Author:
Arora Abishek,Becker Martin,Marques Cátia,Oksanen Marika,Li Danyang,Mastropasqua Francesca,Watts Michelle Evelyn,Arora Manish,Falk Anna,Daub Carsten Oliver,Lanekoff Ingela,Tammimies Kristiina
Abstract
AbstractResearch continues to identify genetic variation, environmental exposures, and their mixtures underlying different diseases and conditions. There is a need for screening methods to understand the molecular outcomes of such factors. Here, we investigate a highly efficient and multiplexable, fractional factorial experimental design (FFED) to study six environmental factors (lead, valproic acid, bisphenol A, ethanol, fluoxetine hydrochloride and zinc deficiency) and four human induced pluripotent stem cell line derived differentiating human neural progenitors. We showcase the FFED coupled with RNA-sequencing to identify the effects of low-grade exposures to these environmental factors and analyse the results in the context of autism spectrum disorder (ASD). We performed this after 5-day exposures on differentiating human neural progenitors accompanied by a layered analytical approach and detected several convergent and divergent, gene and pathway level responses. We revealed significant upregulation of pathways related to synaptic function and lipid metabolism following lead and fluoxetine exposure, respectively. Moreover, fluoxetine exposure elevated several fatty acids when validated using mass spectrometry-based metabolomics. Our study demonstrates that the FFED can be used for multiplexed transcriptomic analyses to detect relevant pathway-level changes in human neural development caused by low-grade environmental risk factors. Future studies will require multiple cell lines with different genetic backgrounds for characterising the effects of environmental exposures in ASD.
Funder
Vetenskapsrådet
Stiftelsen för Strategisk Forskning
Hjärnfonden
Harald och Greta Jeanssons Stiftelse
Åke Wiberg Stiftelse
Strategic Research Area Neuroscience Stratneuro
Swedish Foundation for International Cooperation in Research and Higher Education
Karolinska Institutet
Karolinska Institute
Publisher
Springer Science and Business Media LLC
Cited by
1 articles.
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