{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:14Z","timestamp":1792790354373,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Cell Biology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Environmental Health Sciences","award":["R00ES033259"],"award-info":[{"award-number":["R00ES033259"]}],"id":[{"id":"https:\/\/ror.org\/00j4k1h63","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01tx6pn92","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Chronic exposure to inorganic arsenic affects more than 200 million people, and disease outcome varies widely among individuals with comparable intake. Explanations have centered on arsenic metabolism, which acts on arsenite that is already inside the cell. Uptake sits upstream of metabolism and sets how much arsenite reaches the genome, yet whether it acts as a gene-by-environment modifier of genotoxicity has been asserted far more often than it has been measured. We expressed human aquaporin-3 (AQP3), its point mutants and the paralogues AQP7, AQP9 and AQP10 in three human cell lines, and measured DNA damage as \u03b3H2AX by flow cytometry against a damage threshold re-derived from mock-transfected cells in every experiment. In lung fibroblasts, AQP3 raised the \u03b3H2AX-high fraction 2.36-fold at 5 \u03bcM arsenite. Because a gene-by-environment interaction widens the genotype gap with dose while an independent genotoxin would not, the combination exceeds what the two factors would produce if they simply added by 6.36 percentage points, which is an interaction. The response required the AQP3 sequence, was suppressed by N-acetylcysteine in proportion to arsenite dose, was absent in RKO cells, and was shared with AQP9 and AQP10, which created an arsenite dose-response in a cell line that had none of its own. Low-input RNA sequencing of 135 ten-cell pools located the effect inside the cell: at an identical 1 \u03bcM applied dose and within a single batch, AQP3 raised\n                  <jats:italic>HMOX1<\/jats:italic>\n                  (induced when trivalent arsenic modifies KEAP1 thiols, and so a report of intracellular rather than applied exposure) 3.3-fold, a shift equivalent to 40% of the 1-to-10 \u03bcM interval on the measured dose-response, while AQP3 without arsenite was indistinguishable from untreated. Duplex sequencing detected no consistent change in somatic mutation frequency from arsenite alone at any dose to 10 \u03bcM, in an assay that resolved a 26-fold response to N-ethyl-N-nitrosourea; the arsenite-induced mutation frequency at the\n                  <jats:italic>EGFR<\/jats:italic>\n                  locus nonetheless differed 1.61-fold by AQP3 genotype. The interaction is therefore not unique to AQP3, and aquaglyceroporin complement belongs alongside metabolism among the host factors that set arsenic susceptibility.\n                <\/jats:p>","DOI":"10.64898\/2026.09.23.752800","type":"posted-content","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T15:20:21Z","timestamp":1790263221000},"source":"Crossref","is-referenced-by-count":1,"title":["Aquaporin-3 amplifies arsenite genotoxicity as a dose-dependent gene-by-environment interaction in human cells"],"prefix":"10.64898","author":[{"given":"Shiwei","family":"Yin","sequence":"first","affiliation":[{"name":"Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA"},{"name":"Department of Translational Medical Sciences, Texas A&M University, Houston, TX 77030, USA"},{"name":"Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2759-1624","authenticated-orcid":false,"given":"Bingru","family":"Feng","sequence":"additional","affiliation":[{"name":"Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA"},{"name":"Department of Translational Medical Sciences, Texas A&M University, Houston, TX 77030, USA"},{"name":"Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Vaziripour","sequence":"additional","affiliation":[{"name":"Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA"},{"name":"Department of Translational Medical Sciences, Texas A&M University, Houston, TX 77030, USA"},{"name":"Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon E.","family":"Slewitzke","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail F.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihye","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher I.","family":"Amos","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"UNM Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xia","sequence":"additional","affiliation":[{"name":"Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA"},{"name":"Department of Translational Medical Sciences, Texas A&M University, Houston, TX 77030, USA"},{"name":"Center for Genomic and Precision Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092812001681000_2026.09.23.752800v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba1510"},{"key":"2026092812001681000_2026.09.23.752800v1.2","unstructured":"Cancer IAfRo. 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