Polymorphisms in Genes Encoding Potential Mercury Transporters and Urine Mercury Concentrations in Populations Exposed to Mercury Vapor from Gold Mining

Abstract

Background: Elemental mercury (Hg0) is widely used in small-scale gold mining. Persons working or living in mining areas have high urinary concentrations of Hg (U-Hg). Differences in genes encoding potential Hg-transporters may affect uptake and elimination of Hg.Objective: We aimed to identify single nucleotide polymorphisms (SNPs) in Hg-transporter genes that modify U-Hg.Methods: Men and women (1,017) from Indonesia, the Philippines, Tanzania, and Zimbabwe were classified either as controls (no Hg exposure from gold mining) or as having low (living in a gold-mining area) or high exposure (working as gold miners). U-Hg was analyzed by cold-vapor atomic absorption spectrometry. Eighteen SNPs in eight Hg-transporter genes were analyzed.Results: U-Hg concentrations were higher among ABCC2/MRP2 rs1885301 A–allele carriers than among GG homozygotes in all populations, though differences were not statistically significant in most cases. MRP2 SNPs showed particularly strong associations with U-Hg in the subgroup with highest exposure (miners in Zimbabwe), whereas rs1885301 A–allele carriers had higher U-Hg than GG homozygotes [geometric mean (GM): 36.4 µg/g creatinine vs. 21.9; p = 0.027], rs2273697 GG homozygotes had higher U-Hg than A–allele carriers (GM: 37.4 vs. 16.7; p = 0.001), and rs717620 A–allele carriers had higher U-Hg than GG homozygotes (GM: 83 vs. 28; p = 0.084). The SLC7A5/LAT1 rs33916661 GG genotype was associated with higher U-Hg in all populations (statistically significant for all Tanzanians combined). SNPs in SLC22A6/OAT1 (rs4149170) and SLC22A8/OAT3 (rs4149182) were associated with U-Hg mainly in the Tanzanian study groups.Conclusions: SNPs in putative Hg-transporter genes may influence U-Hg concentrations.

What do drug transporters really do?

“…Recent studies in Slc22a6 ( Oat1 )-knockout mice, or in tissues derived from such mice, have shown impaired handling of many of these compounds, as well as of environmental toxins 35,38,40,61–63 . For example, mercury, which can cause kidney and nervous system toxicity and remains a major environmental concern, is thought to be conjugated in vivo to cysteine (among other molecules); it is effectively ‘handled’ by SLC22A6 in a manner similar to an organic anion 57,63,64 . The Slc22a6 ( Oat1 )-knockout mouse kidney is notably protected from mercury toxicity because mercury conjugates cannot enter kidney proximal tubule cells from the blood side, owing to the lack of SLC22A6 in these animals 63 .…”

“…In addition, coding or non-coding single-nucleotide polymorphisms (SNPs) that result in clinical phenotypes have been reported for SLC22A6 and SLC22A8 (REFS 39,64,78) (TABLE 2). Although more extensive phenotypic analyses of the effects of OAT SNPs needs to be performed, these limited studies seem to be consistent with the in vitro and in vivo knockout data on their role in drug and toxin handling.…”

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…For example, mercury exists in the blood in thiol conjugates (with glutathione and cystathione), which effectively act like organic anions. OAT1 and OAT3 appear to be the major transporters involved in elimination of mercuric conjugates, which can lead to renal and central nervous system toxicity following mercurial exposure (48)(49)(50)(51). The proximal tubule of the kidney of the Oat1 knockout mouse is largely resistant to nephrotoxic damage that occurs from systemic administration of mercuric chloride (Figure 3) (52).…”

“…Early studies of transporter polymorphisms raised the possibility that multiple SNPs in basolateral (e.g., OAT1 and OAT3) (82,83) and apical (e.g., URAT1, OAT4, MRP2, and MRP4) drug transporters may affect the net transport of drugs, toxins, and metabolites from blood to urine (50,84). In addition, noncoding SNPs that regulate drug transporter expression might be particularly important (82,85).…”

“…A noncoding region polymorphism has been identified in patients with diuretic resistance that could affect OAT1 and/or OAT3 expression (86). Polymorphisms in OAT1, OAT3, and MRP2 are more common among miners exhibiting toxicity from mercury-containing vapors (50). Additionally, OAT3 polymorphisms have been associated with altered cephalosporin handling (87), and suggestive evidence indicates the possible involvement of OATs in antiviral and methotrexate elimination (88,89).…”