Construction, evaluation, and AOP framework-based application of the EpPRS as a genetic surrogate for assessing environmental pollutants

Silu Chen; Junyi Xin; Zhutao Ding; Lingyan Zhao; Shuai Ben; Rui Zheng; Shuwei Li; Huiqin Li; Wei Shao; Yifei Cheng; Zhengdong Zhang; Mulong Du; Meilin Wang

doi:10.1016/j.envint.2023.108202

Construction, evaluation, and AOP framework-based application of the EpPRS as a genetic surrogate for assessing environmental pollutants

Environ Int. 2023 Oct:180:108202. doi: 10.1016/j.envint.2023.108202. Epub 2023 Sep 12.

Authors

Silu Chen¹, Junyi Xin², Zhutao Ding¹, Lingyan Zhao¹, Shuai Ben¹, Rui Zheng¹, Shuwei Li¹, Huiqin Li³, Wei Shao¹, Yifei Cheng¹, Zhengdong Zhang¹, Mulong Du³, Meilin Wang⁴

Affiliations

¹ Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
² Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China.
³ Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
⁴ Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China; The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China. Electronic address: mwang@njmu.edu.cn.

PMID: 37734146
DOI: 10.1016/j.envint.2023.108202

Abstract

Background: Environmental pollutant measurement is essential for accurate health risk assessment. However, the detection of humans' internal exposure to pollutants is cost-intensive and consumes time and energy. Polygenic risk scores (PRSs) have been widely applied in genetic studies of complex trait diseases. It is important to construct a genetically relevant environmental surrogate for pollutant exposure and to explore its utility for disease prediction and risk assessment.

Objectives: This study enrolled 714 individuals with complete genomic data and exposomic data on 22 plasma-persistent organic pollutants (POPs).

Methods: We first conducted 22 POP genome-wide association studies (GWAS) and constructed the corresponding environmental pollutant-based PRS (EpPRS) by clumping and P value thresholding (C + T), lassosum, and PRS-CS methods. The best-fit EpPRS was chosen by its regression R². An adverse outcome pathway (AOP) framework was developed to assess the effects of contaminants on candidate diseases. Furthermore, Mendelian randomization (MR) analysis was performed to explore the causal association between POPs and cancer risk.

Results: The C + T method produced the best-performing EpPRSs for 7 PCBs and 4 PBDEs. EpPRSs replicated the correlations of environmental exposure measurements based on consistent patterns. The diagnostic performance of type 2 diabetes mellitus (T2DM) PRS was improved by the combined model of T2DM-EpPRS of PCB126/BDE153. Finally, the AKT1-mediated AOP framework illustrated that PCB126 and BDE153 may increase the risk of T2DM by decreasing AKT1 phosphorylation through the cGMP-PKG pathway and promoting abnormal glucose homeostasis. MR analysis showed that digestive system tumors, such as colorectal cancer and biliary tract cancer, are more sensitive to POP exposure.

Conclusions: EpPRSs can serve as a proxy for assessing pollutant internal exposure. The application of the EpPRS to disease risk assessment can reveal the toxic pathway and mode of action linking exposure and disease in detail, providing a basis for the development of environmental pollutant control strategies.

Keywords: Adverse outcome pathway; Environmental pollutant-based polygenic risk score; Persistent organic pollutants; Risk assessment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adverse Outcome Pathways*
Diabetes Mellitus, Type 2*
Environmental Exposure / adverse effects
Environmental Exposure / analysis
Environmental Pollutants* / analysis
Genome-Wide Association Study
Humans

Substances

Environmental Pollutants
3,4,5,3',4'-pentachlorobiphenyl