Gestational organophosphate pesticide exposure and childhood cardiovascular outcomes

Abstract

Introduction: The general population is chronically exposed to organophosphate pesticides through various routes including ingestion, hand-to-mouth contact, inhalation, and dermal contact. Exposure to organophosphate pesticides during pregnancy impairs fetal development, but the potential long-term effects of gestational organophosphate pesticide exposure are less well understood.

Methods: We investigated associations between gestational organophosphate pesticide exposure and cardiovascular outcomes in 643 children in the Generation R Study, a prospective pregnancy cohort based in Rotterdam, The Netherlands. Urinary organophosphate pesticide metabolites (dimethyl [∑DMAP], diethyl [∑DEAP], and total dialkyl phosphate [∑DAP] metabolites) were quantified in three urine samples collected from pregnant participants, and their children were followed until age 10 years at which time cardiac magnetic resonance imaging, ultrasonography, blood pressure, and serum biomarkers assessed cardiovascular health. Linear regression models estimated associations (β and 95 % confidence interval [CI]) between a one-interquartile range (IQR) increase in averaged gestational exposure biomarker concentrations and z-scored pediatric cardiovascular outcomes. We investigated effect modification of associations by PON1 genotype.

Results: Carotid intima-media thickness z-score was lower (β: -0.14 [95 % CI: -0.25, -0.02]) and HDL cholesterol z-score was higher (β: 0.14 [95 % CI: 0.02, 0.25]) for increases in ∑DEAP concentrations. Carotid intima-media distensibility z-score was lower (β: -0.08 [95 % CI: -0.19, 0.03]) for increases in ∑DMAP concentrations, and systolic blood pressure z-score was higher (β: 0.10 [95 % CI: -0.01, 0.21]) for increases in ∑DMAP and ∑DAP. Among those with PON1-161CC and PON1-L55MTT genotypes, higher organophosphate pesticide concentrations conferred an excess risk of adverse vascular and glycemic outcomes, respectively.

Conclusions: We observed heterogenous associations between gestational organophosphate pesticide exposure and pediatric cardiovascular health: an anti-atherogenic profile was observed for increases in ∑DEAP concentrations, and impairments in multiple aspects of cardiovascular health was observed for increases in ∑DMAP concentrations. PON1-161 and PON1-L55M single nucleotide polymorphisms modified associations for vascular and glycemic outcomes, respectively.

Keywords: Cardiovascular diseases; Endocrine disrupters; Gene polymorphism; Organophosphates; Pesticides; Pregnancy; Prospective Studies.

Figure 1.. Associations for gestational organophosphate pesticide biomarker concentrations and A) cardiac measures, B) vascular measures, and c) cardiovascular biomarkers in childhood in the Generation R Study sample (n=643).

Betas represent the z-score difference in pediatric outcomes at age 10 for a one-IQR increase in gestational exposure biomarker concentrations from a generalized linear regression model adjusted for maternal age, maternal ethnicity, parity, maternal BMI, maternal smoking, maternal alcohol consumption, maternal education, household income, maternal marital status, maternal folic acid supplementation, maternal fruit, vegetable, and total caloric intakes, and child’s age and sex. Abbreviations: Carotid intima-media distensibility (CIMD); Carotid intima-media thickness (CIMT); Diastolic blood pressure (DBP); High-density lipoprotein (HDL); Left ventricular end-diastolic volume (LVEDV); Left ventricular ejection fraction (LVEF); Low-density lipoprotein (LDL); Left ventricular mass (LVM); Left ventricular mass-to-volume (LVMR); Right ventricular end-diastolic volume (RVEDV); Right ventricular ejection fraction (RVEF); Single nucleotide polymorphism (SNP); Sum of diethyl metabolites ($\sum \text{DEAP}$); Sum of dimethyl metabolites ($\sum \text{DMAP}$), Sum of dimethyl and diethyl metabolites ($\sum \text{DAP}$); Systolic blood pressure (SBP)

Figure 2.. Heatmap of genotype-specific associations for gestational organophosphate pesticide biomarker concentrations and A) cardiac measures, B) vascular measures, and c) cardiovascular biomarkers in childhood in the Generation R Study sample with genotyping data (n=430).

Boxes are colored according to the significance of the SNP interaction term p-value (p-int) and the magnitude and direction of effect estimates from generalized linear regression models examining the z-score difference in pediatric outcomes at age 10 for a one-IQR increase in gestational exposure biomarker concentrations. Models were adjusted for maternal age, maternal ethnicity, parity, maternal BMI, maternal smoking, maternal alcohol consumption, maternal education, household income, maternal marital status, maternal folic acid supplementation, maternal fruit, vegetable, and total caloric intakes, and child’s age and sex. Abbreviations: Carotid intima-media distensibility (CIMD); Carotid intima-media thickness (CIMT); Diastolic blood pressure (DBP); High-density lipoprotein (HDL); Left ventricular end-diastolic volume (LVEDV); Left ventricular ejection fraction (LVEF); Low-density lipoprotein (LDL); Left ventricular mass (LVM); Left ventricular mass-to-volume (LVMR); Right ventricular end-diastolic volume (RVEDV); Right ventricular ejection fraction (RVEF); Single nucleotide polymorphism (SNP); Sum of diethyl metabolites ($\sum \text{DEAP}$); Sum of dimethyl metabolites ($\sum \text{DMAP}$), Sum of dimethyl and diethyl metabolites ($\sum \text{DAP}$); Systolic blood pressure (SBP)