Prenatal Exposure to Organophosphate Ester Flame Retardants and Plasticizers (OPEs), Gene-Environment Interaction, and Child Neurodevelopment

The prevalence of autism and attention-deficit/hyperactivity disorder (ADHD) is increasing, yet their etiology is poorly understood. A complex combination of environmental and genetic factors appears to contribute to both conditions but most studies to date have examined these factors in isolation. The incomplete study of gene- environment (GxE) interactions in autism and ADHD remains a significant barrier to progress in understanding their etiology. Many endocrine-disrupting chemicals (EDCs) appear to be neurotoxic and their role in the development of autism and ADHD merits closer scrutiny. Organophosphate ester flame retardants and plasticizers (OPEs) are EDCs of emerging concern, with human exposures increasing rapidly when they replaced polybrominated diphenyl ethers (PBDE) flame retardants starting in the early 2000s. Mounting human evidence suggests that OPE exposure during pregnancy is detrimental to child neurodevelopment. Studies specifically linking prenatal OPE exposure to autism and ADHD related outcomes are concerning; these associations warrant closer examination. Notably, earlier studies of OPEs and neurodevelopment did not consider genetic susceptibility, a concerning knowledge gap that potentially obscures subgroups more sensitive to OPEs. Genetics may modify sensitivity to chemicals by shaping the efficiency of a person’s metabolism of xenobiotics or making certain physiologic pathways more susceptible to exogenous disruption. The proposed study seeks to build on this previous literature and further explore factors that modulate sensitivity to prenatal OPE exposure in the context of child neurodevelopment. Specifically, we propose a novel investigation of the genetic underpinnings of the association of prenatal OPE exposure and child autism and ADHD using the rich and complementary data resources of two cohorts: 1) the diverse participant population of the NIH Environmental Influences on Child Health Outcomes (ECHO) Cohort, which has a large sample size and OPEs measured at one time point during pregnancy and 2) the Kaiser Permanente PETALS cohort, a smaller, diverse cohort with OPEs measured at two pregnancy time points. Our overarching hypothesis is that genetic variation across the genome, potentially in genes critical to neurodevelopment and xenobiotic metabolism, may make some individuals more susceptible to OPE neurotoxicity during the prenatal period. In Aim 1 we will perform a novel genome-wide by environment interaction study (GWEIS) of maternal and child genetics and levels of urinary OPE exposure during pregnancy in relation to child neurodevelopment; Aim 2 will harness polygenic scores (PGS) for autism and ADHD to examine modification of the OPE and child outcomes relationship. In Aim 3, we will replicate and expand on findings from ECHO in the PETALS cohort. The proposed work will lay the groundwork for continued study of GxE with respect to OPEs which could be used to inform policies to protect susceptible subgroups and identify modifiable environmental risk factors to lessen the disability associated with child autism, ADHD, and other neurodevelopmental conditions. Project Number: 1R01ES037332-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Jennifer Ames | Institution: KAISER FOUNDATION RESEARCH INSTITUTE, Oakland, CA | Award Amount: $699,956 | Activity Code: R01 | Study Section: Reproductive, Perinatal and Pediatric Health Study Section[RPPH] View on NIH RePORTER: https://reporter.nih.gov/project-details/11105648