Perinatal Acetaminophen Exposure and Childhood Attention-Deficit/Hyperactivity Disorder (ADHD): Exploring the Role of Umbilical Cord Plasma Metabolites in Oxidative Stress Pathways.

Neha S Anand,Ramkripa Raghavan,Colleen Pearson,Xiumei Hong,Guoying Wang,Xiaobin Wang,Romuladus E Azuine,Barry Zuckerman,Hehuang Xie

doi:10.3390/brainsci11101302

Abstract

Oxidative stress mechanisms may explain associations between perinatal acetaminophen exposure and childhood attention-deficit hyperactivity disorder (ADHD). We investigated whether the changes in umbilical cord plasma amino acids needed to synthesize the antioxidant glutathione and in the oxidative stress biomarker 8-hydroxy-deoxyguanosine may explain the association between cord plasma acetaminophen and ADHD in the Boston Birth Cohort (BBC). Mother–child dyads were followed at the Boston Medical Center between 1998 and 2018. Cord plasma analytes were measured from archived samples collected at birth. Physician diagnoses of childhood ADHD were obtained from medical records. The final sample consisted of 568 participants (child mean age [SD]: 9.3 [3.5] years, 315 (52.8%) male, 248 (43.7%) ADHD, 320 (56.3%) neurotypical development). Cord unmetabolized acetaminophen was positively correlated with methionine (R = 0.33, p < 0.001), serine (R = 0.30, p < 0.001), glycine (R = 0.34, p < 0.001), and glutamate (R = 0.16, p < 0.001). Children with cord acetaminophen levels >50th percentile appeared to have higher risk of ADHD for each increase in cord 8-hydroxy-deoxyguanosine level. Adjusting for covariates, increasing cord methionine, glycine, serine, and 8-hydroxy-deoxyguanosine were associated with significantly higher odds for childhood ADHD. Cord methionine statistically mediated 22.1% (natural indirect effect logOR = 0.167, SE = 0.071, p = 0.019) and glycine mediated 22.0% (natural indirect effect logOR = 0.166, SE = 0.078, p = 0.032) of the association between cord acetaminophen >50th percentile with ADHD. Our findings provide some clues, but additional investigation into oxidative stress pathways and the association of acetaminophen exposure and childhood ADHD is warranted.

Highlights

Acetaminophen is the most-commonly used medication during pregnancy for pain and fever [1,2]
Children with cord acetaminophen >50th percentile were significantly more likely to have childhood attention-deficit hyperactivity disorder (ADHD) diagnosis, mothers who smoked during pregnancy, and low birthweight
In adjusted regressions, increasing levels of cord methionine (aOR: 1.43, 95% CI (1.17, 1.77), p = 0.001), serine (aOR: 1.38, 95% CI (1.14, 1.68), p = 0.008), glycine (aOR: 1.38, 95% CI (1.14, 1.68), p = 0.001), and 8-hydroxy-deoxyguanosine (aOR: 1.24, 95% CI (1.01, 1.52), p = 0.039) were associated with higher odds of ADHD as well but not cord glutamate

Summary

Introduction

Acetaminophen is the most-commonly used medication during pregnancy for pain and fever [1,2]. Studies in Europe, Asia, and the United States have associated perinatal acetaminophen exposure with increased risk of childhood neurodevelopmental disorders [5,6,7,8,9,10,11,12,13,14,15,16,17,18]. Gervin et al found differences in DNA methylation in cord blood samples between children with ADHD versus controls, which were associated with prenatal exposure to acetaminophen for more than 20 days. These differences were found in genes linked to ADHD, neural development, neurotransmission, and pathways involving oxidative stress and the olfactory sensory system. To date, there have been no studies in humans of biomarkers of metabolic pathways hypothesized to explain the association

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