The combined associations of mercury exposure and DNA methylation with sustained attention in children

BACKGROUND AND AIM: Attention deficit disorder (ADHD) is one of the world’s most common neurodevelopmental disorders, yet the etiology is not well-understood. Childhood DNA methylation (DNAm) patterns and exposure to methylmercury have both been implicated in the development of ADHD, though simultaneous assessments of these factors are rare. This study leverages the ELEMENT (Early Life Exposures in Mexico to Environmental Toxicants) cohort to identify the associations of childhood mercury exposure and DNAm with sustained attention in adolescence, and how these associations differ by sex. METHODS: Total mercury was measured in hair and urine from ELEMENT participants aged 6-12, reflecting organic and inorganic sources respectively. Children were followed on average 5.6 years, when adolescent DNAm was quantified in blood leukocytes via the Infinium EPIC array. Conners Continuous Performance Test (CPT3) was used to quantify measures of inattention, impulsivity, sustained attention, and vigilance. Linear regression was used to assess relationships between mercury biomarkers and CPT3 outcomes (N=399). In an epigenome-wide association study, we examined associations between adolescent DNAm and CPT3 performance (N=517). All analyses were adjusted for age, sex, socioeconomic status, and response style in adolescence. RESULTS: Childhood hair and specific gravity-adjusted urine mercury averaged 0.62±0.03 µg/g and 1.09±0.14 µg/L, respectively. Relationships between mercury levels and attention varied by mercury biomarker and CPT3 variable. Hair mercury, for instance, was associated with reduced inattentiveness (β=-0.021(SE=0.0095), p=0.027); urine mercury was not (β=-0.0045(SE=0.0078), p=0.57). Sex modified associations; for instance, urine mercury exposure was related to decreased vigilance in males (β=1.31(SE=0.65), p=0.045), but not in females (β=-0.20(SE=0.81), p=0.80). Lastly, DNAm at certain genes was associated with CPT3 scores. For example, DNAm at a loci in ZNF814 (Zinc Finger Protein-814) was related to increased sustained attention (β=0.97(SE=0.17), q=0.012). CONCLUSIONS: Both DNAm and mercury exposure are associated with adolescent CPT3 performance. KEYWORDS: mercury, sustained attention, DNA methylation, ADHD