{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T10:57:31Z","timestamp":1791975451678,"version":"4.4.0"},"reference-count":109,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Experimental liver injury with hepatocelluar necrosis and abnormal liver tests is caused by exposure to heavy metals (HMs) like aluminum, arsenic, beryllium, cadmium, chromium, cobalt, copper, iron, lead, mercury, molybdenum, nickel, platinum, thallium, titanium, vanadium, and zinc. As pollutants, HMs disturb the ecosystem, and as these substances are toxic, they may affect the health of humans and animals. HMs are not biodegradable and may be deposited preferentially in the liver. The use of animal models can help identify molecular and mechanistic steps leading to the injury. HMs commonly initiate hepatocellular overproduction of ROS (reactive oxygen species) due to oxidative stress, resulting in covalent binding of radicals to macromolecular proteins or lipids existing in membranes of subcellular organelles. Liver injury is facilitated by iron via the Fenton reaction, providing ROS, and is triggered if protective antioxidant systems are exhausted. Ferroptosis syn pyroptosis was recently introduced as mechanistic concept in explanations of nickel (Ni) liver injury. NiCl2 causes increased iron deposition in the liver, upregulation of cyclooxygenase 2 (COX-2) protein and mRNA expression levels, downregulation of glutathione eroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), nuclear receptor coactivator 4 (NCOA4) protein, and mRNA expression levels. Nickel may cause hepatic injury through mitochondrial damage and ferroptosis, defined as mechanism of iron-dependent cell death, similar to glutamate-induced excitotoxicity but likely distinct from apoptosis, necrosis, and autophagy. Under discussion were additional mechanistic concepts of hepatocellular uptake and biliary excretion of mercury in exposed animals. For instance, the organic anion transporter 3 (Oat3) and the multidrug resistance-associated protein 2 (Mrp2) were involved in the hepatic handling of mercury. Mercury treatment modified the expression of Mrp2 and Oat3 as assessed by immunoblotting, partially explaining its impaired biliary excretion. Concomitantly, a decrease in Oat3 abundance in the hepatocyte plasma membranes was observed that limits the hepatic uptake of mercury ions. Most importantly and shown for the first time in liver injury caused by HMs, titanium changed the diversity of gut microbiota and modified their metabolic functions, leading to increased generation of lipopolysaccharides (LPS). As endotoxins, LPS may trigger and perpetuate the liver injury at the level of gut-liver. In sum, mechanistic and molecular steps of experimental liver injury due to HM administration are complex, with ROS as the key promotional compound. However, additional concepts such as iron used in the Fenton reaction, ferroptosis, modification of transporter systems, and endotoxins derived from diversity of intestinal bacteria at the gut-liver level merit further consideration.<\/jats:p>","DOI":"10.3390\/ijms232012213","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T22:21:11Z","timestamp":1665699671000},"page":"12213","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":174,"title":["Aluminum, Arsenic, Beryllium, Cadmium, Chromium, Cobalt, Copper, Iron, Lead, Mercury, Molybdenum, Nickel, Platinum, Thallium, Titanium, Vanadium, and Zinc: Molecular Aspects in Experimental Liver Injury"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8910-1200","authenticated-orcid":false,"given":"Rolf","family":"Teschke","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, 63450 Hanau, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.jinorgbio.2019.03.013","article-title":"The essential metals for humans: A brief overview","volume":"195","author":"Zoroddu","year":"2019","journal-title":"J. Inorg. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"60","DOI":"10.2478\/intox-2014-0009","article-title":"Toxicity, mechanism and health effects of some heavy metals","volume":"7","author":"Jaishankar","year":"2014","journal-title":"Interdiscip. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Karcioglu, O., and Arslan, B. (2019). Mechanism and health effects of heavy metal toxicity in humans. Poisoning in the Modern World\u2014New Tricks for an Old Dog?, IntechOpen.","DOI":"10.5772\/intechopen.73906"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.29121\/granthaalayah.v3.i9SE.2015.3282","article-title":"Effects of heavy metals on human health","volume":"530","author":"Mahurpawar","year":"2015","journal-title":"Int. J. Res. Granthaalayah."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rahman, M.M., Hossain, M.K.F.B., Afrin, S., Saito, T., and Kurasaki, M. (2022). Effects of metals on human health and ecosystem. The Handbook of Environmental Chemistry 2022, Springer.","DOI":"10.1007\/698_2021_825"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e04691","DOI":"10.1016\/j.heliyon.2020.e04691","article-title":"Heavy metal pollution in the environment and their toxicological effects on humans","volume":"6","author":"Briffa","year":"2020","journal-title":"Heliyon"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"21","DOI":"10.21037\/tgh-2020-02","article-title":"Recent advances in Wilson disease","volume":"6","author":"Moini","year":"2021","journal-title":"Trans. Gastroenterol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"122","DOI":"10.33590\/emj\/10310080","article-title":"Pathogenesis, diagnostics, and treatment of hereditary hemochromatosis: A 150-year-long understanding of an iron overload disorder","volume":"2","author":"Asimakopoulou","year":"2017","journal-title":"Eur. Med. J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Teschke, R., and Xuan, T.D. (2022). Heavy metals, halogenated hydrocarbons, phthalates, glyphosate, cordycepin, alcohol, drugs, and herbs, assessed for liver injury and mechanistic steps. Special Issue: Hepatotoxicity: Molecular Mechanisms and Pathophysiology (Guest editor Rolf Teschke). Front. Biosci. Landmark, in press.","DOI":"10.31083\/j.fbl2711314"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"730","DOI":"10.21037\/atm-2020-ubih-05","article-title":"Mechanism of idiosyncratic drug induced liver injury (DILI): Unresolved basic issues","volume":"9","author":"Teschke","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"730","DOI":"10.3389\/fphar.2019.00730","article-title":"Idiosyncratic DILI: Analysis of 46,266 cases assessed for causality by RUCAM and published from 2014 to early 2019. In: Special issue: Clinical drug induced liver injury: Current diagnostic and mechanistic challenges, guest editors: Rolf Teschke, Gaby Danan, James H. Lewis","volume":"10","author":"Teschke","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"129735","DOI":"10.1016\/j.chemosphere.2021.129735","article-title":"Molecular mechanism of heavy metals (Lead, Chromium, Arsenic, Mercury, Nickel and Cadmium)\u2014induced hepatotoxicity\u2014A review","volume":"271","author":"Renu","year":"2021","journal-title":"Chemosphere"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1480553","DOI":"10.1155\/2022\/1480553","article-title":"Aluminum poisoning with emphasis on its mechanism and treatment of intoxication","volume":"2022","author":"Rahimzadeh","year":"2022","journal-title":"Emerg. Med. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.2478\/intox-2019-0007","article-title":"Aluminium toxicosis: A review of toxic actions and effects","volume":"12","author":"Igbokwe","year":"2019","journal-title":"Interdiscip. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.jhep.2011.01.006","article-title":"Reactive oxygen species in the normal and acutely injured liver","volume":"55","author":"Jaeschke","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8082","DOI":"10.3748\/wjg.v20.i25.8082","article-title":"Oxidative stress as a crucial factor in liver diseases","volume":"20","author":"Michalak","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1081\/CLT-100100949","article-title":"Hepatic damage caused by chronic arsenic toxicity in experimental animals","volume":"38","author":"Santra","year":"2000","journal-title":"J. Toxicol. Clin. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.etap.2018.05.012","article-title":"The PKC\u03b4-Nrf2-ARE signalling pathway may be involved in oxidative stress in arsenic-induced liver damage in rats","volume":"62","author":"Hu","year":"2018","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"643972","DOI":"10.3389\/fphar.2021.643972","article-title":"Toxic mechanisms of five heavy metals: Mercury, Lead, Chromium, Cadmium, and Arsenic","volume":"12","author":"Naseri","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, C., Li, P., Tan, Y.M., Lam, S.H., Chan, E.C.Y., and Gong, Z. (2016). Metabolomic characterization of liver injury caused by acute arsenic toxicity in Zebrafish. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151225"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/1476-069X-10-64","article-title":"Dose-response relationship between arsenic exposure and the serum enzymes for liver function tests in the individuals exposed to arsenic: A cross sectional study in Bangladesh","volume":"10","author":"Islam","year":"2011","journal-title":"Environ. Health"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/clinchem\/45.2.301","article-title":"Arsenic speciation in human organs following fatal arsenic trioxide poisoning\u2014A case report","volume":"45","author":"Benramdane","year":"1999","journal-title":"Clin. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"613","DOI":"10.3109\/01480549908993171","article-title":"In vitro methylation of arsenite by rabbit liver cytosol: Effect of metal ions, metal chelating agents, methyltransferase inhibitors and uremic toxins","volume":"22","author":"Cornelis","year":"1999","journal-title":"Drug Chem. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4290","DOI":"10.4049\/jimmunol.165.8.4290","article-title":"Arsenite induces apoptosis of murine T lymphocytes through membrane raft-linked signaling for activation of c-Jun amino-terminal kinase","volume":"165","author":"Hossain","year":"2000","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1089\/15230860260196236","article-title":"Redox-linked cell surface-oriented signaling for T-cell death","volume":"4","author":"Akhand","year":"2002","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mrfmmm.2003.07.009","article-title":"Mechanism of arsenic carcinogenesis: An integrated approach","volume":"533","author":"Rossman","year":"2003","journal-title":"Mutat. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.taap.2007.08.020","article-title":"Subhepatotoxic exposure to arsenic enhances lipopolysaccharide-induced liver injury in mice","volume":"226","author":"Arteel","year":"2008","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1289\/ehp.1103441","article-title":"Arsenic toxicology: Translating between experimental models and human pathology","volume":"119","author":"States","year":"2011","journal-title":"Environ. Health Perspect."},{"key":"ref_29","first-page":"955","article-title":"Reversal of effects of intra peritoneally administered beryllium nitrate by tiron and CaNa3DTPA alone or in combination with alpha-tocopherol","volume":"47","author":"Nirala","year":"2009","journal-title":"Indian J. Exp. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s00204-019-02432-7","article-title":"New insight in beryllium toxicity excluding exposure to beryllium-containing dust: Accumulation patterns, target organs, and elimination","volume":"93","author":"Drobyshev","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_31","first-page":"75","article-title":"Recent advances in understanding the biomolecular basis of chronic beryllium disease: A review","volume":"24","author":"McCleskey","year":"2009","journal-title":"Rev. Environ. Health"},{"key":"ref_32","first-page":"383","article-title":"Selective injury to rat liver Kupffer cells caused by beryllium phosphate: An explanation of reticuloendothelial blockade","volume":"62","author":"Dinsdale","year":"1981","journal-title":"Br. J. Exp. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10534-010-9376-3","article-title":"Chronic beryllium disease: An updated model interactiobetween innate and acquired immunity","volume":"24","author":"Sawyer","year":"2011","journal-title":"Biometals"},{"key":"ref_34","first-page":"849","article-title":"Pathologic liver changes in beryllium poisoning","volume":"95","author":"Lian","year":"1982","journal-title":"Chin. Med. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1006\/abbi.1997.0197","article-title":"Enzyme activity alteration by cadmium administration to rats: The possibility of iron involvement in lipid peroxidation","volume":"346","author":"Casalino","year":"1997","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.tox.2004.03.004","article-title":"Rat liver glutathione S-transferase activity stimulation following acute cadmium or manganese intoxication","volume":"200","author":"Casalino","year":"2004","journal-title":"Toxicology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9564297","DOI":"10.1155\/2021\/9564297","article-title":"Role of autophagy in cadmium-induced hepatotoxicity and liver diseases","volume":"2021","author":"Niture","year":"2021","journal-title":"J. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/(SICI)1099-0461(2000)14:2<110::AID-JBT7>3.0.CO;2-J","article-title":"Mechanisms of cadmium-mediated acute hepatotoxicity","volume":"14","author":"Rikans","year":"2000","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s12011-019-1641-x","article-title":"Glutathione might attenuate cadmium-induced liver oxidative stress and hepatic stellate cell activation","volume":"191","author":"Ren","year":"2019","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1191\/0960327102ht243oa","article-title":"Comparative histological studies on liver of mice exposed to Cr(VI) and Cr(V) compounds","volume":"21","author":"Santos","year":"2002","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1021\/tx200251t","article-title":"Chromium in drinking water: Sources, metabolism, and cancer risk","volume":"24","author":"Zhitkovich","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/jes.2016.85","article-title":"Biomarkers of oxidative stress in electroplating workers exposed to hexavalent chromium","volume":"28","author":"Pan","year":"2018","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jare.2021.04.002","article-title":"The link between deacetylation and hepatotoxicity induced by exposure to hexavalent chromium","volume":"35","author":"Yang","year":"2022","journal-title":"J. Adv. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1177\/0748233713498446","article-title":"The protective effect of propylthiouracil against hepatotoxicity induced by chromium in adult mice","volume":"32","author":"Troudi","year":"2016","journal-title":"Toxicol. Ind. Health"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1002\/tox.23483","article-title":"Hexavalent chromium induces hepatocyte apoptosis via regulation of apoptosis signal-regulating kinase 1\/c-Jun amino-terminal kinase signaling","volume":"37","author":"Jin","year":"2022","journal-title":"Environ. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.etp.2009.09.003","article-title":"Cobalt chloride induces hepatotoxicity in adult rats and their suckling pups","volume":"63","author":"Garouiel","year":"2011","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e00453","DOI":"10.1016\/j.btre.2020.e00453","article-title":"In vitro effects of cobalt nanoparticles on aspartate aminotransferase and alanine aminotransferase activities of wistar rats","volume":"26","author":"Rasool","year":"2020","journal-title":"Biotechnol. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.biocel.2008.07.012","article-title":"Cobalt induces oxidative stress in isolated liver mitochondria responsible for permeability transition and intrinsic apoptosis in hepatocyte primary cultures","volume":"41","author":"Battaglia","year":"2009","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1002\/tox.22412","article-title":"Cobalt chloride exposure dose-dependently induced hepatotoxicity through enhancement of cyclooxygenase-2 (COX-2)\/B-cell associated protein X (BAX) signaling and genotoxicity in Wistar rats","volume":"32","author":"Awoyemi","year":"2017","journal-title":"Environ. Toxicol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1007\/s00204-014-1355-y","article-title":"Copper: Toxicological relevance and mechanisms","volume":"88","author":"Gaetke","year":"2014","journal-title":"Arch. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Lizaola-Mayo, B.C., Dickson, R.C., Lam-Himlin, D.M., and Chascsa, D.M. (2021). Exogenous copper exposure causing clinical Wilson disease in a patient with copper deficiency. BMC Gastroenterol., 21.","DOI":"10.1186\/s12876-021-01859-6"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1084\/jem.110.5.801","article-title":"The deposition of exogenous copper under experimental conditions with observations on its neurotoxic and nephrotoxic properties in relation to Wilson\u2019s disease","volume":"110","author":"Vogel","year":"1959","journal-title":"J. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Barber, R.G., Grenier, Z.A., and Burkhead, J.L. (2021). Copper toxicity is not just oxidative damage: Zinc systems and insight from Wilson disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9030316"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1476-5926-2-5","article-title":"Animal models of copper-associated liver disease","volume":"2","author":"Fuentealba","year":"2003","journal-title":"Comp. Hepatol."},{"key":"ref_55","first-page":"1263","article-title":"Cirrhosis of the liver induced by cupric nitrilotriacetate in Wistar rats. An experimental model of copper toxicosis","volume":"134","author":"Toyokuni","year":"1989","journal-title":"Am. J. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3389\/fphar.2014.00033","article-title":"Zebrafish in the sea of mineral (iron, zinc, and copper) metabolism","volume":"5","author":"Zhao","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12302-019-0214-0","article-title":"Liver toxicity assessments in rats following sub-chronic oral exposure to copper nanoparticles","volume":"31","author":"Tang","year":"2019","journal-title":"Environ. Sci. Eur."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"G117","DOI":"10.1152\/ajpgi.00246.2015","article-title":"Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice","volume":"310","author":"Handa","year":"2016","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"mfab057","DOI":"10.1093\/mtomcs\/mfab057","article-title":"Lipidomics reveals perturbations in the liver lipid profile of iron-overloaded mice","volume":"13","author":"Ding","year":"2021","journal-title":"Metallomics"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"G1490","DOI":"10.1152\/ajpgi.00455.2006","article-title":"Proteomic analysis of hepatic iron overload in mice suggests dysregulation of urea cycle, impairment of fatty acid oxidation, and changes in the methylation cycle","volume":"292","author":"Petrak","year":"2007","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s12185-008-0120-5","article-title":"Body iron metabolism and pathophysiology of iron overload","volume":"88","author":"Kohgo","year":"2008","journal-title":"Int. J. Hematol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Bloomer, S.A., and Brown, K.E. (2019). Iron-induced liver injury: A critical reappraisal. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092132"},{"key":"ref_63","first-page":"518","article-title":"Lead hepatotoxicity & potential health effects","volume":"126","author":"Mudipalli","year":"2007","journal-title":"Indian J. Med. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.foodchem.2007.07.076","article-title":"Role of transition metals, Fe(II), Cr(II), Pb(II), and Cd(II) in lipid peroxidation","volume":"107","author":"Benedet","year":"2008","journal-title":"Food Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.toxrep.2022.02.009","article-title":"Effect of occupational exposure to lead on serum levels of lipid profile and liver enzymes: An occupational cohort study","volume":"9","author":"Firoozichahak","year":"2022","journal-title":"Toxicol. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Quan, N.V., Xuan, T.D., and Teschke, R. (2020). Potential hepatotoxicins found in herbal medicinal products: A systematic review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145011"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4621","DOI":"10.3402\/ljm.v5i0.4621","article-title":"Amelioration of lead-induced hepatotoxicity by Allium sativum extracts in Swiss albino mice","volume":"5","author":"Sharma","year":"2010","journal-title":"Libyan J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"660","DOI":"10.14202\/vetworld.2016.660-671","article-title":"The detrimental effects of lead on human and animal health","volume":"9","author":"Assi","year":"2016","journal-title":"Vet. World"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1515\/intox-2015-0009","article-title":"Lead toxicity: A review","volume":"8","author":"Wani","year":"2015","journal-title":"Interdiscip. Toxicol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Kim, D.W., Ock, J., Moon, K.W., and Park, C.H. (2021). Association between Pb, Cd, and Hg exposure and liver injury among Korean adults. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18136783"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1002\/tox.22706","article-title":"Chronic exposure to low doses of Pb induces hepatotoxicity at the physiological, biochemical, and transcriptomic levels of mice","volume":"34","author":"Luo","year":"2019","journal-title":"Environ. Toxicol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s12291-012-0241-8","article-title":"Biochemical effects of lead exposure on battery manufacture workers with reference to blood pressure, calcium metabolism and bone mineral density","volume":"28","author":"Dongre","year":"2013","journal-title":"Indian Clin. Biochem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"595335","DOI":"10.3389\/fphar.2020.595335","article-title":"Heavy metal contaminations in herbal medicines: Determination, comprehensive risk assessments, and solutions","volume":"11","author":"Luo","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/jbt.20067","article-title":"Endogenous antioxidant defence system in rat liver following mercury chloride oral intoxication","volume":"19","author":"Bando","year":"2005","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Macirella, R., and Brunelli, E. (2017). Morphofunctional alterations in zebrafish (Danio rerio) gills after exposure to mercury chloride. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040824"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.chemosphere.2018.03.106","article-title":"Gender differences in mercury-induced hepatotoxicity: Potential mechanisms","volume":"202","author":"Hazelhoff","year":"2018","journal-title":"Chemosphere"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s12011-015-0450-0","article-title":"Mitochondrial oxidative stress-induced hepatocyte apoptosis reflects increased molybdenum intake in caprine","volume":"170","author":"Zhuang","year":"2016","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1093\/advances\/nmx001","article-title":"Molybdenum","volume":"9","author":"Novotny","year":"2018","journal-title":"Adv. Nutr."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1515\/jbcpp-2017-0171","article-title":"Primary concept of nickel toxicity: An overview","volume":"30","author":"Das","year":"2018","journal-title":"J. Basic Clin. Physiol. Pharmacol."},{"key":"ref_80","first-page":"3133","article-title":"Role of oxidative stress in liver toxicity induced by nickel oxide nanoparticles in rats","volume":"17","author":"Yu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"737","DOI":"10.2131\/jts.44.737","article-title":"A comparative study of nickel nanoparticle and ionic nickel toxicities in zebrafish: Histopathological changes and oxidative stress","volume":"44","author":"Yokota","year":"2019","journal-title":"J. Toxicol. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/(SICI)1097-4636(199804)40:1<40::AID-JBM5>3.0.CO;2-R","article-title":"Evaluation of nickel toxicity on liver, spleen, and kidney of mice after administration of high-dose metal ion","volume":"40","author":"Pereira","year":"1998","journal-title":"J. Biomed. Mater. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1177\/07482337211034711","article-title":"Nickel nanoparticles induce hepatotoxicity via oxidative and nitrative stress-mediated apoptosis and inflammation","volume":"37","author":"Iqbal","year":"2021","journal-title":"Toxicol. Ind. Health"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"153068","DOI":"10.1016\/j.tox.2021.153068","article-title":"Mitochondria damage and ferroptosis involved in Ni-induced hepatotoxicity in mice","volume":"466","author":"Wei","year":"2022","journal-title":"Toxicology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Morrison B. Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e202105043","DOI":"10.1083\/jcb.202105043","article-title":"Mitochondrial regulation of ferroptosis","volume":"220","author":"Gan","year":"2021","journal-title":"J. Cell Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"876550","DOI":"10.3389\/fphar.2022.876550","article-title":"Targeting mitochondrial ROS-mediated ferroptosis by quercetin allivates high-fat diet-induced hepatic lipotoxicity","volume":"13","author":"Jiang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Zhang, H., Zhang, E., and Hu, H. (2021). Role of ferroptosis in non-alcoholic fatty liver disease and its implications for therapeutic strategies. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111660"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Mac\u00edas-Rodr\u00edguez, R.U., Inzaugarat, M.E., Ruiz-Marg\u00e1in, A., Nelson, L.J., Trautwein, C., and Cubero, F.J. (2020). Reclassifying hepatic cell death during liver damage: Ferroptosis\u2014A novel form of non-apoptotic cell death?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051651"},{"key":"ref_90","first-page":"1058","article-title":"Ferroptosis in COVID-19-related liver injury: A potential mechanism and therapeutic target","volume":"12","author":"Chen","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Teschke, R., M\u00e9ndez-S\u00e1nchez, N., and Eickhoff, A. (2022). Liver injury in COVID-19 patients with drugs as causatives: A systematic review of 996 DILI cases published 2020\/2021 based on RUCAM as causality assessment method. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094828"},{"key":"ref_92","first-page":"2266","article-title":"The hepatoprotective role of reduced glutathione and its underlying mechanism in oxaliplatin-induced aute liver injury","volume":"15","author":"Lin","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/hpb.12010","article-title":"An experimental study to identify the potential role of pharmacogenomics in determining the occurrence of oxaliplatin-induced liver injury","volume":"15","author":"Robinson","year":"2013","journal-title":"HPB"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1055\/s-2002-23204","article-title":"Toxic injury to hepatic sinusoids: Sinusoidal obstruction syndrome (veno-occlusive disease)","volume":"22","author":"DeLeve","year":"2002","journal-title":"Semin. Liver Dis."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Teschke, R., Vongdala, N., Quan, N.V., Quy, T.N., and Xuan, T.D. (2021). Metabolic toxification of 1,2-unsaturated pyrrolizidine alkaloids causes human hepatic sinusoidal obstruction syndrome: The update. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910419"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/tox.21900","article-title":"Toxicity of thallium on isolated rat liver mitochondria: The role of oxidative stress and MPT pore opening","volume":"30","author":"Eskandari","year":"2015","journal-title":"Environ. Toxicol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"135618","DOI":"10.1016\/j.chemosphere.2022.135618","article-title":"Thallium(I and III) exposure leads to liver damage and disorders of fatty acid metabolism in mice","volume":"307","author":"Li","year":"2022","journal-title":"Chemosphere"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12989-019-0332-2","article-title":"Hepatotoxicity and the role of the gut-liver axis in rats after oral administration of titanium dioxide nanoparticles","volume":"16","author":"Chen","year":"2019","journal-title":"Part. Fibre Toxicol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"112001","DOI":"10.1088\/0957-4484\/27\/11\/112001","article-title":"Murine liver damage caused by exposure to nano-titanium dioxide","volume":"27","author":"Hong","year":"2016","journal-title":"Nanotechnology"},{"key":"ref_100","first-page":"9","article-title":"Alcoholic liver disease and the co-triggering role of MEOS with its CYP 2E1 catalytic cycle and ROS","volume":"2","author":"Teschke","year":"2021","journal-title":"Arch. Gastroenterol. Res."},{"key":"ref_101","first-page":"11","article-title":"Opinion: Intestinal microbiome, endotoxins, cytochrome P450 2E1, and the gut-liver axis in alcoholic liver disease","volume":"5","author":"Teschke","year":"2019","journal-title":"EC Gastroenterol. Dig. Syst."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s12011-011-9185-8","article-title":"Dietary high vanadium causes oxidative damage-induced renal and hepatic toxicity in broilers","volume":"145","author":"Liu","year":"2012","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.mrgentox.2011.12.009","article-title":"Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles","volume":"745","author":"Sharma","year":"2012","journal-title":"Mutat. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0014-4800(03)00097-2","article-title":"Oxidative stress, toxic hepatitis, and antioxidants with particular emphasis on zinc","volume":"75","author":"Stehbens","year":"2003","journal-title":"Exp. Mol. Pathol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1002\/jat.1263","article-title":"Zinc toxicity alters mitochondrial metabolism and leads to decreased ATP production in hepatocytes","volume":"28","author":"Lemire","year":"2008","journal-title":"J. Appl. Toxicol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"8767","DOI":"10.1021\/nn302502u","article-title":"Peptide-functionalized gold nanorods increase liver injury in hepatitis","volume":"6","author":"Ritz","year":"2012","journal-title":"ACS Nano"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1007\/s12011-020-02067-1","article-title":"Liver function of male rats exposed to manganese at different time points","volume":"198","author":"Bartneck","year":"2020","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.etp.2004.05.001","article-title":"Effects of selenium on histopathological and enzymatic changes in experimental liver injury of rats","volume":"56","author":"Ozardali","year":"2004","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s13205-019-1651-6","article-title":"Silver nanoparticles engineered by thermal co-reduction approach induces liver damage in Wistar rats: Acute and sub-chronic toxicity analysis","volume":"9","author":"Dasgupta","year":"2019","journal-title":"3 Biotech"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12213\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:53:21Z","timestamp":1760144001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12213"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,13]]},"references-count":109,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms232012213"],"URL":"https:\/\/doi.org\/10.3390\/ijms232012213","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,13]]}}}