, Dankook UniversityDepartment of Microbiology, College of Science & Technology, Dankook UniversityDepartment of Environmental Health Sciences, Graduate School of Public Health, Seoul National UniversityDepartment of Environmental Health Sciences, Graduate School of Public Health, Seoul National UniversityDepartment of Environmental Health Sciences, Graduate School of Public Health, Seoul National UniversityInstitute of Health and Environment, Graduate School of Public Health, Seoul National UniversityAbstract Exposure to mixtures of toxic metals is known to cause adverse health effects through epigenetic alterations. Here we aimed to examine the unexplored area of aberrant DNA methylation in the H19/IGF2 domain following combined toxic metal exposure. An in vitro epigenotoxicity assay using the human normal liver epithelial cell line THLE-3 was conducted. When THLE-3 cells were exposed to specific concentrations of either organic arsenic or MeHgCl, an increase in the H19 lncRNA levels and a marked reduction in the IGF2 mRNA levels were observed. In contrast, combined exposures coupled with CdCl2 resulted in the transcriptional repression of H19 and transcriptional activation of IGF2. It should be noted that the correlation between the dysregulated expression of H19/IGF2 and the hypermethylated CpG sites within the H19 differentially methylated region (DMR) was statistically significant. Furthermore, we performed transcriptomic analysis of the hepatocytes exposed to toxic metal combinations indicating enrichment of pro-inflammatory and anti-proliferative pathways compared to the unexposed cells. Our results suggest that hazardous metal mixtures may trigger epigenetic aberrations at the H19/IGF2 locus. We propose that altered CpG methylation in the H19 DMR could be a candidate biomarker for hepatic epigenotoxicity, in part, due to environmental exposure.https://doi.org/10.1038/s41598-024-80142-6Toxic metalsMixture exposureEpigenotoxicityH19/IGF2DNA methylation |
| spellingShingle | Yehoon Jo Eugene Lim Jihye Park Keunsoo Kang Mi-Yeon Shin Jeong Weon Choi Sungkyoon Kim Jaehyouk Lee Epigenetic dysregulation of H19/IGF2 in hepatic cells exposed to toxic metal mixtures in vitro Scientific Reports Toxic metals Mixture exposure Epigenotoxicity H19/IGF2 DNA methylation |
| title | Epigenetic dysregulation of H19/IGF2 in hepatic cells exposed to toxic metal mixtures in vitro |
| title_full | Epigenetic dysregulation of H19/IGF2 in hepatic cells exposed to toxic metal mixtures in vitro |
| title_fullStr | Epigenetic dysregulation of H19/IGF2 in hepatic cells exposed to toxic metal mixtures in vitro |
| title_full_unstemmed | Epigenetic dysregulation of H19/IGF2 in hepatic cells exposed to toxic metal mixtures in vitro |
| title_short | Epigenetic dysregulation of H19/IGF2 in hepatic cells exposed to toxic metal mixtures in vitro |
| title_sort | epigenetic dysregulation of h19 igf2 in hepatic cells exposed to toxic metal mixtures in vitro |
| topic | Toxic metals Mixture exposure Epigenotoxicity H19/IGF2 DNA methylation |
| url | https://doi.org/10.1038/s41598-024-80142-6 |
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