A pathway-based genetic score for inflammation: An indicator of vulnerability to phthalate-induced adverse neurodevelopment outcomes

Introduction: Phthalates, chemical additives used to enhance plastic products' flexibility, are easily released into the environment, and can harm the brain development through various mechanisms including inflammation. Genetic variation influencing an individual's susceptibility to inflammation may play a role in the effects of phthalate exposure on neurodevelopment however there is no summary measure developed for genetic susceptibility to inflammation. Methods: We developed a genetic pathway function score for inflammation (gPFSⁱⁿ), based on the transcriptional activity of the inflammatory response pathway in the brain and other tissues. Using the Barwon Infant Study (a birth cohort of n = 1074), we examined the connection between gPFSⁱⁿ and key neurodevelopmental outcomes, along with the interplay between prenatal phthalate levels, children's genetic susceptibility to inflammation (gPFSⁱⁿ), and adverse neurodevelopmental outcomes. Results: Regression techniques revealed consistent associations between gPFSⁱⁿ-phthalate combinations and key neurodevelopmental outcomes. A high gPFSⁱⁿ score was associated with an increased risk of doctor-diagnosed Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) by age 11.5 years, with adjusted odds ratios of 2.15 (p = 0.039) and 2.42 (p = 0.005), respectively. Furthermore, individuals with both high gPFSⁱⁿ and prenatal phthalate exposure exhibited more neurodevelopmental problems. This included associations of high gPFSⁱⁿ and bis(2-ethylhexyl) phthalate (DEHP) levels with parent-reported ASD traits and doctor-diagnosed ASD. The attributable proportions due to this interaction were 0.39 (p = 0.045) and 0.37 (p = 0.037), respectively. Conclusion: These findings contribute to the evidence linking gestational phthalate exposure and inflammation to adverse neurodevelopment and underscoring increased risks in children with higher genetic susceptibility to inflammation.