Genetic susceptibility to methylmercury developmental neurotoxicity matters

Abstract

Epidemiological studies have demon-strated the developmental neurotoxicityassociated with prenatal methylmercuryexposure (Grandjean and Landrigan,2006); However, susceptibility tomethylmercury toxicity may be increasedby genetic factors. This observationraises the question of possible depen-dence of developmental neurotoxicity ongenetic predisposition. A few years ago, aNational Research Council (NRC) eval-uation of the scientific background forrisk assessment concluded that “atten-tion should be directed to vulnerableindividuals and subpopulations thatmay be particularly susceptible or morehighly exposed” (National ResearchCouncil, 2009). The panel also notedthat “variability in susceptibility andvulnerability has received less detailedevaluation in most EPA health effectsassessments.” A previous NRC reviewestimated that, under certain circum-stances, individual susceptibility couldrange up to 50,000-fold, and as muchas 5% of the population could well beat least 25-fold more susceptible thanthe average (National Research Council,2000).In risk assessment, an uncertaintyfactor of 10 is commonly used to takeinto account intraspecies susceptibil-ity. In regard to methylmercury, at therecommendation of the NRC (NationalResearch Council, 2009), EPA used thedefault 10-fold intraspecies uncertaintyfactor. In contrast, the European FoodSafety Authority recently argued that,for methylmercury, a partial uncer-tainty factor of 2 would be sufficientwhen a benchmark dose level (BMDL)hadbeenobtainedfromabirthcohortthat would represent the most vul-nerable population (European FoodSafety Authority, 2012). The magni-tude of the intraspecies uncertaintyfactor therefore appears controversial,and better scientific documentationhas been recommended (Dorne, 2010).Given that gene-environment interac-tion (GxE) may also play a role in regardto disease pathogenesis in a more gen-eral sense, as highlighted by a recentNIH workshop (Bookman et al., 2011),the variability in susceptibility to neu-rotoxicity between population groupsappears to be an important researchpriority.The recent findings on GxE formethylmercury neurotoxicity are sup-ported by several previous studies. Thus,mutations in certain genes seem to conveya greater risk of elemental mercury-associated neurobehavioral deficits orsymptoms in adults working in dentalclinics(Echeverriaetal.,2006,2010;Heyeret al., 2008, 2009). This evidence wasrecently extended to children exposed toinorganic mercury from amalgam fillings(Woodsetal.,2012,2013).Thereasonsforsuch interactions are only partially under-stood, but some gene variants may predictagreaterretentionofmercurycompoundsin the body.Thus, gene mutations seem to affectthe retention of inorganic mercury andmethylmercury in the body, e.g., genesthat affect glutathione (GSH) and metal-lothionein metabolism (Gundacker et al.,2007; Schlawicke Engstrom et al., 2008;Wang et al., 2012). Other studies havealso considered absorption-distribution-metabolism-elimination (ADME) genesthat may be of importance. Thus,methylmercury is eliminated from theliver as GSH conjugates, and the rate-limiting enzyme for GSH synthesis isglutamyl-cysteine ligase (GCL), which iscomposed of a catalytic subunit (GCLC)and a modifier subunit (GCLM). Further,the glutathione-S-transferases (GST) cat-alyze the conjugation of GSH (Gundackeret al., 2007). A recent study in Swedenindicates that a