Identification of Functional Genetic Components Modulating Toxicity Response to PFOS using Genome-wide CRISPR Screens...

Area of Science:

• Toxicology
• Genomics
• Environmental Health

Background:

• Perfluorooctane sulfonate (PFOS) is a persistent environmental contaminant linked to liver toxicity.
• The precise molecular mechanisms underlying PFOS-induced adverse effects remain unclear.

Purpose of the Study:

• To identify genes and pathways that modulate PFOS-induced cytotoxicity using genome-wide CRISPR screens.
• To elucidate novel mechanisms of PFOS toxicity and identify potential therapeutic targets.

Main Methods:

• Genome-wide CRISPR knockout screens were performed in HepG2/C3A human liver cells exposed to PFOS.
• Candidate genes, including SLC6A9 (GlyT1) and CPSF2, were validated through individual disruption.
• Molecular docking, gene-disease association, pathway enrichment, and cross-species conservation analyses were conducted.

Main Results:

• 340 candidate genes influencing PFOS cytotoxicity were identified; 189 increased sensitivity and 151 increased resistance.
• Disruption of SLC6A9 (GlyT1) and CPSF2 conferred resistance to PFOS.
• PFOS was predicted to directly bind GlyT1, and GlyT1 inhibition increased PFOS resistance.
• Enrichment analysis revealed pathways related to DNA damage response and cell cycle, with associations to cancer and liver diseases.

Conclusions:

• This study identifies key genes and pathways involved in PFOS-induced cytotoxicity, offering new mechanistic insights.
• SLC6A9 (GlyT1) is a potential direct target for mitigating PFOS toxicity.
• Findings provide a foundation for cross-species toxicogenomic modeling of PFOS health effects.