{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:29:05Z","timestamp":1792729745135,"version":"4.5.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T00:00:00Z","timestamp":1665014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R01 ES014901 F32 ES024070"],"award-info":[{"award-number":["R01 ES014901 F32 ES024070"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Toxicol."],"abstract":"<jats:p>Although their production was banned in the United States in 1977, polychlorinated biphenyls (PCBs) continue to pose significant risks to the developing nervous system. Perinatal exposure to PCBs is associated with increased risk of neuropsychiatric disorders, perhaps due to altered patterns of dendritic arborization of central neurons. Non-dioxin-like (NDL) PCB congeners enhance dendritic arborization of developing mammalian neurons via sensitization of ryanodine receptors (RYR). Structure-activity relationships (SAR) of RYR sensitization by PCBs have been demonstrated using mammalian and rainbow trout (<jats:italic>Oncorhynchus mykiss<\/jats:italic>) tissue homogenates. The purpose of this study is to determine whether this SAR translates to developmental neurotoxicity (DNT) of PCBs <jats:italic>in vivo<\/jats:italic>, a question that has yet to be tested. To address this gap, we leveraged a zebrafish model to evaluate the developmental neurotoxicity potential of PCBs 28, 66, 84, 95, 138, and 153, congeners previously shown to have broadly different potencies towards sensitizing RYR. We first confirmed that these PCB congeners exhibited differing potency in sensitizing RYR in zebrafish muscle ranging from negligible (PCB 66) to moderate (PCB 153) to high (PCB 95) RYR activity. Next, enzymatically dechorionated embryos were statically exposed to varying concentrations (0.1\u201310\u00a0\u03bcM) of each PCB congener from 6\u00a0h post-fertilization to 5\u00a0days post-fertilization (dpf). Embryos were observed daily using stereomicroscopy to assess mortality and gross malformations and photomotor behavior was assessed in larval zebrafish at 3, 4, and 5\u00a0dpf. The body burden of each PCB was measured by gas chromatography. The key findings are: 1) None of these PCBs caused death or overt teratology at the concentrations tested; 2) A subset of these PCB congeners altered photomotor behavior in larval zebrafish and the SAR for PCB behavioral effects mirrored the SAR for RYR sensitization; and 3) Quantification of PCB levels in larval zebrafish ruled out the possibility that congener-specific effects on behavior were due to differential uptake of PCB congeners. Collectively, the findings from this study provide <jats:italic>in vivo<\/jats:italic> evidence in support of the hypothesis that RYR sensitization contributes to the DNT of PCBs.<\/jats:p>","DOI":"10.3389\/ftox.2022.947795","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T12:50:35Z","timestamp":1665060635000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Ryanodine receptor-active non-dioxin-like polychlorinated biphenyls cause neurobehavioral deficits in larval zebrafish"],"prefix":"10.3389","volume":"4","author":[{"given":"Bianca","family":"Yaghoobi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galen W.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika B.","family":"Holland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueshu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Joachim","family":"Lehmler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac N.","family":"Pessah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela J.","family":"Lein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1093\/toxsci\/kfz217","article-title":"Developmental exposure to PCB153 (2,2',4,4',5,5'-Hexachlorobiphenyl) alters circadian rhythms and the expression of clock and metabolic genes","volume":"173","author":"Aluru","year":"2020","journal-title":"Toxicol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.chemosphere.2009.01.041","article-title":"Comparison of peak integration methods for the determination of enantiomeric fraction in environmental samples","volume":"75","author":"Asher","year":"2009","journal-title":"Chemosphere"},{"key":"B3","doi-asserted-by":"publisher","first-page":"23","DOI":"10.3390\/biomedicines7010023","article-title":"Zebrafish larvae as a behavioral model in neuropharmacology","volume":"7","author":"Basnet","year":"2019","journal-title":"Biomedicines"},{"key":"B4","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1007\/s00204-015-1463-3","article-title":"Developmental neurotoxicity of persistent organic pollutants: An update on childhood outcome","volume":"89","author":"Berghuis","year":"2015","journal-title":"Arch. Toxicol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1093\/toxsci\/kfu196","article-title":"Prenatal exposure to polychlorinated biphenyls and their hydroxylated metabolites is associated with neurological functioning in 3-month-old infants","volume":"142","author":"Berghuis","year":"2014","journal-title":"Toxicol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/978-1-4419-0032-6_5","article-title":"Environmental fate and global distribution of polychlorinated biphenyls","volume":"201","author":"Beyer","year":"2009","journal-title":"Rev. Environ. Contam. Toxicol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"7360","DOI":"10.1074\/jbc.272.11.7360","article-title":"Dyspedic mouse skeletal muscle expresses major elements of the triadic junction but lacks detectable ryanodine receptor protein and function","volume":"272","author":"Buck","year":"1997","journal-title":"J. Biol. Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1096\/fj.05-4497fje","article-title":"Heat\u2010 and anesthesia\u2010induced malignant hyperthermia in an RyR1 knock\u2010in mouse","volume":"20","author":"Chelu","year":"2006","journal-title":"FASEB J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1093\/toxsci\/kfy266","article-title":"Teratological and behavioral screening of the national toxicology program 91-compound library in zebrafish (Danio rerio)","volume":"167","author":"Dach","year":"2019","journal-title":"Toxicol. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/j.cbpb.2009.09.003","article-title":"A comparative study of ryanodine receptor (RyR) gene expression levels in a basal ray-finned fish, bichir (Polypterus ornatipinnis) and the derived euteleost zebrafish (Danio rerio)","volume":"154","author":"Darbandi","year":"2009","journal-title":"Comp. Biochem. Physiology Part B Biochem. Mol. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.aquatox.2013.06.003","article-title":"Structure-activity relationship of non-coplanar polychlorinated biphenyls toward skeletal muscle ryanodine receptors in rainbow trout (Oncorhynchus mykiss)","author":"Fritsch","year":"2013","journal-title":"Aquat. Toxicol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3389\/fnana.2020.00015","article-title":"Calsequestrins New calcium store markers of adult zebrafish cerebellum and optic tectum","volume":"14","author":"Furlan","year":"2020","journal-title":"Front. Neuroanat."},{"key":"B13","volume-title":"Developmental biology","author":"Gilbert","year":"2010"},{"key":"B14","volume-title":"The laboratory zebrafish, Laboratory animal pocket reference series","author":"Harper","year":"2011"},{"key":"B15","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1093\/toxsci\/kfw189","article-title":"An extended structure-activity relationship of nondioxin-like PCBs evaluates and supports modeling predictions and identifies picomolar potency of PCB 202 towards ryanodine receptors","volume":"155","author":"Holland","year":"","journal-title":"Toxicol. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.aquatox.2017.09.002","article-title":"Ryanodine receptor and FK506 binding protein 1 in the atlantic killifish (Fundulus heteroclitus): A phylogenetic and population-based comparison","volume":"192","author":"Holland","year":"","journal-title":"Aquat. Toxicol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/s0041-008x(03)00156-x","article-title":"Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor","volume":"190","author":"Howard","year":"2003","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/nature12111","article-title":"The zebrafish reference genome sequence and its relationship to the human genome","volume":"496","author":"Howe","year":"2013","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/j.jglr.2011.03.001","article-title":"Sedimentary records of non-aroclor and aroclor PCB mixtures in the great lakes","volume":"37","author":"Hu","year":"2011","journal-title":"J. Gt. Lakes. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"11875","DOI":"10.1021\/acs.est.5b02865","article-title":"Toxicity evaluation of exposure to an atmospheric mixture of polychlorinated biphenyls by nose-only and whole-body inhalation regimens","volume":"49","author":"Hu","year":"2015","journal-title":"Environ. Sci. Technol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1016\/j.scitotenv.2017.09.267","article-title":"Effects of low-level prenatal exposure to dioxins on cognitive development in Japanese children at 42months","volume":"618","author":"Ikeno","year":"2018","journal-title":"Sci. Total Environ."},{"key":"B22","doi-asserted-by":"publisher","first-page":"5187","DOI":"10.1021\/acs.est.9b01087","article-title":"PCB emissions from paint colorants","volume":"53","author":"Jahnke","year":"2019","journal-title":"Environ. Sci. Technol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"9590","DOI":"10.1021\/es2014727","article-title":"Gas chromatographic analysis with chiral cyclodextrin phases reveals the enantioselective formation of hydroxylated polychlorinated biphenyls by rat liver microsomes","volume":"45","author":"Kania-Korwel","year":"2011","journal-title":"Environ. Sci. Technol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"3704","DOI":"10.1021\/es0602086","article-title":"Distribution of chiral PCBs in selected tissues in the laboratory rat","volume":"40","author":"Kania-Korwel","year":"2006","journal-title":"Environ. Sci. Technol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1002\/chir.20342","article-title":"Enantioselective disposition of PCB 136 (2,2 ',3,3 ',6,6 '-hexachlorobiphenyl) in C57BL\/6 mice after oral and intraperitoneal administration","volume":"19","author":"Kania-Korwel","year":"2007","journal-title":"Chirality"},{"key":"B26","doi-asserted-by":"publisher","first-page":"3163","DOI":"10.1007\/s00204-018-2285-x","article-title":"PCB 95 promotes dendritic growth in primary rat hippocampal neurons via mTOR-dependent mechanisms","volume":"92","author":"Keil","year":"2018","journal-title":"Arch. Toxicol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"7646","DOI":"10.1073\/pnas.0701944104","article-title":"Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex","volume":"104","author":"Kenet","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B28","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1002\/aja.1002030302","article-title":"Stages of embryonic development of the zebrafish","volume":"203","author":"Kimmel","year":"1995","journal-title":"Dev. Dyn."},{"key":"B29","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.devcel.2018.04.013","article-title":"Intracellular calcium mobilization is required for sonic hedgehog signaling","volume":"45","author":"Klatt Shaw","year":"2018","journal-title":"Dev. Cell"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21031013","article-title":"Evidence implicating non-dioxin-like congeners as the key mediators of polychlorinated biphenyl (PCB) developmental neurotoxicity","volume":"21","author":"Klocke","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"8105","DOI":"10.1021\/acs.est.5b01854","article-title":"Human serum from urban and rural adolescents and their mothers shows exposure to polychlorinated biphenyls not found in commercial mixtures","volume":"49","author":"Koh","year":"2015","journal-title":"Environ. Sci. Technol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.envint.2016.09.012","article-title":"Prenatal exposure to persistent organic pollutants in association with offspring neuropsychological development at 4years of age: The Rhea mother-child cohort, Crete, Greece","volume":"97","author":"Kyriklaki","year":"2016","journal-title":"Environ. Int."},{"key":"B33","doi-asserted-by":"publisher","first-page":"16508","DOI":"10.1007\/s11356-017-1162-0","article-title":"Authentication of synthetic environmental contaminants and their (bio)transformation products in toxicology: Polychlorinated biphenyls as an example","volume":"25","author":"Li","year":"2018","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"B34","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1289\/EHP277","article-title":"Polychlorinated biphenyl and organochlorine pesticide concentrations in maternal mid-pregnancy serum samples: Association with autism spectrum disorder and intellectual disability","volume":"125","author":"Lyall","year":"2017","journal-title":"Environ. Health Perspect."},{"key":"B35","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.envpol.2011.10.028","article-title":"Spatial distribution of chlordanes and PCB congeners in soil in Cedar Rapids, Iowa, USA","volume":"161","author":"Martinez","year":"2012","journal-title":"Environ. Pollut."},{"key":"B36","doi-asserted-by":"publisher","first-page":"3","DOI":"10.3389\/neuro.08.003.2009","article-title":"Comprehensive behavioral phenotyping of ryanodine receptor type 3 (RyR3) knockout mice: Decreased social contact duration in two social interaction tests","volume":"3","author":"Matsuo","year":"2009","journal-title":"Front. Behav. Neurosci."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/toxics8030070","article-title":"Polychlorinated biphenyls (PCBs): Risk factors for autism spectrum disorder?","volume":"8","author":"Panesar","year":"2020","journal-title":"Toxics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.pharmthera.2009.10.009","article-title":"Minding the calcium store: Ryanodine receptor activation as a convergent mechanism of PCB toxicity","volume":"125","author":"Pessah","year":"2010","journal-title":"Pharmacol. Ther."},{"key":"B39","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1021\/tx050196m","article-title":"Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1)","volume":"19","author":"Pessah","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1007\/s00401-019-01978-1","article-title":"Neurotoxicity of polychlorinated biphenyls and related organohalogens","volume":"138","author":"Pessah","year":"2019","journal-title":"Acta Neuropathol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1890","DOI":"10.1101\/gr.164800","article-title":"Zebrafish comparative genomics and the origins of vertebrate chromosomes","volume":"10","author":"Postlethwait","year":"2000","journal-title":"Genome Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1002\/etc.4587","article-title":"Embryonic exposure to 2,2',3,5',6-pentachlorobiphenyl (PCB-95) causes developmental malformations in zebrafish","volume":"39","author":"Ranasinghe","year":"2020","journal-title":"Environ. Toxicol. Chem."},{"key":"B43","first-page":"457","article-title":"Long-term effects of developmental exposure to 2,2',3,5',6-pentachlorobiphenyl (PCB 95) on locomotor activity, spatial learning and memory and brain ryanodine binding","volume":"18","author":"Schantz","year":"1997","journal-title":"Neurotoxicology"},{"key":"B44","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1289\/ehp.5461","article-title":"Effects of PCB exposure on neuropsychological function in children","volume":"111","author":"Schantz","year":"2003","journal-title":"Environ. Health Perspect."},{"key":"B45","doi-asserted-by":"publisher","first-page":"3948","DOI":"10.1021\/acs.est.9b00535","article-title":"Comparative analyses of the 12 most abundant PCB congeners detected in human maternal serum for activity at the thyroid hormone receptor and ryanodine receptor","volume":"53","author":"Sethi","year":"2019","journal-title":"Environ. Sci. Technol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1038\/369556a0","article-title":"Excitation-contraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene","volume":"369","author":"Takeshima","year":"1994","journal-title":"Nature"},{"key":"B47","doi-asserted-by":"publisher","first-page":"3309","DOI":"10.1093\/emboj\/17.12.3309","article-title":"Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2","volume":"17","author":"Takeshima","year":"1998","journal-title":"EMBO J."},{"key":"B48","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.cotox.2020.05.004","article-title":"Translational toxicology in zebrafish","author":"Tal","year":"2020","journal-title":"Curr. Opin. Toxicol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1016\/j.envint.2009.01.013","article-title":"Improved syntheses of non-dioxin-like polychlorinated biphenyls (PCBs) and some of their sulfur-containing metabolites","volume":"36","author":"Telu","year":"2010","journal-title":"Environ. Int."},{"key":"B50","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1007\/978-1-60761-849-2_16","article-title":"Evaluation of embryotoxicity using the zebrafish model","volume":"691","author":"Truong","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1021\/acs.chemrestox.6b00371","article-title":"2,2 ',3,5 ',6-Pentachlorobiphenyl (PCB 95) is atropselectively metabolized to para-hydroxylated metabolites by human liver microsomes","volume":"29","author":"Uwimana","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1289\/ehp.1104833","article-title":"PCB-95 modulates the calcium-dependent signaling pathway responsible for activity-dependent dendritic growth","volume":"120","author":"Wayman","year":"","journal-title":"Environ. Health Perspect."},{"key":"B53","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1289\/ehp.1104832","article-title":"PCB-95 promotes dendritic growth via ryanodine receptor-dependent mechanisms","volume":"120","author":"Wayman","year":"","journal-title":"Environ. Health Perspect."},{"key":"B54","volume-title":"The zebrafish book a guide for the laboratory use of zebrafish Danio (Brachydanio) rerio","author":"Westerfield","year":"2000"},{"key":"B55","doi-asserted-by":"publisher","first-page":"15145","DOI":"10.1074\/jbc.272.24.15145","article-title":"Ortho-substituted polychlorinated biphenyls alter microsomal calcium transport by direct interaction with ryanodine receptors of mammalian brain","volume":"272","author":"Wong","year":"1997","journal-title":"J. Biol. Chem."},{"key":"B56","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1186\/1756-0500-4-541","article-title":"Ryanodine receptors, a family of intracellular calcium ion channels, are expressed throughout early vertebrate development","volume":"4","author":"Wu","year":"2011","journal-title":"BMC Res. Notes"},{"key":"B57","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1021\/es504766p","article-title":"Hepatic metabolism affects the atropselective disposition of 2,2 ',3,3 ',6,6 '-Hexachlorobiphenyl (PCB 136) in mice","volume":"49","author":"Wu","year":"2015","journal-title":"Environ. Sci. Technol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"933","DOI":"10.3109\/00498254.2013.785626","article-title":"Metabolism of 2,2 ',3,3 ',6,6 '-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent","volume":"43","author":"Wu","year":"2013","journal-title":"Xenobiotica"},{"key":"B59","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1289\/ehp.11771","article-title":"Developmental exposure to polychlorinated biphenyls interferes with experience-dependent dendritic plasticity and ryanodine receptor expression in weanling rats","volume":"117","author":"Yang","year":"2009","journal-title":"Environ. Health Perspect."},{"key":"B60","first-page":"70","article-title":"Polychlorinated biphenyls increase apoptosis in the developing rat brain","volume":"1","author":"Yang","year":"2010","journal-title":"Curr. Neurobiol."}],"container-title":["Frontiers in Toxicology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2022.947795\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T12:50:44Z","timestamp":1665060644000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2022.947795\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,6]]},"references-count":60,"alternative-id":["10.3389\/ftox.2022.947795"],"URL":"https:\/\/doi.org\/10.3389\/ftox.2022.947795","relation":{},"ISSN":["2673-3080"],"issn-type":[{"value":"2673-3080","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,6]]},"article-number":"947795"}}