{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:26:32Z","timestamp":1787318792729,"version":"build-2736575974"},"reference-count":33,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2013,10,21]],"date-time":"2013-10-21T00:00:00Z","timestamp":1382313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Exposure to persistent environmental pollutants may constitute an important factor on the onset of a number of neurological disorders such as autism, Parkinson\u2019s disease, and Attention Deficit Disorder (ADD), which have also been linked to reduced GABAergic neuronal function. GABAergic neurons produce \u03b3-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the brain. However, the lack of appropriate models has hindered the study of suspected environmental pollutants on GABAergic function. In this work, we have examined the effect of hexachlorobenzene (HCB), a persistent and bioaccumulative environmental pollutant, on the function and morphology of GABAergic neurons generated in vitro from mouse embryonic stem (ES) cells. We observed that: (1) treatment with 0.5 nM HCB did not affect cell viability, but affected the neuronal differentiation of ES cells; (2) HCB induced the production of reactive oxygen species (ROS); and (3) HCB repressed neurite outgrowth in GABAergic neurons, but this effect was reversed by the ROS scavenger N-acetylcysteine (NAC). Our study also revealed that HCB did not significantly interfere with the function of K+ ion channels in the neuronal soma, which indicates that this pollutant does not affect the maturation of the GABAergic neuronal soma. Our results suggest a mechanism by which environmental pollutants interfere with normal GABAergic neuronal function and may promote the onset of a number of neurological disorders such as autism and ADD.<\/jats:p>","DOI":"10.3390\/ijerph10105244","type":"journal-article","created":{"date-parts":[[2013,10,21]],"date-time":"2013-10-21T14:49:22Z","timestamp":1382366962000},"page":"5244-5256","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Effect of the Environmental Pollutant Hexachlorobenzene (HCB) on the Neuronal Differentiation of Mouse Embryonic Stem Cells"],"prefix":"10.3390","volume":"10","author":[{"given":"Cynthia","family":"Addae","sequence":"first","affiliation":[{"name":"Department of Biological Sciences and Environmental Toxicology Program, Southern University and A&M College, Baton Rouge, LA 70813, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrique","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Martinez-Ceballos","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Environmental Toxicology Program, Southern University and A&M College, Baton Rouge, LA 70813, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/336684a0","article-title":"Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells","volume":"336","author":"Williams","year":"1988","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S1043-6618(03)00037-9","article-title":"Stem cells for cell therapy in Parkinson\u2019s disease","volume":"47","author":"Lindvall","year":"2003","journal-title":"Pharmacol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1098\/rstb.2006.1886","article-title":"Cell replacement therapy in neurological disease","volume":"361","author":"Goldman","year":"2006","journal-title":"Philos. Trans. R. Soc. Lond. B. Biol. Sci."},{"key":"ref_4","unstructured":"Toxicological Profile for Hexachlorobenzene, Available online:www.atsdr.cdc.gov\/toxprofiles\/tp.asp?id = 627&tid = 115."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/sj.jes.7500525","article-title":"Factors predicting organochlorine pesticide levels in pregnant Latina women living in a United States agricultural area","volume":"17","author":"Bradman","year":"2007","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1515\/REVEH.2007.22.3.213","article-title":"Environmental toxicology and health effects associated with hexachlorobenzene exposure","volume":"22","author":"Reed","year":"2007","journal-title":"Rev. Environ. Health"},{"key":"ref_7","unstructured":"Johnson, W.W., and Finley, M.T. (1980). Handbook of Acute Toxicity of Chemicals to Fish and Aquatic Invertebrates, U. S. Department of the Interior, Fish and Wildlife Service."},{"key":"ref_8","unstructured":"Hexachlorobenzene in Drinking-Water. Available online:www.who.int\/water_sanitation_health\/dwq\/chemicals\/hexachlorobenzene.pdf."},{"key":"ref_9","first-page":"235","article-title":"Pesticide exposure and child neurodevelopment: Summary and implications","volume":"60","author":"Liu","year":"2012","journal-title":"Workplace Health Saf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/jes.2009.47","article-title":"Prenatal exposure to organochlorine compounds and neonatal thyroid stimulating hormone levels","volume":"20","author":"Vizcaino","year":"2010","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1289\/ehp.106-1533492","article-title":"Hexachlorobenzene as a possible major contributor to the dioxin activity of human milk","volume":"106","year":"1998","journal-title":"Environ. Health Perspect."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1093\/carcin\/23.7.1243","article-title":"Decreased gap junctional intercellular communication in hexachlorobenzene-induced gender-specific hepatic tumor formation in the rat","volume":"23","author":"Plante","year":"2002","journal-title":"Carcinogenesis"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1093\/toxsci\/kfq390","article-title":"Activation of c-Src\/HER1\/STAT5b and HER1\/ERK1\/2 signaling pathways and cell migration by hexachlorobenzene in MDA-MB-231 human breast cancer cell line","volume":"120","author":"Pontillo","year":"2011","journal-title":"Toxicol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S0887-2333(02)00054-1","article-title":"Effects of hexachlorobenzene on embryonic mammalian cells","volume":"16","author":"Salmon","year":"2002","journal-title":"Toxicol. In Vitro"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16484","DOI":"10.1074\/jbc.M414397200","article-title":"Differences in gene expression between wild type and Hoxa1 knockout embryonic stem cells after retinoic acid treatment or leukemia inhibitory factor (LIF) removal","volume":"280","author":"Chambon","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.diff.2012.03.001","article-title":"All-trans-retinoid acid induces the differentiation of encapsulated mouse embryonic stem cells into GABAergic neurons","volume":"83","author":"Addae","year":"2012","journal-title":"Differentiation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1002\/jnr.21729","article-title":"Hoxa1 is required for the retinoic acid-induced differentiation of embryonic stem cells into neurons","volume":"86","author":"Gudas","year":"2008","journal-title":"J. Neurosci. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4142","DOI":"10.1210\/endo.140.9.6996","article-title":"Hexachlorobenzene, a dioxin-type compound, increases malic enzyme gene transcription through a mechanism involving the thyroid hormone response element","volume":"140","author":"Seisdedos","year":"1999","journal-title":"Endocrinology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1191\/0960327105ht549oa","article-title":"Evaluation of oxidative stress and genotoxicity in organophosphorus insecticide formulators","volume":"24","author":"Shadnia","year":"2005","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.reprotox.2011.09.007","article-title":"Investigation on sodium valproate induced germ cell damage, oxidative stress and genotoxicity in male Swiss mice","volume":"32","author":"Khan","year":"2011","journal-title":"Reprod. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4449","DOI":"10.1523\/JNEUROSCI.15-06-04449.1995","article-title":"Potassium currents responsible for inward and outward rectification in rat neostriatal spiny projection neurons","volume":"15","author":"Nisenbaum","year":"1995","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/cne.20819","article-title":"Neurochemical and electrophysiological characteristics of rat striatal neurons in primary culture","volume":"494","author":"Falk","year":"2006","journal-title":"J. Comp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5144","DOI":"10.1167\/iovs.08-1907","article-title":"Differentiation and production of action potentials by embryonic rat retina stem cells in vitro","volume":"49","author":"Chen","year":"2008","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/j.1365-2133.1984.tb06603.x","article-title":"Porphyria turcica due to hexachlorobenzene: A 20 to 30 year follow-up study on 204 patients","volume":"111","author":"Cripps","year":"1984","journal-title":"Br. J. Dermatol."},{"key":"ref_25","unstructured":"Gocmen, A., Peters, H.A., Cripps, D.J., Morris, C.R., and Dogramaci, I. (1986). Porphyria turcica: Hexachlorobenzene-induced porphyria. IARC Sci. Publ., 567\u2013573."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1007\/s002040050257","article-title":"Impairment of schedule-controlled behavior by pre- and postnatal exposure to hexachlorobenzene in rats","volume":"70","author":"Lilienthal","year":"1996","journal-title":"Arch. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.physbeh.2011.03.016","article-title":"Further analysis of behavioral and endocrine consequences of chronic exposure of male Wistar rats to subtoxic doses of endocrine disruptor chlorobenzenes","volume":"103","author":"Valkusz","year":"2011","journal-title":"Physiol. Behav."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1093\/toxsci\/kfj023","article-title":"Hexachlorobenzene is a tumor co-carcinogen and induces alterations in insulin-growth factors signaling pathway in the rat mammary gland","volume":"89","author":"Randi","year":"2006","journal-title":"Toxicol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.bone.2004.07.019","article-title":"Osteogenic and chondrogenic differentiation of embryonic stem cells in response to specific growth factors","volume":"36","author":"Kawaguchi","year":"2005","journal-title":"Bone"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.toxlet.2008.01.003","article-title":"Hexachlorobenzene triggers AhR translocation to the nucleus, c-Src activation and EGFR transactivation in rat liver","volume":"177","author":"Randi","year":"2008","journal-title":"Toxicol. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4179","DOI":"10.1128\/MCB.01352-06","article-title":"CSK controls retinoic acid receptor (RAR) signaling: A RAR-c-SRC signaling axis is required for neuritogenic differentiation","volume":"27","author":"Dey","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1016\/S0891-5849(02)01115-2","article-title":"Chromium(III)-induced apoptosis of lymphocytes: Death decision by ROS and Src-family tyrosine kinases","volume":"33","author":"Balamurugan","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1203\/01.pdr.0000185133.65966.4e","article-title":"Signal transduction pathways involved in oxidative stress-induced intestinal epithelial cell apoptosis","volume":"58","author":"Zhou","year":"2005","journal-title":"Pediatr. Res."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/10\/10\/5244\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:50:00Z","timestamp":1760219400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/10\/10\/5244"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,10,21]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2013,10]]}},"alternative-id":["ijerph10105244"],"URL":"https:\/\/doi.org\/10.3390\/ijerph10105244","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,10,21]]}}}