Maternal exposure to organophosphate pesticides such as diazinon during pregnancy was correlated with ADHD symptoms in their children five years later, researchers said.
Led by Brenda Eskenazi, PhD, of the University of California in Berkeley, the researchers also identified genetic variants that may make children more susceptible to neurodevelopmental abnormalities from exposure to organophosphates.
The studies, published online in Environmental Health Perspectives, add to a growing body of evidence linking the chemicals to ADHD and other developmental problems.
Organophosphates — a group of compounds that also include the sarin and VX nerve gases — irreversibly inhibit acetylcholinesterase. Those used as commercial insecticides have low potency and degrade rapidly in the environment, but human toxicity from acute exposure is well established. Whether low-level chronic exposures also can affect human health has been debated.
Earlier this year, a different group of researchers reported that children with high levels of dialkyl phosphate metabolites — an objective measure of organophosphate exposure — had a significantly increased the likelihood of an ADHD diagnosis.
Eskenazi and colleagues noted that prenatal exposure is also a concern, because disruption of acetylcholine signalling in the developing brain could have permanent consequences.
They investigated the relationship in more than 300 Mexican-American children in the heavily agricultural Salinas Valley of California, part of a prospective birth cohort study called CHAMACOS investigating relationships between environmental exposures and the health of pregnant women and their offspring.
Mothers in the study had urine levels of dialkyl phosphate metabolites measured during pregnancy and completed standard questionnaires on their children’s behavior when the latter reached 42 months of age and again at 60 months.
The investigators also directly assessed the children at both ages, and an independent psychometric evaluation was performed at 60 months.
Behavioral data were available for 329 children at age 42 months and 322 at 60 months.
There was no significant relationship between prenatal organophosphate exposure and behavioral problems at the first evaluation, but at age 60 months there was a strong correlation.
For each 10-fold increase in prenatal urine levels of dialkyl phosphate metabolites, the odds ratio of ADHD, according to combined scores on the three instruments, was 3.6 (95% CI 1.2 to 11.0) after adjusting for potential confounders such as childcare, breastfeeding, and maternal education.
The effect was largely confined to boys in the sample. Their odds ratio for ADHD according to the combined indicator was 13.2 (95% CI 2.0 to 86.5) compared with 1.2 (95% CI 0.2 to 7.1) in girls.
Behavioral results did not correlate with dialkyl phosphate metabolites in the children’s urine.
Eskenazi and colleagues also performed a genotype analysis in 353 children in the CHAMACOS cohort for genomic variants in the PON1 promoter region. The main PON1 gene encodes an enzyme called paraoxonase-1, functions of which include breakdown of organophosphates in vivo.
Polymorphisms in this gene had previously been linked to a variety of neurological illnesses including Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, and brain tumors.
When evaluated at age 2, children carrying a PON1 promoter variant called -108T had lower scores on the Mental Development Index and the Psychomotor Development Index.
Those with one -108T allele had mean deficits of 3.9 and 1.4 points on the two instruments, respectively, compared with children homozygous for the -108C variant. Children homozygous for the -108T variant had mean deficits of 5.7 and 2.8 points, respectively.
Only the differences in the Mental Development Index reached statistical significance, however (P<0.01). Children with one or two -108T alleles also showed nonsignificant trends toward higher scores for pervasive development disorder extracted from mothers' responses to the Child Behavior Checklist. High pervasive developmental disorder scores were less likely when they showed signs of greater functionality in the PON1 gene product, exemplified by greater activity of paraoxonase and a related enzyme, arylesterase. The researchers found a hint that responses to prenatal organophosphate exposure may differ according to PON1 genotype. Maternal dialkyl phosphate metabolites in urine during pregnancy were weakly correlated with Mental Development Scores in their 2-year-old offspring. "The association ... was strongest in children with [the -108T] allele," the researchers indicated, but it still fell short of statistical significance. "Additional research is needed to confirm if [PON1] modifies the relation with in utero organophosphate exposure," Eskenazi and colleagues wrote. "We do observe a consistent trend and our results need replication in other populations and perhaps pooling with similar studies to provide adequate sample sizes," they added. The authors noted that both studies were limited by measurement of urine dialkyl phosphate metabolites, which are "an imperfect measure of exposure" since organophosphates break down quickly in the human body. source: Environmental Health Perspectives