Prenatal exposure to organophosphates, paraoxonase 1, and cognitive development in childhood

Abstract

Background: Prenatal exposure to organophosphate pesticides has been shown to negatively affect child neurobehavioral development. Paraoxonase 1 (PON1) is a key enzyme in the metabolism of organophosphates.

Objective: We examined the relationship between biomarkers of organophosphate exposure, PON1, and cognitive development at ages 12 and 24 months and 6-9 years.

Methods: The Mount Sinai Children's Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urine samples were collected and analyzed for organophosphate metabolites (n = 360). Prenatal maternal blood was analyzed for PON1 activity and genotype. Children returned for neurodevelopment assessments ages 12 months (n = 200), 24 months (n = 276), and 6-9 (n = 169) years of age.

Results: Prenatal total dialkylphosphate metabolite level was associated with a decrement in mental development at 12 months among blacks and Hispanics. These associations appeared to be enhanced among children of mothers who carried the PON1 Q192R QR/RR genotype. In later childhood, increasing prenatal total dialkyl- and dimethylphosphate metabolites were associated with decrements in perceptual reasoning in the maternal PON1 Q192R QQ genotype, which imparts slow catalytic activity for chlorpyrifos oxon, with a monotonic trend consistent with greater decrements with increasing prenatal exposure.

Conclusion: Our findings suggest that prenatal exposure to organophosphates is negatively associated with cognitive development, particularly perceptual reasoning, with evidence of effects beginning at 12 months and continuing through early childhood. PON1 may be an important susceptibility factor for these deleterious effects.

Figure 1

Multivariate adjusted mean estimates and 95% CIs according to tertiles (T) of exposure and PON1 Q192R genotype. Among the children of mothers with the PON1 192QQ genotype (triangles), increasing tertile of ΣDAP, ΣDEP, and ΣDMP exposure was generally associated with a monotonic decline in the combined WISC-IV/WPPSI-III FSIQ and Perceptual Reasoning domains, adjusted for sex, race/ethnicity, maternal education, language in the home, alcohol use in pregnancy, batch and season of urine collection, urinary creatinine, and an indicator variable to designate the WISC-IV or WPPSI-III instrument. We found no consistent patterns in the QR/RR genotype group (squares). There was considerable imprecision in all estimates. The first- versus third-tertile contrasts for Perceptual Reasoning were significantly different at p < 0.05 for ΣDAP and ΣDMP.