es6b02328_si_001.pdf (2.27 MB)
Functional Toxicogenomic Assessment of Triclosan in Human HepG2 Cells Using Genome-Wide CRISPR-Cas9 Screening
journal contribution
posted on 2016-07-26, 00:00 authored by Pu Xia, Xiaowei Zhang, Yuwei Xie, Miao Guan, Daniel L. Villeneuve, Hongxia YuThere
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