Prenatal Pyrethroid Exposure, Placental Gene Network Modules, and Neonatal Neurobehavior

Abstract

Prenatal pesticide exposure may adversely affect child neurodevelopment, and this may partly arise from impairing the placenta's vital role in fetal development. In a cohort of pregnant farmworkers from Thailand (N=248), we examined the links between urinary metabolites of pyrethroid pesticides during pregnancy, placental gene expression networks derived from transcriptome sequencing, and newborn neurobehavior assessed using the NICU Network Neurobehavioral Scales (NNNS) at 5 weeks of age. The urinary concentrations of cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA) during pregnancy were found to be significantly positively correlated with the NNNS scores for attention (β = 0.49, p = 0.005), handling (β = 1.04, p = 0.04), and excitability (β = 0.15, p = 0.02). The urinary concentrations of trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (trans-DCCA) also showed a significant positive association with attention (β = 0.49, p = 0.01). Focusing on the 21 gene network modules in the placenta identified by Weighted Gene Co-expression Network Analysis (WGCNA), our analysis revealed significant associations between metabolites and nine distinct modules, and between thirteen modules and NNNS, with eight modules showing overlap. Notably, stress was negatively associated with the middleblue module (interferon alpha response) and the salmon module (Myc target). The middleblue module was correlated with attention, arousal, and quality of movement. The analysis also highlighted the first and third trimesters as critical periods for the influence of exposures on placental function, with pyrethroid metabolites measured early in pregnancy significantly negatively associated with the turquoise module (protein secretion), and those measured later in pregnancy having negative associations with modules related to Oxidative Phosphorylation (OXPHOS) and DNA repair. Additionally, the cumulative sum of 3PBA across pregnancy was significantly negatively associated with the lightyellow module (OXPHOS). These findings suggest that prenatal exposure to pyrethroid pesticides may influence neonatal neurobehavior through specific placental mechanisms that impact gene expression and metabolic pathway, and that the effects of environmental pyrethroid exposures on fetal neurodevelopment varies throughout pregnancy. These results offer valuable insights for future risk assessment and intervention strategies.