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Genetic Polymorphisms in Nuclear Receptors Drive Variations in Responses to Environmental Exposures.

Shaoqi Zuo1, Kun Zhang1, Jiayin Dai1

  • 1State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.

Environmental Science & Technology
|September 11, 2025
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Summary

Single nucleotide polymorphisms (SNPs) influence how individuals respond to environmental chemicals by altering nuclear receptor functions. Genetic variations in nuclear receptors impact susceptibility to environmental exposures, affecting population health.

Keywords:
allele frequency distributionbinding activityenvironmental exposureligand-binding domainnuclear receptorsingle nucleotide polymorphism

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Area of Science:

  • Genomics
  • Environmental Toxicology
  • Molecular Biology

Background:

  • Single nucleotide polymorphisms (SNPs) are known to affect drug responses and disease susceptibility.
  • The role of SNPs in mediating environmental responses, particularly through nuclear receptors (NRs), is largely unexplored.

Purpose of the Study:

  • To systematically investigate the impact of SNPs within the ligand-binding domains (LBDs) of 48 NRs on receptor-ligand interactions.
  • To assess how these genetic variations influence responses to environmental chemicals.

Main Methods:

  • Integrated genomic databases to identify missense SNPs (minor allele frequency >0.001) in NR LBDs.
  • Employed structure-based molecular docking to evaluate changes in ligand-binding affinity.
  • Performed functional validation assays to assess transcriptional activity of variant receptors.

Main Results:

  • Identified 27 missense SNPs across NR LBDs with significant variations in ligand-binding affinities compared to wild-type receptors.
  • Demonstrated altered transcriptional activity for estrogen-related receptor alpha (ERRα) and retinoid X receptor alpha (RXRα) variants in response to environmental chemicals.
  • Observed divergent responses to modulators for ERRα variants and attenuated activation for RXRα variants, especially to organotin compounds.

Conclusions:

  • SNPs in NR LBDs play a critical role in modulating individual and population-level responses to environmental exposures.
  • Genetic variations can lead to differential susceptibility to environmental chemicals.
  • Incorporating SNP data into toxicological risk assessment is crucial for understanding environmental health impacts.