Genetic Modulation of Mercury Exposure on Perinatal and Birth Outcomes: A Systematic Review and Meta-Analysis of Gene-Environment Interactions

Genetic polymorphisms can modulate susceptibility to mercury (Hg) toxicity by altering metabolic and detoxification pathways. This review evaluated the association between genetic variants, Hg exposure, and obstetric outcomes. A systematic search of Scopus, PubMed and ScienceDirect through May 2025 identified 12 eligible studies (<i>n</i> = 4995), conducted in accordance with PRISMA guidelines, with methodological quality assessed using the Newcastle-Ottawa Scale. Meta-analysis was selectively performed only for genetically and methodologically comparable studies. The most frequently examined genes were <i>GSTP1</i>, <i>GCLC</i>, <i>GCLM</i>, <i>GPX1</i>, <i>MT1A</i>, <i>ALAD</i>, and <i>APOE</i>. Meta-analysis of <i>GSTP1</i> rs1695, showed no statistically significant association between the Val105 allele and hair mercury concentrations (MD = -0.08 µg/g; 95% CI: -0.18 to 0.02; <i>p</i> = 0.13), although the direction of effect suggested a potential protective trend. Polymorphisms in other glutathione-related genes (<i>GCLC</i>, <i>GCLM</i>, and <i>GPX1</i>) were consistently associated with increased risks of small-for-gestational-age infants, preeclampsia, and impaired neurodevelopmental outcomes in offspring. In contrast, the <i>APOE ε4</i> allele appeared to be associated with reduced fetal mercury burden, whereas polymorphisms in <i>ALAD</i> and <i>MT1A</i> were linked to higher mercury levels and adverse pregnancy-related outcomes. By integrating epidemiological evidence with mechanistic insights within a gene-environment interaction framework, this review helps to address important gaps in the existing literature. These findings underscore the importance of incorporating genetic susceptibility into Hg risk assessment and precision-based prenatal interventions.