{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:33:18Z","timestamp":1789565598528,"version":"build-2803163510"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Excessive alcohol intake is an important cause of major public health problem in East Asian countries. Growing evidence suggests that genetic factors are associated with alcohol consumption and the risk for alcohol-associated disease, and these factors contribute to the risk of developing chronic diseases, including diabetes. This study aims to investigate the association of type 2 diabetes with genetic polymorphisms within <jats:italic>HECTD4<\/jats:italic> based on alcohol exposure. We performed a genome-wide association study involving the cohorts of the KoGES-HEXA study (<jats:italic>n<\/jats:italic>\u2009=\u200950,028) and Ansan and Ansung study (<jats:italic>n<\/jats:italic>\u2009=\u20097,980), both of which are prospective cohort studies in Korea. The top three single-nucleotide polymorphisms (SNPs) of the <jats:italic>HECTD4<\/jats:italic> gene, specifically rs77768175, rs2074356 and rs11066280, were found to be significantly associated with alcohol consumption. We found that individuals carrying the variant allele in these SNPs had lower fasting blood glucose, triglyceride, and GGT levels than those with the wild-type allele. Multiple logistic regression showed that statistically significant associations of <jats:italic>HECTD4<\/jats:italic> gene polymorphisms with an increased risk of type 2 diabetes were found in drinkers. Namely, these SNPs were associated with decreased odds of diabetes in the presence of alcohol consumption. As a result of examining the effect of alcohol on the expression of the <jats:italic>HECTD4<\/jats:italic> gene, ethanol increased the expression of HECTD4 in cells, but the level was decreased by NAC treatment. Similar results were obtained from liver samples of mice treated with alcohol. Moreover, a loss of HECTD4 resulted in reduced levels of CYP2E1 and lipogenic gene expression in ethanol-treated cells, while the level of ALDH2 expression increased, indicating a reduction in ethanol-induced hepatotoxicity.<\/jats:p>","DOI":"10.1007\/s00204-022-03325-y","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T15:03:40Z","timestamp":1655478220000},"page":"2487-2499","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The potential effects of HECTD4 variants on fasting glucose and triglyceride levels in relation to prevalence of type 2 diabetes based on alcohol intake"],"prefix":"10.1007","volume":"96","author":[{"given":"Yoo Jeong","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hansongyi","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han Byul","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Gyu","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumin","family":"Im","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Kyung","family":"Koo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7120-1809","authenticated-orcid":false,"given":"Hye-Ja","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,6,17]]},"reference":[{"issue":"3","key":"3325_CR1","doi-asserted-by":"publisher","first-page":"444","DOI":"10.15288\/jsad.2011.72.444","volume":"72","author":"A Agrawal","year":"2011","unstructured":"Agrawal A, Lynskey MT, Heath AC, Chassin L (2011) Developing a genetically informative measure of alcohol consumption using past-12-month indices. J Stud Alcohol Drugs 72(3):444\u2013452. https:\/\/doi.org\/10.15288\/jsad.2011.72.444","journal-title":"J Stud Alcohol Drugs"},{"issue":"9","key":"3325_CR2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0238641","volume":"15","author":"I Baik","year":"2020","unstructured":"Baik I, Park SI (2020) Associations of alcohol consumption and physical activity with lean type 2 diabetes mellitus among Korean adults: A prospective cohort study. PLoS ONE 15(9):e0238641. https:\/\/doi.org\/10.1371\/journal.pone.0238641","journal-title":"PLoS ONE"},{"issue":"4","key":"3325_CR3","doi-asserted-by":"publisher","first-page":"809","DOI":"10.3945\/ajcn.110.001776","volume":"93","author":"I Baik","year":"2011","unstructured":"Baik I, Cho NH, Kim SH, Han BG, Shin C (2011) Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. Am J Clin Nutr 93(4):809\u2013816. https:\/\/doi.org\/10.3945\/ajcn.110.001776","journal-title":"Am J Clin Nutr"},{"issue":"1","key":"3325_CR4","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.ccr.2008.06.001","volume":"14","author":"F Bernassola","year":"2008","unstructured":"Bernassola F, Karin M, Ciechanover A, Melino G (2008) The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell 14(1):10\u201321. https:\/\/doi.org\/10.1016\/j.ccr.2008.06.001","journal-title":"Cancer Cell"},{"issue":"9","key":"3325_CR5","doi-asserted-by":"publisher","first-page":"2388","DOI":"10.2337\/db07-0181","volume":"56","author":"JW Beulens","year":"2007","unstructured":"Beulens JW, Rimm EB, Hendriks HF et al (2007) Alcohol consumption and type 2 diabetes: influence of genetic variation in alcohol dehydrogenase. Diabetes 56(9):2388\u20132394. https:\/\/doi.org\/10.2337\/db07-0181","journal-title":"Diabetes"},{"issue":"6","key":"3325_CR6","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1016\/s0168-8278(00)80108-7","volume":"32","author":"A Casini","year":"2000","unstructured":"Casini A (2000) Alcohol-induced fatty liver and inflammation: where do Kupffer cells act? J Hepatol 32(6):1026\u20131030. https:\/\/doi.org\/10.1016\/s0168-8278(00)80108-7","journal-title":"J Hepatol"},{"issue":"12","key":"3325_CR7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0145220","volume":"10","author":"S Cha","year":"2015","unstructured":"Cha S, Park AY, Kang C (2015) A genome-wide association study uncovers a genetic locus associated with thoracic-to-hip ratio in Koreans. PLoS ONE 10(12):e0145220. https:\/\/doi.org\/10.1371\/journal.pone.0145220","journal-title":"PLoS ONE"},{"issue":"5","key":"3325_CR8","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/ng.357","volume":"41","author":"YS Cho","year":"2009","unstructured":"Cho YS, Go MJ, Kim YJ et al (2009) A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 41(5):527\u2013534. https:\/\/doi.org\/10.1038\/ng.357","journal-title":"Nat Genet"},{"issue":"3","key":"3325_CR9","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1046\/j.1365-2362.2002.00970.x","volume":"32","author":"DE Flanagan","year":"2002","unstructured":"Flanagan DE, Pratt E, Murphy J et al (2002) Alcohol consumption alters insulin secretion and cardiac autonomic activity. Eur J Clin Invest 32(3):187\u2013192. https:\/\/doi.org\/10.1046\/j.1365-2362.2002.00970.x","journal-title":"Eur J Clin Invest"},{"issue":"3","key":"3325_CR10","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1111\/j.1360-0443.2006.01694.x","volume":"102","author":"T Fowler","year":"2007","unstructured":"Fowler T, Lifford K, Shelton K et al (2007) Exploring the relationship between genetic and environmental influences on initiation and progression of substance use. Addiction 102(3):413\u2013422. https:\/\/doi.org\/10.1111\/j.1360-0443.2006.01694.x","journal-title":"Addiction"},{"issue":"5","key":"3325_CR11","doi-asserted-by":"publisher","first-page":"375","DOI":"10.4093\/dmj.2014.38.5.375","volume":"38","author":"MJ Go","year":"2014","unstructured":"Go MJ, Hwang JY, Park TJ et al (2014) Genome-wide association study identifies two novel Loci with sex-specific effects for type 2 diabetes mellitus and glycemic traits in a Korean population. Diabetes Metab J 38(5):375\u2013387. https:\/\/doi.org\/10.4093\/dmj.2014.38.5.375","journal-title":"Diabetes Metab J"},{"issue":"3","key":"3325_CR12","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/j.jhep.2014.10.009","volume":"62","author":"R Guo","year":"2015","unstructured":"Guo R, Xu X, Babcock SA, Zhang Y, Ren J (2015) Aldehyde dedydrogenase-2 plays a beneficial role in ameliorating chronic alcohol-induced hepatic steatosis and inflammation through regulation of autophagy. J Hepatol 62(3):647\u2013656. https:\/\/doi.org\/10.1016\/j.jhep.2014.10.009","journal-title":"J Hepatol"},{"key":"3325_CR13","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21186678","author":"LA Hsu","year":"2020","unstructured":"Hsu LA, Tsai FC, Yeh YH et al (2020) Aldehyde dehydrogenase 2 ameliorates chronic alcohol consumption-induced atrial fibrillation through detoxification of 4-HNE. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms21186678","journal-title":"Int J Mol Sci"},{"issue":"2","key":"3325_CR14","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1002\/hep.24708","volume":"55","author":"M Hu","year":"2012","unstructured":"Hu M, Wang F, Li X et al (2012) Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase\/sterol regulatory element-binding protein 1 signaling in mice. Hepatology 55(2):437\u2013446. https:\/\/doi.org\/10.1002\/hep.24708","journal-title":"Hepatology"},{"issue":"4","key":"3325_CR15","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1194\/jlr.R119000547","volume":"61","author":"S Jeon","year":"2020","unstructured":"Jeon S, Carr R (2020) Alcohol effects on hepatic lipid metabolism. J Lipid Res 61(4):470\u2013479. https:\/\/doi.org\/10.1194\/jlr.R119000547","journal-title":"J Lipid Res"},{"issue":"2","key":"3325_CR16","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyv316","volume":"46","author":"Y Kim","year":"2017","unstructured":"Kim Y, Han BG (2017) Cohort profile: The Korean genome and epidemiology study (KoGES) consortium. Int J Epidemiol 46(2):e20. https:\/\/doi.org\/10.1093\/ije\/dyv316","journal-title":"Int J Epidemiol"},{"issue":"10","key":"3325_CR17","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1038\/ng.939","volume":"43","author":"YJ Kim","year":"2011","unstructured":"Kim YJ, Go MJ, Hu C et al (2011) Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits. Nat Genet 43(10):990\u2013995. https:\/\/doi.org\/10.1038\/ng.939","journal-title":"Nat Genet"},{"issue":"39","key":"3325_CR18","doi-asserted-by":"publisher","first-page":"27065","DOI":"10.1074\/jbc.M114.585653","volume":"289","author":"JY Kim","year":"2014","unstructured":"Kim JY, Hwang JY, Lee DY et al (2014) Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo. J Biol Chem 289(39):27065\u201327079. https:\/\/doi.org\/10.1074\/jbc.M114.585653","journal-title":"J Biol Chem"},{"issue":"2","key":"3325_CR19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0149321","volume":"11","author":"J Kim","year":"2016","unstructured":"Kim J, Oh B, Lim JE, Kim MK (2016) No interaction with alcohol consumption, but independent effect of C12orf51 (HECTD4) on Type 2 diabetes mellitus in Korean adults aged 40\u201369 years: The KoGES_Ansan and Ansung study. PLoS ONE 11(2):e0149321. https:\/\/doi.org\/10.1371\/journal.pone.0149321","journal-title":"PLoS ONE"},{"issue":"3","key":"3325_CR20","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1111\/j.1440-1819.2011.02190.x","volume":"65","author":"M Kimura","year":"2011","unstructured":"Kimura M, Higuchi S (2011) Genetics of alcohol dependence. Psychiatry Clin Neurosci 65(3):213\u2013225. https:\/\/doi.org\/10.1111\/j.1440-1819.2011.02190.x","journal-title":"Psychiatry Clin Neurosci"},{"issue":"1","key":"3325_CR21","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1111\/ijcp.12507","volume":"69","author":"SK Kunutsor","year":"2015","unstructured":"Kunutsor SK, Apekey TA, Seddoh D (2015) Gamma glutamyltransferase and metabolic syndrome risk: a systematic review and dose-response meta-analysis. Int J Clin Pract 69(1):136\u2013144. https:\/\/doi.org\/10.1111\/ijcp.12507","journal-title":"Int J Clin Pract"},{"issue":"6","key":"3325_CR22","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1080\/10715760410001694026","volume":"38","author":"DH Lee","year":"2004","unstructured":"Lee DH, Blomhoff R, Jacobs DR Jr (2004) Is serum gamma glutamyltransferase a marker of oxidative stress? Free Radic Res 38(6):535\u2013539. https:\/\/doi.org\/10.1080\/10715760410001694026","journal-title":"Free Radic Res"},{"issue":"1","key":"3325_CR23","doi-asserted-by":"publisher","first-page":"7322","DOI":"10.1038\/s41598-017-07549-2","volume":"7","author":"DY Lee","year":"2017","unstructured":"Lee DY, Yoo MG, Kim HJ et al (2017) Association between alcohol consumption pattern and the incidence risk of type 2 diabetes in Korean men: A 12-years follow-up study. Sci Rep 7(1):7322. https:\/\/doi.org\/10.1038\/s41598-017-07549-2","journal-title":"Sci Rep"},{"issue":"8","key":"3325_CR24","doi-asserted-by":"publisher","first-page":"4184","DOI":"10.1039\/c8fo00650d","volume":"9","author":"S Liu","year":"2018","unstructured":"Liu S, Tian L, Chai G, Wen B, Wang B (2018) Targeting heme oxygenase-1 by quercetin ameliorates alcohol-induced acute liver injury via inhibiting NLRP3 inflammasome activation. Food Funct 9(8):4184\u20134193. https:\/\/doi.org\/10.1039\/c8fo00650d","journal-title":"Food Funct"},{"issue":"5","key":"3325_CR25","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1002\/hep.21372","volume":"44","author":"KH Moon","year":"2006","unstructured":"Moon KH, Hood BL, Kim BJ et al (2006) Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats. Hepatology 44(5):1218\u20131230. https:\/\/doi.org\/10.1002\/hep.21372","journal-title":"Hepatology"},{"issue":"12","key":"3325_CR26","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1111\/acer.13888","volume":"42","author":"S Park","year":"2018","unstructured":"Park S, Liu M, Kang S (2018) Alcohol intake interacts with CDKAL1, HHEX, and OAS3 genetic variants, associated with the Risk of Type 2 diabetes by lowering insulin secretion in Korean adults. Alcohol Clin Exp Res 42(12):2326\u20132336. https:\/\/doi.org\/10.1111\/acer.13888","journal-title":"Alcohol Clin Exp Res"},{"key":"3325_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2019.107843","volume":"157","author":"P Saeedi","year":"2019","unstructured":"Saeedi P, Petersohn I, Salpea P et al (2019) Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract 157:107843. https:\/\/doi.org\/10.1016\/j.diabres.2019.107843","journal-title":"Diabetes Res Clin Pract"},{"issue":"17","key":"3325_CR28","doi-asserted-by":"publisher","first-page":"7119","DOI":"10.1073\/pnas.1017288108","volume":"108","author":"G Schumann","year":"2011","unstructured":"Schumann G, Coin LJ, Lourdusamy A et al (2011) Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci U S A 108(17):7119\u20137124. https:\/\/doi.org\/10.1073\/pnas.1017288108","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"50","key":"3325_CR29","doi-asserted-by":"publisher","first-page":"14372","DOI":"10.1073\/pnas.1611243113","volume":"113","author":"G Schumann","year":"2016","unstructured":"Schumann G, Liu C, O\u2019Reilly P et al (2016) KLB is associated with alcohol drinking, and its gene product \u03b2-Klotho is necessary for FGF21 regulation of alcohol preference. Proc Natl Acad Sci U S A 113(50):14372\u201314377. https:\/\/doi.org\/10.1073\/pnas.1611243113","journal-title":"Proc Natl Acad Sci U S A"},{"key":"3325_CR30","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.diabres.2017.10.021","volume":"135","author":"Y Tatsumi","year":"2018","unstructured":"Tatsumi Y, Morimoto A, Asayama K et al (2018) Association between alcohol consumption and incidence of impaired insulin secretion and insulin resistance in Japanese: The Saku study. Diabetes Res Clin Pract 135:11\u201317. https:\/\/doi.org\/10.1016\/j.diabres.2017.10.021","journal-title":"Diabetes Res Clin Pract"},{"key":"3325_CR31","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aay5034","author":"A Thompson","year":"2020","unstructured":"Thompson A, Cook J, Choquet H et al (2020) Functional validity, role, and implications of heavy alcohol consumption genetic loci. Sci Adv. https:\/\/doi.org\/10.1126\/sciadv.aay5034","journal-title":"Sci Adv"},{"issue":"2","key":"3325_CR32","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1042\/bj1880549","volume":"188","author":"J Vi\u00f1a","year":"1980","unstructured":"Vi\u00f1a J, Estrela JM, Guerri C, Romero FJ (1980) Effect of ethanol on glutathione concentration in isolated hepatocytes. Biochem J 188(2):549\u2013552. https:\/\/doi.org\/10.1042\/bj1880549","journal-title":"Biochem J"},{"key":"3325_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.109916","volume":"125","author":"T Wan","year":"2020","unstructured":"Wan T, Wang H, Gou M et al (2020) LncRNA HEIH promotes cell proliferation, migration and invasion in cholangiocarcinoma by modulating miR-98-5p\/HECTD4. Biomed Pharmacother 125:109916. https:\/\/doi.org\/10.1016\/j.biopha.2020.109916","journal-title":"Biomed Pharmacother"},{"key":"3325_CR34","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.228072","author":"Y Wang","year":"2020","unstructured":"Wang Y, Argiles-Castillo D, Kane EI, Zhou A, Spratt DE (2020) HECT E3 ubiquitin ligases - emerging insights into their biological roles and disease relevance. J Cell Sci. https:\/\/doi.org\/10.1242\/jcs.228072","journal-title":"J Cell Sci"},{"issue":"3","key":"3325_CR35","doi-asserted-by":"publisher","first-page":"545","DOI":"10.3945\/ajcn.112.046482","volume":"97","author":"X Yang","year":"2013","unstructured":"Yang X, Lu X, Wang L et al (2013) Common variants at 12q24 are associated with drinking behavior in Han Chinese. Am J Clin Nutr 97(3):545\u2013551. https:\/\/doi.org\/10.3945\/ajcn.112.046482","journal-title":"Am J Clin Nutr"},{"key":"3325_CR36","doi-asserted-by":"publisher","first-page":"495","DOI":"10.3389\/fphar.2019.00495","volume":"10","author":"L Yang","year":"2019","unstructured":"Yang L, Yang C, Thomes PG et al (2019) Lipophagy and alcohol-induced fatty liver. Front Pharmacol 10:495. https:\/\/doi.org\/10.3389\/fphar.2019.00495","journal-title":"Front Pharmacol"},{"key":"3325_CR37","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/s12986-019-0396-x","volume":"16","author":"H Yu","year":"2019","unstructured":"Yu H, Wang T, Zhang R et al (2019) Alcohol consumption and its interaction with genetic variants are strongly associated with the risk of type 2 diabetes: a prospective cohort study. Nutr Metab (lond) 16:64. https:\/\/doi.org\/10.1186\/s12986-019-0396-x","journal-title":"Nutr Metab (lond)"},{"issue":"6","key":"3325_CR38","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1016\/j.jhep.2014.12.022","volume":"62","author":"W Zhong","year":"2015","unstructured":"Zhong W, Zhang W, Li Q et al (2015) Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice. J Hepatol 62(6):1375\u20131381. https:\/\/doi.org\/10.1016\/j.jhep.2014.12.022","journal-title":"J Hepatol"},{"issue":"6865","key":"3325_CR39","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1038\/414782a","volume":"414","author":"P Zimmet","year":"2001","unstructured":"Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414(6865):782\u2013787. https:\/\/doi.org\/10.1038\/414782a","journal-title":"Nature"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-022-03325-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-022-03325-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-022-03325-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T13:23:15Z","timestamp":1658928195000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-022-03325-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,17]]},"references-count":39,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["3325"],"URL":"https:\/\/doi.org\/10.1007\/s00204-022-03325-y","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,17]]},"assertion":[{"value":"8 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 May 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}