Identification of the mechanisms underlying per- and polyfluoroalkyl substance-induced hippocampal neurotoxicity as determined by network pharmacology and molecular docking analyses

Shirui Li; Zhihui Gao; Meihan Zhong; Haoran Bi; Jianan Li

doi:10.1093/toxres/tfad104

Identification of the mechanisms underlying per- and polyfluoroalkyl substance-induced hippocampal neurotoxicity as determined by network pharmacology and molecular docking analyses

Toxicol Res (Camb). 2023 Nov 7;12(6):1126-1134. doi: 10.1093/toxres/tfad104. eCollection 2023 Dec.

Authors

Shirui Li¹, Zhihui Gao¹, Meihan Zhong¹, Haoran Bi¹, Jianan Li²

Affiliations

¹ Department of Biostatistics, College of Public Health, Xuzhou Medical University, 209 Tongshan Road, Yun Long District, Xuzhou 221000, China.
² Department of Occupational and Environmental Health, College of Public Health, Xuzhou Medical University, 209 Tongshan Road, Yun Long District, Xuzhou 221000, China.

PMID: 38145100
PMCID: PMC10734622 (available on 2024-11-07)
DOI: 10.1093/toxres/tfad104

Abstract

Background: Per- and polyfluoroalkyl substances (PFASs) are a class of environmental contaminants that pose significant health risks to both animals and humans. Although the hippocampal neurotoxic effects of numerous PFASs have been reported, the underlying mechanisms of combined exposure to PFASs-induced hippocampal neurotoxicity remain unclear.

Methods: In this study, network pharmacology analysis was performed to identify the intersectional targets of PFASs for possible associations with hippocampal neurotoxicity. The evaluation of the influence of PFASs on intersectional targets was assessed using a weighted method. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the screened targets were performed, the intersected hub targets calculated by various algorithms were screened in the network and molecular docking was also used to analyze binding activities.

Results: Our results indicated that eight PFASs, which acted on key targets (MYC, ESR1, STAT3, RELA, MAPK3) impacted the NF-κB signaling pathway, STAT3 signaling pathway, and MAPK signaling pathways to exert neurotoxicity in the hippocampus. The molecular docking results revealed that PFASs have strong binding potential to the hub targets.

Conclusions: Our findings provided a basis for future studies to investigate the detailed mechanisms of PFASs-induced hippocampal neurotoxicity and to develop preventative and control strategies.

Keywords: hippocampal neurotoxicity; molecular docking; network pharmacology; neurotoxic mechanisms; per- and polyfluoroalkyl substances.