PMID- 33333158 OWN - NLM STAT- MEDLINE DCOM- 20211028 LR - 20240331 IS - 1873-1708 (Electronic) IS - 0890-6238 (Print) IS - 0890-6238 (Linking) VI - 100 DP - 2021 Mar TI - Exposure to human relevant mixtures of halogenated persistent organic pollutants (POPs) alters neurodevelopmental processes in human neural stem cells undergoing differentiation. PG - 17-34 LID - S0890-6238(20)30286-0 [pii] LID - 10.1016/j.reprotox.2020.12.013 [doi] AB - Halogenated persistent organic pollutants (POPs) like perfluorinated alkylated substances (PFASs), brominated flame retardants (BFRs), organochlorine pesticides and polychlorinated biphenyls (PCBs) are known to cause cancer, immunotoxicity, neurotoxicity and interfere with reproduction and development. Concerns have been raised about the impact of POPs upon brain development and possibly neurodevelopmental disorders. The developing brain is a particularly vulnerable organ due to dynamic and complex neurodevelopmental processes occurring early in life. However, very few studies have reported on the effects of POP mixtures at human relevant exposures, and their impact on key neurodevelopmental processes using human in vitro test systems. Aiming to reduce this knowledge gap, we exposed mixed neuronal/glial cultures differentiated from neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) to reconstructed mixtures of 29 different POPs using concentrations comparable to Scandinavian human blood levels. Effects of the POP mixtures on neuronal proliferation, differentiation and synaptogenesis were evaluated using in vitro assays anchored to common key events identified in the existing developmental neurotoxicity (DNT) adverse outcome pathways (AOPs). The present study showed that mixtures of POPs (in particular brominated and chlorinated compounds) at human relevant concentrations increased proliferation of NSCs and decreased synapse number. Based on a mathematical modelling, synaptogenesis and neurite outgrowth seem to be the most sensitive DNT in vitro endpoints. Our results indicate that prenatal exposure to POPs may affect human brain development, potentially contributing to recently observed learning and memory deficits in children. CI - Copyright (c) 2020 The Author(s). Published by Elsevier Inc. All rights reserved. FAU - Davidsen, Nichlas AU - Davidsen N AD - Department of Environmental Health, Section for Toxicology and Risk Assessment, Norwegian Institute of Public Health, Oslo, Norway. FAU - Lauvas, Anna Jacobsen AU - Lauvas AJ AD - Department of Environmental Health, Section for Toxicology and Risk Assessment, Norwegian Institute of Public Health, Oslo, Norway. FAU - Myhre, Oddvar AU - Myhre O AD - Department of Environmental Health, Section for Toxicology and Risk Assessment, Norwegian Institute of Public Health, Oslo, Norway. FAU - Ropstad, Erik AU - Ropstad E AD - Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Oslo, Norway. FAU - Carpi, Donatella AU - Carpi D AD - European Commission, Joint Research Centre (JRC), Ispra, Italy. FAU - Gyves, Emilio Mendoza-de AU - Gyves EM AD - European Commission, Joint Research Centre (JRC), Ispra, Italy. FAU - Berntsen, Hanne Friis AU - Berntsen HF AD - Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Oslo, Norway; National Institute of Occupational Health, Oslo, Norway. FAU - Dirven, Hubert AU - Dirven H AD - Department of Environmental Health, Section for Toxicology and Risk Assessment, Norwegian Institute of Public Health, Oslo, Norway. FAU - Paulsen, Ragnhild E AU - Paulsen RE AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Norway. FAU - Bal-Price, Anna AU - Bal-Price A AD - European Commission, Joint Research Centre (JRC), Ispra, Italy. FAU - Pistollato, Francesca AU - Pistollato F AD - European Commission, Joint Research Centre (JRC), Ispra, Italy. Electronic address: francesca.pistollato@ec.europa.eu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201214 PL - United States TA - Reprod Toxicol JT - Reproductive toxicology (Elmsford, N.Y.) JID - 8803591 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Receptors, Aryl Hydrocarbon) RN - 7171WSG8A2 (BDNF protein, human) SB - IM MH - Brain/drug effects/growth & development MH - Brain-Derived Neurotrophic Factor/analysis MH - Cell Differentiation/*drug effects MH - Female MH - Gene Expression/drug effects MH - *Halogenation MH - Humans MH - Models, Theoretical MH - Neural Stem Cells/chemistry/*physiology MH - Neurites/drug effects MH - Neurodevelopmental Disorders/chemically induced MH - Persistent Organic Pollutants/blood/*toxicity MH - Pregnancy MH - Prenatal Exposure Delayed Effects MH - Receptors, Aryl Hydrocarbon/genetics MH - Synapses/*physiology PMC - PMC7992035 OTO - NOTNLM OT - Aryl hydrocarbon receptor OT - Developmental neurotoxicity OT - Human neural stem cells OT - Mathematical modelling OT - Neurite outgrowth OT - Persistent organic pollutants OT - Synaptogenesis COIS- The authors report no declarations of interest. EDAT- 2020/12/18 06:00 MHDA- 2021/10/29 06:00 PMCR- 2021/03/01 CRDT- 2020/12/17 20:11 PHST- 2020/04/05 00:00 [received] PHST- 2020/12/03 00:00 [revised] PHST- 2020/12/11 00:00 [accepted] PHST- 2020/12/18 06:00 [pubmed] PHST- 2021/10/29 06:00 [medline] PHST- 2020/12/17 20:11 [entrez] PHST- 2021/03/01 00:00 [pmc-release] AID - S0890-6238(20)30286-0 [pii] AID - 10.1016/j.reprotox.2020.12.013 [doi] PST - ppublish SO - Reprod Toxicol. 2021 Mar;100:17-34. doi: 10.1016/j.reprotox.2020.12.013. Epub 2020 Dec 14.