The associations among organophosphate pesticide exposure, oxidative stress, and genetic polymorphisms of paraoxonases in children with attention deficit/hyperactivity disorder

Chia-Huang Chang; Ching-Jung Yu; Jung-Chieh Du; Hsien-Chih Chiou; Jia-Woei Hou; Winnie Yang; Chian-Feng Chen; Hsin-Chang Chen; Ying-Sheue Chen; Betau Hwang; Mei-Lien Chen

doi:10.1016/j.scitotenv.2021.145604

The associations among organophosphate pesticide exposure, oxidative stress, and genetic polymorphisms of paraoxonases in children with attention deficit/hyperactivity disorder

Sci Total Environ. 2021 Jun 15:773:145604. doi: 10.1016/j.scitotenv.2021.145604. Epub 2021 Feb 4.

Authors

Affiliations

¹ School of Public Health, Taipei Medical University, Taipei, Taiwan.
² Institute of Environmental and Occupational Health Sciences, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
³ Department of Pediatrics, Taipei City Hospital, Zhongxiao Branch, Taipei, Taiwan.
⁴ Department of Child and Adolescent Psychiatry, Taipei City Hospital, Songde Branch, Taipei, Taiwan.
⁵ Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan.
⁶ Department of Pediatrics, Taipei City Hospital, Yangming Branch, Taipei, Taiwan.
⁷ VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
⁸ Institute of Food Safety and Health, National Taiwan University, Taipei, Taiwan.
⁹ Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁰ Institute of Environmental and Occupational Health Sciences, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. Electronic address: mlchen7239@gmail.com.

PMID: 33592467
DOI: 10.1016/j.scitotenv.2021.145604

Abstract

This study will help to clarify the relationship between organophosphate pesticides (OPs) and attention deficit/hyperactivity disorder (ADHD) related to oxidative stress and paraoxonases (PON) polymorphisms to further characterize the gene-environment interaction. This case-control study enrolled 85 children with ADHD and 96 control subjects. Urinary OP levels were analyzed by using gas chromatography-mass spectrometry (GC-MS). Oxidative stress biomarkers, such as 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2-Gua), 8-iso-prostaglandin F2α (8-iso-PGF2α), and 4-hydroxy-2-nonenoic acid-mercapturic acid (HNE-MA), were analyzed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S) were calculated to evaluate the additive interactions between OP exposure and PON genetic polymorphism on ADHD. A causal mediation analysis was conducted to clarify the mediation effects of oxidative stress due to OP exposure on ADHD. Children with ADHD had significantly higher DMP (238.95 nmol/g cre. vs. 164.83 nmol/g cre., p value = 0.01) and HNE-MA (30.75 μg/g cre. vs. 18.41 μg/g cre., p value<0.01) concentrations than control children. Children who carried the PON1 GG genotype (rs705379) had low urinary DMP levels, and the level increased with increasing numbers of allele variants. The risk for developing ADHD reached 2.06-fold (OR = 2.06, 95% CI:1.23-3.44) and 1.43-fold (OR = 1.45, 95% CI:1.04-2.03) when the DMP and HNE-MA levels increased by 1 natural log of the concentration, respectively. The estimated AP value was 0.66 (95% CI: 0.17-1.15), indicating that 66% of ADHD cases in DMP-exposed children with the PON1 CT/TT (rs705381) genotype were due to gene-environment interactions. No significant mediation of HNE-MA was observed between DMP exposure and the risk of ADHD. The estimated proportion mediated was only 7.0% (95% CI: -0.08-0.46). This research suggests the role of OP exposure in the occurrence of ADHD after adjusting for covariates.

Keywords: Additive interaction; Attention deficit/hyperactivity disorder; Organophosphate pesticides; Oxidative stress; Paraoxonases.

MeSH terms

Aryldialkylphosphatase* / genetics
Attention Deficit Disorder with Hyperactivity* / chemically induced
Attention Deficit Disorder with Hyperactivity* / epidemiology
Attention Deficit Disorder with Hyperactivity* / genetics
Case-Control Studies
Child
Chromatography, Liquid
Humans
Organophosphates / adverse effects
Oxidative Stress
Polymorphism, Genetic
Tandem Mass Spectrometry

Substances

Organophosphates
Aryldialkylphosphatase
PON1 protein, human