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Studies in cultured cells and animal models have shown that As- or F-induced hepatotoxicity is primarily associated with redox disturbance and altered mitochondrial homeostasis. To explore the hepatotoxic effects of chronic combined exposure to As and F<jats:sup>\u2212<\/jats:sup> in drinking water, pregnant CD-1 mice were exposed to 2\u00a0mg\/L As (sodium arsenite) and\/or 25\u00a0mg\/L F<jats:sup>\u2212<\/jats:sup> (sodium fluoride). The male offspring continued the exposure treatment up to 30 (P30) or 90 (P90) postnatal days. GSH levels, cysteine synthesis enzyme activities, and cysteine transporter levels were investigated in liver homogenates, as well as the expression of biomarkers of ferroptosis and mitochondrial biogenesis-related proteins. Serum transaminase levels and Hematoxylin\u2013Eosin and Masson trichrome-stained liver tissue slices were examined. Combined exposure at P30 significantly reduced GSH levels and the mitochondrial transcription factor A (TFAM) expression while increasing lipid peroxidation, free Fe <jats:sup>2+<\/jats:sup>, p53 expression, and serum ALT activity. At P90, the upregulation of cysteine uptake and synthesis was associated with a recovery of GSH levels. Nevertheless, the downregulation of TFAM continued and was now associated with a downstream inhibition of the expression of MT-CO2 and reduced levels of mtDNA and fibrotic liver damage. Our experimental approach using human-relevant doses gives evidence of the increased risk for early liver damage associated with elevated levels of As and F<jats:sup>\u2212<\/jats:sup> in the diet during intrauterine and postnatal period.<\/jats:p>","DOI":"10.1007\/s12011-024-04198-1","type":"journal-article","created":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T04:02:20Z","timestamp":1714190540000},"page":"930-943","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Chronic Exposure to Arsenic and Fluoride Starting at Gestation Alters Liver Mitochondrial Protein Expression and Induces Early Onset of Liver Fibrosis in Male Mouse Offspring"],"prefix":"10.1007","volume":"203","author":[{"given":"Wendy L.","family":"Gonz\u00e1lez-Alfonso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Petrosyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luz M.","family":"Del Razo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luz C.","family":"S\u00e1nchez-Pe\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Tapia-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolando","family":"Hern\u00e1ndez-Mu\u00f1oz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2653-8039","authenticated-orcid":false,"given":"Mar\u00eda E.","family":"Gonsebatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,27]]},"reference":[{"key":"4198_CR1","unstructured":"Howard G, Bartram J, Pedley S, Schmoll O, Chorus I, Berger P (2006) Groundwater and public health. 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The experimental protocol was approved by the Institutional Animal Care and Use Committee of the Instituto de Investigaciones Biom\u00e9dicas, UNAM. Animals were handled following the \u201cPrinciples of Laboratory Animal Care\u201d guidelines (NIH publication #85\u201323, revised 1985) and \u201cEspecificaciones t\u00e9cnicas para la producci\u00f3n, cuidado y uso de los animales de laboratorio (Clave NOM-062-ZOO-1999)\u201d of the \u201cNorma Oficial Mexicana de la Secretar\u00eda de Agricultura, Ganader\u00eda, Desarrollo Rural, Pesca y Alimentaci\u00f3n (SAGARPA)\u201d (published in August 2001).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"This article did not include research involving human subjects.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"This article did not include research involving human subjects. We affirm that all the authors have agreed to the submission of this research paper to Environmental Science and Pollution Research.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}]}}