## 3 Human Genetic Diversity
### MeHg Exposure and Human Genetic Diversity
[PERSON] and colleagues [55] analyzed Single-Nucleotide Polymorphisms (SNPs; genetic variants due to a base substitution or the insertion or deletion of a single base) variability in a cohort of dental professionals exposed to inorganic Hg via dental amalgams and to MeHg via seafood consumption, in order to investigate potential associations with Hg levels in hair and urine. In this study, fish consumption as estimated by a self-administered survey was the best predictor of measured hair Hg level, and two SNPs were associated with this biomarker. In particular, SEPP1 3'UTR (rs7579) T allele was associated with lower hair Hg per unit of intake from fish consumption, while the GSS 5' (rs3761144) minor allele (i.e., the less common allele of a SNP) (G) was associated with increasing \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Study** & **Genes** & **Biomarker** & **Sample** \\ \hline
[68] & XRCC1 & Sperm PAH–DNA adducts & Infertile adult men from Nanjing, China \\ \hline
[69] & MPO; NAT2; ERCC5 & Blood PAH–DNA adducts & Non-smoking healthy women from eastern Golestan Province, Iran \\ \hline
[36] & CYP1A1; GSTT2; CYP1B & Cord blood B(a)P–DNA adducts & Mother–infant pairs from Krakow, Poland \\ \hline \hline \end{tabular}
\end{table} 
Table 2: List of epidemiological studies investigating the influence of genetic polymorphisms on PAHs toxicokinetics. Genes in which the above polymorphisms were identified, biomarkers affected, and samples studied are shown for each study. Figure 1: Schematic representation of the role played by several genes in MeHg elimination from the body. (**a**) The GCLC and GCLM genes encode the catalytic and modifier subunits of the glutamate–cysteine ligase (GCL) enzyme, respectively. The GCL is the first rate-limiting enzyme of glutathione (GSH) synthesis. The GSS gene encodes the glutathione synthetase (GSS), another enzyme involved in GSH synthesis. (**b**) The GSTM1 and GSTP1 genes encode the glutathione S-transferases (GST) Mu1 and Pi1, respectively, which catalyze the conjugation of GSH to MeHg. hair Hg concentration per unit of fish Hg. SEPP1 encodes a selenoprotein, which combats the oxidative stress created by Hg by binding the toxicant directly via a selenocysteine residue. The latter is an amino acid unique to selenoproteins that can bind Hg-selenium conjugates or MeHg. Interestingly, as demonstrated by previous studies, the 3'UTR T allele is linked to greater SEPP1 expression and Hg-binding capacity. The GSS gene encodes for an enzyme, glutathione synthetase (Figure 1a), that is involved in the synthesis of GSH, to which Hg is conjugated before being eliminated (Figure 1b). The association of the minor allele with increasing hair Hg concentration may be ascribable to a decreased expression of GSS and, thus, to decreased GSH synthesis, which in turn could impact the body's ability to eliminate MeHg as a GSH conjugate, with the higher body burden reflected in hair Hg levels. The study of [PERSON] and colleagues [60] was the first to investigate the genetic predisposition to mercury accumulation in the plasma, where this pollutant is more bioavailable and therefore potentially harmful to human health. In this study, authors focused on riverside communities of the Brazilian Amazon, for which the only source of Hg exposure was the intake of contaminated fish. They genotyped two glutathione-related genes, GSTM1 and GCLC. The first encodes a glutathione S-transferase, an enzyme that catalyzes the conjugation of GSH to MeHg (Figure 1b), while the second encodes the catalytic subunit of the glutamate-cysteine ligase (GCL), the first rate-limiting enzyme of glutathione synthesis (Figure 1a). What the study found is that null homozyggotes for GSTM1, that is, individuals that possess two copies of a non-functional allele for this gene, showed higher plasmatic MeHg levels (MeHgP) compared to subjects with functional GSTM1, which may be related to their lower MeHg-conjugating activity, lower MeHg excretion, and a higher MeHg retention.