{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:51:24Z","timestamp":1787316684834,"version":"build-2736575974"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wesleyan University's Bailey College of the Environment"},{"name":"Wesleyan University's Bailey College of the Environment"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Amyotrophic Lateral Sclerosis (ALS) is a debilitating and incurable neurodegenerative disease with unsolved etiology. Due to the large proportion of patients lacking direct disease inheritance, understanding the environmental factors that contribute to ALS development is of high priority. Epidemiological studies have implicated pesticides and other environmental exposures as possible contributors to ALS pathogenesis. Recently, our group determined that the organochlorine pesticide cis-chlordane is toxic to human motor neurons in a dose-dependent manner, causing an ALS-like phenotype in culture and animals with a mode of action independent of its known GABA\n                    <jats:sub>A<\/jats:sub>\n                    antagonism. Here, we aimed to characterize downstream motor neuron phenotypes associated with\n                    <jats:italic>cis<\/jats:italic>\n                    -chlordane treatment. We performed bulk RNA sequencing, live imaging, immunofluorescent labeling, and real-time metabolic assays on stem cell-derived motor neurons to assess chlordane-associated phenotypes in vitro. We demonstrate that\n                    <jats:italic>cis<\/jats:italic>\n                    -chlordane treatment causes a highly altered mitochondrial phenotype in motor neurons, including increased production of reactive oxygen species, decreased oxygen consumption rate and ATP production, and loss of mitochondrial membrane potential. We further implicate\n                    <jats:italic>cis<\/jats:italic>\n                    -chlordane as a possible mediator of potent motor neuron damage, with exposure to the pesticide inducing mitochondrial phenotypes akin to those seen in ALS. Our findings contribute to the growing body of evidence that future studies of investigating the role of pesticides in ALS development should focus on organochlorine molecules.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0332422","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T17:27:33Z","timestamp":1760462853000},"page":"e0332422","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exposure to the organochlorine pesticide cis-chlordane induces ALS-like mitochondrial perturbations in stem cell-derived motor neurons"],"prefix":"10.1371","volume":"20","author":[{"given":"Oliver","family":"Clackson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Reza","family":"Hamid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adithi","family":"Wijesekera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kulick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0759-4740","authenticated-orcid":true,"given":"Alison Linsley","family":"O\u2019Neil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"pone.0332422.ref001","article-title":"Amotrophic lateral sclerosis","author":"O Hardiman","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"pone.0332422.ref002","doi-asserted-by":"crossref","first-page":"3429","DOI":"10.1093\/brain\/awr296","article-title":"Familial versus sporadic amyotrophic lateral sclerosis--a false dichotomy?","volume":"134","author":"K Talbot","year":"2011","journal-title":"Brain"},{"issue":"3","key":"pone.0332422.ref003","article-title":"Exposure to pesticides and risk of amyotrophic lateral sclerosis: a population-based case-control study","volume":"46","author":"F Bonvicini","year":"2010","journal-title":"Environ Issues Health Concern"},{"key":"pone.0332422.ref004","doi-asserted-by":"crossref","DOI":"10.1016\/j.neuro.2021.09.004","article-title":"Pesticides applied to crops and amyotrophic lateral sclerosis risk in the U.S","volume":"87","author":"JZ Andrew","year":"2021","journal-title":"NeuroToxicology"},{"key":"pone.0332422.ref005","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.envres.2012.06.007","article-title":"Pesticide exposure as a risk factor for amyotrophic lateral sclerosis: a meta-analysis of epidemiological studies: pesticide exposure as a risk factor for ALS","volume":"117","author":"AM Malek","year":"2012","journal-title":"Environ Res"},{"issue":"2","key":"pone.0332422.ref006","doi-asserted-by":"crossref","DOI":"10.1289\/ehp.8095","article-title":"Pesticides and Parkinson\u2019s disease\u2014Is there a link?","volume":"114","author":"TP Brown","year":"2005","journal-title":"Environ Health Perspectives"},{"issue":"2","key":"pone.0332422.ref007","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.toxlet.2014.01.039","article-title":"Pesticides exposure as etiological factors of Parkinson\u2019s disease and other neurodegenerative diseases--a mechanistic approach","volume":"230","author":"MT Baltazar","year":"2014","journal-title":"Toxicol Lett"},{"key":"pone.0332422.ref008","doi-asserted-by":"crossref","first-page":"32222","DOI":"10.1038\/srep32222","article-title":"Pesticide exposure and risk of Alzheimer\u2019s disease: a systematic review and meta-analysis","volume":"6","author":"D Yan","year":"2016","journal-title":"Sci 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Degener"},{"key":"pone.0332422.ref012","volume-title":"Hazardous chemicals: overview, toxicological profile, challenges, and future perspectives","author":"KTD Trivedi","year":"2024"},{"issue":"1","key":"pone.0332422.ref013","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1007\/BF01685030","article-title":"Persistence and distribution of chlordane and dieldrin applied as termiticides","volume":"11","author":"GW Bennett","year":"1974","journal-title":"Bull Environ Contam Toxicol"},{"key":"pone.0332422.ref014","volume-title":"Wildlife toxicity assessments for chemicals of military concern","author":"EMN Einke","year":"2015"},{"key":"pone.0332422.ref015","volume-title":"Toxilogical profile for chlordane","author":"P Breysse","year":"2018"},{"key":"pone.0332422.ref016","unstructured":"Anderson M. The EPA blog: EPA. 2013 [Accessed 2020 July 28]. https:\/\/www.epa.gov\/perspectives\/2013\/06\/17\/30-years-after-the-epa-ban-chlordane-still-poisons-local-birds\/"},{"issue":"20","key":"pone.0332422.ref017","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1016\/0024-3205(86)90295-X","article-title":"Polychlorocycloalkane insecticide-induced convulsions in mice in relation to disruption of the GABA-regulated chloride ionophore","volume":"39","author":"LM Cole","year":"1986","journal-title":"Life Sci"},{"key":"pone.0332422.ref018","doi-asserted-by":"crossref","DOI":"10.1016\/B978-0-12-801238-3.65834-8","volume-title":"Organochlorine and pyrethroid insecticides","author":"A Moretto","year":"2018"},{"key":"pone.0332422.ref019","doi-asserted-by":"crossref","first-page":"114024","DOI":"10.1016\/j.fct.2023.114024","article-title":"Sex-specific effects of acute chlordane exposure in the context of steatotic liver disease, energy metabolism and endocrine disruption","volume":"180","author":"J Luo","year":"2023","journal-title":"Food Chem Toxicol"},{"issue":"1","key":"pone.0332422.ref020","doi-asserted-by":"crossref","first-page":"14546","DOI":"10.1038\/s41598-021-93868-4","article-title":"The association between environmental exposures to chlordanes, adiposity and diabetes-related features: a systematic review and meta-analysis","volume":"11","author":"V Mendes","year":"2021","journal-title":"Sci Rep"},{"key":"pone.0332422.ref021","doi-asserted-by":"crossref","first-page":"112739","DOI":"10.1016\/j.ecoenv.2021.112739","article-title":"Chlordane exposure causes developmental delay and metabolic disorders in Drosophila melanogaster","volume":"225","author":"Q Wu","year":"2021","journal-title":"Ecotoxicol Environ Saf"},{"issue":"1","key":"pone.0332422.ref022","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0378-4274(89)90187-2","article-title":"Effect of chlordane on hepatic mitochondrial respiration","volume":"48","author":"M Ogata","year":"1989","journal-title":"Toxicol Lett"},{"key":"pone.0332422.ref023","doi-asserted-by":"crossref","first-page":"122","DOI":"10.3389\/fendo.2019.00122","article-title":"Oxidative phosphorylation impairment by DDT and DDE","volume":"10","author":"SE Elmore","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"24","key":"pone.0332422.ref024","doi-asserted-by":"crossref","first-page":"3567","DOI":"10.1021\/acschemneuro.2c00452","article-title":"Amyotrophic lateral sclerosis-associated persistent organic pollutant cis-Chlordane causes GABAA-Independent toxicity to motor neurons, providing evidence toward an environmental component of sporadic amyotrophic lateral sclerosis","volume":"13","author":"D Kulick","year":"2022","journal-title":"ACS Chem Neurosci"},{"issue":"6","key":"pone.0332422.ref025","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.stemcr.2016.05.010","article-title":"Large-scale production of mature neurons from human pluripotent stem cells in a three-dimensional suspension culture system","volume":"6","author":"A Rigamonti","year":"2016","journal-title":"Stem Cell Reports"},{"issue":"7251","key":"pone.0332422.ref026","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nature08191","article-title":"Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages","volume":"460","author":"L Bu","year":"2009","journal-title":"Nature"},{"key":"pone.0332422.ref027","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gky379","article-title":"The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update","volume":"46","author":"E Afgan","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pone.0332422.ref028","unstructured":"Gruening BA. Galaxy wrapper. 2014."},{"key":"pone.0332422.ref029","unstructured":"Andrews S. FastQC: a quality control tool for high throughput sequence data. 2010."},{"issue":"3","key":"pone.0332422.ref030","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"SF Altschul","year":"1990","journal-title":"J Mol Biol"},{"issue":"4","key":"pone.0332422.ref031","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: a fast spliced aligner with low memory requirements","volume":"12","author":"D Kim","year":"2015","journal-title":"Nat Methods"},{"issue":"1","key":"pone.0332422.ref032","first-page":"710","article-title":"Ensembl 2016","volume":"44","author":"A Yates","year":"2015","journal-title":"Nucleic Acids Res"},{"issue":"534","key":"pone.0332422.ref033","article-title":"iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data","volume":"19","author":"ST Ge","year":"2018","journal-title":"BMC Bioinform"},{"issue":"1","key":"pone.0332422.ref034","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"M Ashburner","year":"2000","journal-title":"Nat Genet"},{"key":"pone.0332422.ref035","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/1471-2105-10-161","article-title":"GAGE: generally applicable gene set enrichment for pathway analysis","volume":"10","author":"W Luo","year":"2009","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"pone.0332422.ref036","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"M Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"pone.0332422.ref037","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.jns.2019.02.030","article-title":"Genetics of amyotrophic lateral sclerosis: a review","volume":"399","author":"S Mathis","year":"2019","journal-title":"J Neurol Sci"},{"issue":"5","key":"pone.0332422.ref038","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1046\/j.1471-4159.1997.69052064.x","article-title":"Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis","volume":"69","author":"RJ Ferrante","year":"1997","journal-title":"J Neurochem"},{"issue":"9","key":"pone.0332422.ref039","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/j.bbabio.2018.05.019","article-title":"Mitochondrial uncoupling, ROS generation and cardioprotection","volume":"1859","author":"S Cadenas","year":"2018","journal-title":"Biochim Biophys Acta Bioenerg"},{"issue":"4","key":"pone.0332422.ref040","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1046\/j.0022-3042.2001.00731.x","article-title":"Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients","volume":"80","author":"FR Wiedemann","year":"2002","journal-title":"J Neurochem"},{"key":"pone.0332422.ref041","unstructured":"O\u2019Neil AL. Created in Biorender. 2025. https:\/\/BioRender.com\/jsvjefs"},{"issue":"6","key":"pone.0332422.ref042","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.3390\/biomedicines10061307","article-title":"Metabolic profile and pathological alterations in the muscle of patients with early-stage amyotrophic lateral sclerosis","volume":"10","author":"D Lanznaster","year":"2022","journal-title":"Biomedicines"},{"issue":"7","key":"pone.0332422.ref043","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.3390\/cells11071246","article-title":"Alteration of mitochondrial integrity as upstream event in the pathophysiology of SOD1-ALS","volume":"11","author":"R G\u00fcnther","year":"2022","journal-title":"Cells"},{"issue":"19","key":"pone.0332422.ref044","doi-asserted-by":"crossref","first-page":"3947","DOI":"10.1093\/hmg\/ddt249","article-title":"Mitochondrial damage revealed by immunoselection for ALS-linked misfolded SOD1","volume":"22","author":"S Pickles","year":"2013","journal-title":"Hum Mol Genet"},{"issue":"2","key":"pone.0332422.ref045","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s12035-009-8054-3","article-title":"ER stress and unfolded protein response in amyotrophic lateral sclerosis","volume":"39","author":"K Kanekura","year":"2009","journal-title":"Mol Neurobiol"},{"key":"pone.0332422.ref046","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2017.00123","article-title":"Protein homeostasis in amyotrophic lateral sclerosis: therapeutic opportunities?","volume":"10","author":"CP Webster","year":"2017","journal-title":"Front Mol Neurosci"},{"key":"pone.0332422.ref047","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.nbd.2018.07.005","article-title":"Autophagy and mitophagy in ALS","volume":"122","author":"CS Evans","year":"2020","journal-title":"Neurobiol Dis"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0332422","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T17:27:42Z","timestamp":1760462862000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0332422"}},"subtitle":[],"editor":[{"given":"Sayyed Mohammad Hadi","family":"Alavi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,10,14]]},"references-count":47,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0332422","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.06.05.658119","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,14]]}}}