title: Functional Toxicogenomic Assessment of Triclosan in Human HepG2 Cells Using Genome-Wide CRISPR-Cas9 Screening.
abstract: There are thousands of chemicals used by humans and detected in the environment for which limited or no toxicological data are available. Rapid and cost-effective approaches for assessing the toxicological properties of chemicals are needed. We used CRISPR-Cas9 functional genomic screening to identify the potential molecular mechanism of a widely used antimicrobial triclosan (TCS) in HepG2 cells. Resistant genes at IC50 (the concentration causing a 50% reduction in cell viability) were significantly enriched in the adherens junction pathway, MAPK signaling pathway, and PPAR signaling pathway, suggesting a potential role in the molecular mechanism of TCS-induced cytotoxicity. Evaluation of the top-ranked resistant genes, FTO (encoding an mRNA demethylase) and MAP2K3 (a MAP kinase kinase family gene), revealed that their loss conferred resistance to TCS. In contrast, sensitive genes at IC10 and IC20 were specifically enriched in pathways involved with immune responses, which was concordant with transcriptomic profiling of TCS at concentrations of <IC10. It is suggested that the CRISPR-Cas9 fingerprint may reveal the patterns of TCS toxicity at low concentration levels. Moreover, we retrieved the potential connection between CRISPR-Cas9 fingerprint and disease terms, obesity, and breast cancer from an existing chemical-gene-disease database. Overall, CRISPR-Cas9 functional genomic screening offers an alternative approach for chemical toxicity testing.
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University , Nanjing 210023, People's Republic of China.
authors.forename: Pu
authors.initials: P
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University , Nanjing 210023, People's Republic of China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University , Nanjing 210023, People's Republic of China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University , Nanjing 210023, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Guan
authors.affiliation: Mid-Continent Ecology Division, United States Environmental Protection Agency , Duluth, Minnesota 55804, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Villeneuve
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University , Nanjing 210023, People's Republic of China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Yu
mesh_terms: D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D056945:Hep G2 Cells; D006801:Humans; D043922:Toxicogenetics; D014260:Triclosan
chemical_list: D014260:Triclosan