Interactions Between Polycyclic Aromatic Hydrocarbon Exposure and Epigenetic Regulatory Genes in Embryonic Arrest.

Abstract

Embryonic arrest poses a significant clinical challenge, yet the interplay between environmental toxicants and epigenetic modifiers remain poorly understood. This is the first study to systematically investigate whether genetic variants in N6-methyladenosine (m6A) methylation enzymes mediate the toxicity polycyclic aromatic hydrocarbons (PAHs) in early pregnancy loss. In a case-control study of 151 embryonic arrest patients and 151 controls, we quantified PAH-DNA adducts and m6A regulators (methyltransferase-like 3 [METTL3] and AlkB homolog 5 [ALKBH5]) in villus tissues. Three key single nucleotide polymorphisms (SNPs) in METTL3 and ALKBH5 were genotyped. Strikingly, high PAH-DNA adduct levels conferred a dramatically elevated risk of embryonic arrest (OR=18.57, 95% CI: 7.90-43.67, P<0.001). While METTL3 levels remained unchanged, ALKBH5 protein was significantly upregulated in cases (P<0.001). Crucially, the ALKBH5 rs4925144 TT genotype exhibited a strong protective effect against embryonic arrest (aOR=0.35, 95% CI: 0.14-0.87, P=0.024). Generalized multifactor dimensionality reduction (GMDR) revealed a significant synergistic interaction, wherein high PAHs exposure combined with the rs4925144 CC/CT genotypes drastically amplified risk. Structural equation modeling (SEM) confirmed that both PAH-DNA adducts (β=0.480, P<0.001) and ALKBH5 expression (β=0.178, P<0.001) directly drive embryonic arrest pathogenesis. These findings identify a novel gene-environment interaction underlying embryonic arrest and suggest that combining ALKBH5 rs4925144 genotyping with PAHs exposure assessment could serve as a valuable biomarker for early risk stratification, informing targeted intervention to prevent pregnancy loss.