{"doi":"10.7302/23811","title":"The Combined Effects of Mercury Exposure and DNA Methylation on the Developing Human Brain","abstract":"The diagnosis of Attention-deficit/hyperactivity disorder (ADHD) is continuously increasing in child and adult populations worldwide. Despite its marked prevalence, the complex etiology of ADHD remains poorly understood. Previous research suggests aberrant DNA methylation (DNAm) and mercury (Hg) exposure are potential ADHD risk factors. Still, combined assessments of these two proposed ADHD predictors are rare. The first factor, DNAm, is a mitotically heritable epigenetic mechanism characterized by the addition of methyl groups to cytosine bases of DNA without altering the genetic sequence. This stable modification is dynamic and potentially reversible, making it an excellent target for potential interventions. The second main risk factor assessed in this study is exposure to Hg, a potent neurotoxicant that people are commonly exposed to through consumption of contaminated seafood. Past research predominantly focuses on the effects of prenatal methyl-Hg exposures and DNAm on subsequent neurodevelopmental outcomes, leaving other relevant windows of susceptibility under-studied. Childhood through adolescence, for example, is a critical period in the development of executive functioning skills, when individuals may be particularly vulnerable to epigenetic and toxic influences. In a two-tiered approach, leveraging both in vitro (SH-SY5Y cell line) and epidemiological methodologies (Early Life Exposures in Mexico to ENvironmental Toxicants (ELEMENT) cohort), this dissertation addressed gaps in the literature, by assessing the effects of both post-natal DNAm and Hg exposures on the developing human brain. We conjectured that epigenetic susceptibility to toxicant-related health effects may help explain ADHD etiology by interacting with childhood Hg exposure to impact ADHD-like behaviors. This dissertation’s over-arching hypothesis states that childhood Hg exposure and DNAm marks are both important predictors of ADHD symptoms. This hypothesis was tested in three aims, designed to (1) examine associations between adolescent DNAm and performance on the Conners Continuous Performance Test, 3rd edition (CPT3), (2) analyze the role of DNAm in adolescence in the relationship between childhood Hg exposure and CPT3 performance, and (3) identify mercury-induced gene expression and DNAm changes in cultured human neurons. Using data generated from ELEMENT children, we identified significant associations between both predictors and CPT3 scores individually, as well as significant interactions between the two terms when modeled together. In Aim 1, we discovered ZNF814, ELF4, and OR6K6 DNAm levels were significantly associated with vigilance and sustained attention CPT3 scores. Functional enrichment for ferroptosis, inflammation, immune response, and neurotransmission pathways were also significantly related to multiple CPT3 outcomes. In Aim 2, we first identified significant positive and negative associations between hair and urine Hg and CPT3 performance, which depended upon the CPT3 and Hg variable used. When the effects of the two main predictors were modeled together, significant interactions were identified for inattention and vigilance. Associations described in Aims 1 and 2 were often modified by gender. Notably, in interaction models from Aim 2, hair Hg significantly interacted with DNAm at 157 CpG sites in females for the inattentiveness models; three significant interactions were identified for the perseveration models in males. In Aim 3, significant differential expression and methylation in dopaminergic-like neurons were observed for several genes, including those encoding two novel proteins differentially responding to low/biologically relevant methyl-Hg exposures. This aim provided mechanistic insight suggesting epigenetics, immune response, and cell motility are all related to Hg-induced neurotoxicity. Inflammation and epigenetic mechanisms were related to neurobehavior and/or function across findings from all three aims of this dis","journal":"Deep Blue (University of Michigan)","year":2024,"id":491782,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1080662,"name":"Jessa Ehlinger","orcid":"0000-0002-8546-7675","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:08:45.247225Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}