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

Abstract

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.

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