ИСТИНА

Background: We have published that peripubertal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and lead were associated with poorer semen quality in young adulthood. Here we evaluated the association of peripubertal serum TCDD concentration and blood lead level (BLL) with sperm DNA methylation. Design and Methods: The Russian Children’s Study is a prospective cohort of 516 boys who were enrolled at 8-9 years of age and provided semen samples at 18-19 years. At enrollment, serum TCDD and BLL were measured. RRBS of 16 sperm samples from fractionated ejaculates was conducted using HiSeq 2000. DMRcate was used to identify differentially methylated regions (DMRs) in multivariate regression analyses adjusted for birthweight, parental education, subject’s BMI, smoking, sperm layer and semen quality. Online bioinformatics database Metascape was used for pathway enrichment analyses. Main Results: The median (range) was 3.2 (2.0-4.7) pg/g lipid and 3 (2-3) mcg/dl for TCDD and BLL, respectively. Multivariate regression found 311 and 162 DMRs for peripuberital TCDD and BLL, respectively, in which 20 DMRs overlapped between exposures. Ontology analyses revealed that extracellular matrix organization and axonogenesis were top scoring networks for TCDD and neuron recognition and opioid signaling for BLL. Conclusions: We suggest that peripubertal environmental exposures may be associated with subsequent altered sperm methylation profiles in young adults.