{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T13:06:47Z","timestamp":1793106407515,"version":"4.5.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T00:00:00Z","timestamp":1730764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Objective: Cadmium (Cd) and lead (Pb) are non-biodegradable heavy metals (HMs) that persistently contaminate ecosystems and accumulate in bones, where they exert harmful effects. This study aimed to investigate the protective effect of fucoxanthin (FX) against the chemical toxicity induced by Cd and Pb in human bone osteoblasts in vitro, using various biochemical and molecular assays. Methods: The effect of metals and FX on osteoblasts viability was assayed by MTT, then the effect of Pb, Cd, and FX on the cells\u2019 mitochondrial parameters was studied via assays for ATP, mitochondrial membrane potential (MMP), mitochondrial complexes, and lactate production. Also, the effect of metals on oxidative stress was assessed by reactive oxygen species, lipid peroxidation and antioxidant enzymes assays. Also the effect of FX and metals on apoptosis caspases and related genes was assessed. Results: When Cd and Pb were added to human osteoblast cultures at concentrations ranging from 1\u201320\u00a0\u03bcM for 72\u00a0h, they significantly reduced osteoblast viability in a time and concentration-dependent manner. The cytotoxic effect of Cd on osteoblasts was greater than that of Pb, with estimated EC50 of 8 and 12\u00a0\u03bcM, respectively, after 72\u00a0h of exposure. FX (10 and 20\u00a0\u03bcM) alleviated the cytotoxicity of the metals. Bioenergetics assays, including ATP, MMP, and mitochondrial complexes I and III activities, revealed that HMs at 1 and 10\u00a0\u03bcM concentrations inhibited cellular bioenergetics after 72\u00a0h of exposure. Cd and Pb also increased lipid peroxidation and reactive oxygen species while reducing catalase and superoxide dismutase antioxidant activities and oxidative stress-related genes. This was accompanied by increased caspases \u22123, \u22128, and\u00a0\u2212\u00a09 and Bax\/bCl-2 ratio. Co-treatment with FX (10 and 20\u00a0\u03bcM) mitigated the disruption of bioenergetics, oxidative damage, and apoptosis induced by the metals, showing a concentration-dependent pattern to varying extents. Conclusion: These findings strongly support the role of FX in managing toxicities induced by environmental pollutants in bones and in addressing bone diseases associated with molecular bases of oxidative stress, apoptosis, and bioenergetic disruption.<\/jats:p>","DOI":"10.1093\/toxres\/tfae218","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T07:44:19Z","timestamp":1734594259000},"source":"Crossref","is-referenced-by-count":3,"title":["Fucoxanthin alleviates the cytotoxic effects of cadmium and lead on a human osteoblast cell line"],"prefix":"10.1093","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7444-2499","authenticated-orcid":false,"given":"Ekramy M","family":"Elmorsy","sequence":"first","affiliation":[{"name":"Pathology Department, Faculty of Medicine, Northern Border University , Arar 91431 ,","place":["Saudi Arabia"]},{"name":"Center for Health Research, Northern Border University , Arar 91431 ,","place":["Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9156-4263","authenticated-orcid":false,"given":"Ayat B","family":"Al-Ghafari","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, King Abdulaziz University , Jeddah 21589 ,","place":["Saudi Arabia"]},{"name":"Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University , Jeddah 21589 ,","place":["Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6192-8326","authenticated-orcid":false,"given":"Huda A","family":"Al Doghaither","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, King Abdulaziz University , Jeddah 21589 ,","place":["Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,12,19]]},"reference":[{"key":"2024121907440270300_ref1","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.matpr.2021.06.278","article-title":"Effect of heavy metals: an overview","volume":"51","author":"Bharti","year":"2022","journal-title":"Mater Today Proc"},{"issue":"21","key":"2024121907440270300_ref2","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.3390\/w14213432","article-title":"A review on cadmium and lead contamination: sources, fate, mechanism, health effects and remediation methods","volume":"14","author":"Bouida","year":"2022","journal-title":"Water"},{"issue":"19","key":"2024121907440270300_ref3","doi-asserted-by":"crossref","first-page":"2000383","DOI":"10.1002\/advs.202000383","article-title":"Adverse impact of heavy metals on bone cells and bone metabolism dependently and independently through anemia","volume":"7","author":"Zhang","year":"2020","journal-title":"Adv Sci (Weinh)"},{"issue":"7","key":"2024121907440270300_ref4","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1289\/ehp.9716","article-title":"The association between blood lead levels and osteoporosis among adults--results from the third national health and nutrition examination survey (NHANES III)","volume":"115","author":"Campbell","year":"2007","journal-title":"Environ Health Perspect"},{"key":"2024121907440270300_ref5","doi-asserted-by":"crossref","first-page":"928752","DOI":"10.3389\/fendo.2022.928752","article-title":"Blood lead level is negatively associated with bone mineral density in U.S. children and adolescents aged 8-19 years","volume":"13","author":"Cui","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"6","key":"2024121907440270300_ref6","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1002\/jbmr.22","article-title":"Occupational cadmium exposure and calcium excretion, bone density, and osteoporosis in men","volume":"25","author":"Nawrot","year":"2010","journal-title":"J Bone Miner Res"},{"issue":"4","key":"2024121907440270300_ref7","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1002\/jbmr.2743","article-title":"Low-level cadmium exposure is associated with decreased bone mineral density and increased risk of incident fractures in elderly men: the MrOS Sweden study","volume":"31","author":"Wallin","year":"2016","journal-title":"J Bone Miner Res"},{"issue":"9","key":"2024121907440270300_ref8","doi-asserted-by":"crossref","first-page":"4254","DOI":"10.1007\/s12011-022-03521-y","article-title":"Race and gender differences in the associations between cadmium exposure and bone mineral density in US adults","volume":"201","author":"Xie","year":"2023","journal-title":"Biol Trace Elem Res"},{"issue":"4","key":"2024121907440270300_ref9","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1080\/09603123.2013.835032","article-title":"Cellular mechanisms of cadmium-induced toxicity: a review","volume":"24","author":"Rani","year":"2014","journal-title":"Int J Environ Health Res"},{"issue":"7\u20138","key":"2024121907440270300_ref10","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1080\/10408363.2017.1408562","article-title":"Clinical and molecular aspects of lead toxicity: an update","volume":"54","author":"Mitra","year":"2017","journal-title":"Crit Rev Clin Lab Sci"},{"issue":"9","key":"2024121907440270300_ref11","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1007\/s00198-020-05429-6","article-title":"Exposure to heavy metals and the risk of osteopenia or osteoporosis: a systematic review and meta-analysis","volume":"31","author":"Jalili","year":"2020","journal-title":"Osteoporos Int"},{"key":"2024121907440270300_ref12","doi-asserted-by":"crossref","first-page":"421746","DOI":"10.1155\/2015\/421746","article-title":"Biology of bone tissue: structure, function, and factors that influence bone cells","volume":"2015","author":"Florencio-Silva","year":"2015","journal-title":"Biomed Res Int"},{"issue":"4","key":"2024121907440270300_ref13","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.3390\/md13042196","article-title":"Anti-obesity activity of the marine carotenoid fucoxanthin","volume":"13","author":"Gammone","year":"2015","journal-title":"Mar Drugs"},{"issue":"6","key":"2024121907440270300_ref14","doi-asserted-by":"crossref","first-page":"897","DOI":"10.3892\/mmr_00000189","article-title":"Anti-obesity and anti-diabetic effects of fucoxanthin on diet-induced obesity conditions in a murine model","volume":"2","author":"Maeda","year":"2009","journal-title":"Mol Med Rep"},{"issue":"8","key":"2024121907440270300_ref15","doi-asserted-by":"crossref","first-page":"4784","DOI":"10.3390\/md13084784","article-title":"Fucoxanthin and its metabolite Fucoxanthinol in cancer prevention and treatment","volume":"13","author":"Martin","year":"2015","journal-title":"Mar Drugs."},{"issue":"8","key":"2024121907440270300_ref16","doi-asserted-by":"crossref","first-page":"239","DOI":"10.3390\/antiox8080239","article-title":"Fucoxanthin-an antibacterial carotenoid","volume":"8","author":"Karpi\u0144ski","year":"2019","journal-title":"Antioxidants (Basel)."},{"issue":"1","key":"2024121907440270300_ref17","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12906-018-2164-2","article-title":"Fucoxanthin, the constituent of Laminaria japonica, triggers AMPK-mediated cytoprotection and autophagy in hepatocytes under oxidative stress","volume":"18","author":"Jang","year":"2018","journal-title":"BMC Complement Altern Med"},{"issue":"6","key":"2024121907440270300_ref18","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3390\/antiox8060183","article-title":"Fucoxanthin, a carotenoid derived from Phaeodactylum tricornutum exerts antiproliferative and antioxidant activities in vitro","volume":"8","author":"Neumann","year":"2019","journal-title":"Antioxidants (Basel)"},{"issue":"4","key":"2024121907440270300_ref19","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.1039\/D0FO00442A","article-title":"Fucoxanthin alleviates palmitate-induced inflammation in RAW 264.7 cells through improving lipid metabolism and attenuating mitochondrial dysfunction","volume":"11","author":"Li","year":"2020","journal-title":"Food Funct"},{"issue":"4","key":"2024121907440270300_ref20","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3390\/md14040070","article-title":"Influences of fucoxanthin on alveolar bone resorption in induced periodontitis in rat molars","volume":"14","author":"Kose","year":"2016","journal-title":"Mar Drugs."},{"issue":"2","key":"2024121907440270300_ref21","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1089\/109662003322233459","article-title":"Lycopene I--effect on osteoclasts: lycopene inhibits basal and parathyroid hormone-stimulated osteoclast formation and mineral resorption mediated by reactive oxygen species in rat bone marrow cultures","volume":"6","author":"Rao","year":"2003","journal-title":"J Med Food"},{"issue":"2","key":"2024121907440270300_ref22","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1248\/bpb.27.232","article-title":"Oral administration of beta-cryptoxanthin induces anabolic effects on bone components in the femoral tissues of rats in vivo","volume":"27","author":"Uchiyama","year":"2004","journal-title":"Biol Pharm Bull"},{"issue":"1","key":"2024121907440270300_ref23","first-page":"15","article-title":"Oral administration of beta-cryptoxanthin prevents bone loss in ovariectomized rats","volume":"17","author":"Uchiyama","year":"2006","journal-title":"Int J Mol Med"},{"issue":"6","key":"2024121907440270300_ref24","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/nprot.2012.058","article-title":"Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells","volume":"7","author":"Spinazzi","year":"2012","journal-title":"Nat Protoc"},{"key":"2024121907440270300_ref25","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.brainres.2014.08.011","article-title":"Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood-brain barrier","volume":"1583","author":"Elmorsy","year":"2014","journal-title":"Brain Res"},{"issue":"2","key":"2024121907440270300_ref26","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.abb.2007.12.008","article-title":"Comparative study of catalase-peroxidases (KatGs)","volume":"471","author":"Singh","year":"2008","journal-title":"Arch Biochem Biophys"},{"issue":"7","key":"2024121907440270300_ref27","doi-asserted-by":"crossref","first-page":"13763","DOI":"10.3390\/ijms140713763","article-title":"Biosynthetic pathway and health benefits of fucoxanthin, an algae-specific xanthophyll in brown seaweeds","volume":"14","author":"Mikami","year":"2013","journal-title":"Int J Mol Sci"},{"key":"2024121907440270300_ref28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.phytol.2015.09.007","article-title":"Bioactive compounds from brown seaweeds: Phloroglucinol, fucoxanthin and fucoidan as promising therapeutic agents against breast cancer","volume":"14","author":"P\u00e1dua","year":"2015","journal-title":"Phytochem Lett"},{"issue":"7","key":"2024121907440270300_ref29","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.injury.2013.02.029","article-title":"Osteoporosis influences osteogenic but not angiogenic response during bone defect healing in a rat model","volume":"44","author":"Liu","year":"2013","journal-title":"Injury"},{"key":"2024121907440270300_ref30","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.abb.2014.07.006","article-title":"Role of angiogenesis in bone repair","volume":"561","author":"Saran","year":"2014","journal-title":"Arch Biochem Biophys"},{"issue":"1","key":"2024121907440270300_ref31","doi-asserted-by":"crossref","first-page":"13601","DOI":"10.1038\/ncomms13601","article-title":"Blood flow controls bone vascular function and osteogenesis","volume":"7","author":"Ramasamy","year":"2016","journal-title":"Nat Commun"},{"issue":"2","key":"2024121907440270300_ref32","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.abb.2008.03.027","article-title":"Osteoclast-osteoblast communication","volume":"473","author":"Matsuo","year":"2008","journal-title":"Arch Biochem Biophys"},{"issue":"8","key":"2024121907440270300_ref33","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1002\/jbm.a.34937","article-title":"A phenotypic comparison of osteoblast cell lines versus human primary osteoblasts for biomaterials testing","volume":"102","author":"Czekanska","year":"2014","journal-title":"J Biomed Mater Res A"},{"issue":"2","key":"2024121907440270300_ref34","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1007\/s12291-017-0680-3","article-title":"Lead: tiny but mighty poison","volume":"33","author":"Sachdeva","year":"2018","journal-title":"Indian J Clin Biochem"},{"issue":"5","key":"2024121907440270300_ref35","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1136\/oemed-2018-105505","article-title":"Bone lead associations with blood lead, kidney function and blood pressure among US, lead-exposed workers in a surveillance programme","volume":"76","author":"Barry","year":"2019","journal-title":"Occup Environ Med"},{"issue":"7","key":"2024121907440270300_ref36","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1136\/oem.55.7.446","article-title":"Measurement of vitamin D3 metabolites in smelter workers exposed to lead and cadmium","volume":"55","author":"Chalkley","year":"1998","journal-title":"Occup Environ Med"},{"issue":"20","key":"2024121907440270300_ref37","doi-asserted-by":"crossref","first-page":"7382","DOI":"10.3390\/ijerph17207382","article-title":"Cadmium and lead levels in blood and arsenic levels in urine among schoolchildren living in contaminated glassworks areas, Sweden","volume":"17","author":"Mattisson","year":"2020","journal-title":"Int J Environ Res Public Health"},{"issue":"6","key":"2024121907440270300_ref38","doi-asserted-by":"crossref","first-page":"5582","DOI":"10.1007\/s11356-017-0661-3","article-title":"Protective effects of fucoxanthin and fucoxanthinol against tributyltin-induced oxidative stress in HepG2 cells","volume":"25","author":"Zeng","year":"2018","journal-title":"Environ Sci Pollut Res Int"},{"issue":"1","key":"2024121907440270300_ref39","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s00217-008-0918-7","article-title":"Cytoprotective effect of fucoxanthin isolated from brown algae Sargassum siliquastrum against H2O2-induced cell damage","volume":"228","author":"Heo","year":"2008","journal-title":"Eur Food Res Technol"},{"issue":"2","key":"2024121907440270300_ref40","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1021\/acs.jafc.5b05436","article-title":"Protective effect of Fucoxanthin isolated from Laminaria japonica against visible light-induced retinal damage both in vitro and in vivo","volume":"64","author":"Liu","year":"2016","journal-title":"J Agric Food Chem"},{"issue":"4","key":"2024121907440270300_ref41","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1271\/bbb.110040","article-title":"Protective effect of Fucoxanthin against UVB-induced skin photoaging in hairless mice","volume":"75","author":"Urikura","year":"2011","journal-title":"Biosci Biotechnol Biochem"},{"key":"2024121907440270300_ref42","first-page":"100245","article-title":"Fucoxanthin metabolites exert anti-fibrogenic and antioxidant effects in hepatic stellate cells","volume":"6","author":"Li","year":"2021","journal-title":"J Agric Food Res"},{"issue":"6337","key":"2024121907440270300_ref43","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1126\/science.aal3535","article-title":"Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages","volume":"356","author":"Ip","year":"2017","journal-title":"Science"},{"issue":"Suppl 1","key":"2024121907440270300_ref44","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1093\/cdn\/nzac064.006","article-title":"Neuroprotective function of Fucoxanthin in oxidative stress-mediated mitochondrial dysfunction","volume":"6","author":"Ferdous","year":"2022","journal-title":"Curr Dev Nutr"},{"issue":"7","key":"2024121907440270300_ref45","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1002\/aocs.12092","article-title":"Isolation of fucoxanthin from brown algae and its antioxidant activity: in vitro and 5% fish oil-in-water emulsion","volume":"95","author":"Koduvayur Habeebullah","year":"2018","journal-title":"J Am Oil Chem Soc"},{"issue":"6","key":"2024121907440270300_ref46","first-page":"2901","article-title":"Optimization of production and antioxidant activity of fucoxanthin from marine haptophyte algae, Isochrysis galbana","volume":"19","author":"Mousavi Nadushan","year":"2020","journal-title":"Iran J Fisheries Sci"},{"issue":"3","key":"2024121907440270300_ref47","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1615\/JEnvironPatholToxicolOncol.2019030154","article-title":"Assessment of the therapeutic effects of fucoxanthin by attenuating inflammation in ovalbumin-induced asthma in an experimental animal model","volume":"38","author":"Yang","year":"2019","journal-title":"J Environ Pathol Toxicol Oncol"},{"issue":"10","key":"2024121907440270300_ref48","doi-asserted-by":"crossref","first-page":"552","DOI":"10.3390\/md17100552","article-title":"Protective effects of fucoxanthin against alcoholic liver injury by activation of Nrf2-mediated antioxidant defense and inhibition of TLR4-mediated inflammation","volume":"17","author":"Zheng","year":"2019","journal-title":"Mar Drugs"},{"issue":"12","key":"2024121907440270300_ref49","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.3390\/antiox9121176","article-title":"Protective effects of fucoxanthin on high glucose- and 4-Hydroxynonenal (4-HNE)-induced injury in human retinal pigment epithelial cells","volume":"9","author":"Chiang","year":"2020","journal-title":"Antioxidants (Basel)."},{"issue":"4","key":"2024121907440270300_ref50","doi-asserted-by":"crossref","first-page":"328","DOI":"10.3390\/antiox9040328","article-title":"Fucoxanthin for topical administration, a phototoxic vs. photoprotective potential in a tiered strategy assessed by in vitro methods","volume":"9","author":"Tavares","year":"2020","journal-title":"Antioxidants (Basel)"},{"issue":"1","key":"2024121907440270300_ref51","doi-asserted-by":"crossref","first-page":"7235","DOI":"10.1080\/21655979.2021.1973875","article-title":"Role of fucoxanthin towards cadmium-induced renal impairment with the antioxidant and anti-lipid peroxide activities","volume":"12","author":"Yang","year":"2021","journal-title":"Bioengineered"}],"container-title":["Toxicology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxres\/article-pdf\/13\/6\/tfae218\/61233021\/tfae218.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxres\/article-pdf\/13\/6\/tfae218\/61233021\/tfae218.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T07:44:37Z","timestamp":1734594277000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxres\/article\/doi\/10.1093\/toxres\/tfae218\/7928274"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,5]]},"references-count":51,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,11,5]]}},"URL":"https:\/\/doi.org\/10.1093\/toxres\/tfae218","relation":{},"ISSN":["2045-4538"],"issn-type":[{"value":"2045-4538","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,12]]},"published":{"date-parts":[[2024,11,5]]},"article-number":"tfae218"}}