Genetic variation in glutathione-related genes and body burden of methylmercury.
BACKGROUND
Exposure to toxic methylmercury (MeHg) through fish consumption is a large problem worldwide, and it has led to governmental recommendations of reduced fish consumption and blacklisting of mercury-contaminated fish. The elimination kinetics of MeHg varies greatly among individuals. Knowledge about the reasons for such variation is of importance for improving the risk assessment for MeHg. One possible explanation is hereditary differences in MeHg metabolism. MeHg is eliminated from the body as a glutathione (GSH) conjugate.


OBJECTIVE
We conducted this study to assess the influence of polymorphisms in GSH-synthesizing [glutamyl-cysteine ligase modifier subunit (GCLM-588) and glutamyl-cysteine ligase catalytic subunit (GCLC-129)] or GSH-conjugating [glutathione S-transferase pi 1 (GSTP1-105 and GSTP1-114)] genes on MeHg retention.


METHODS
Based on information obtained from questionnaires, 292 subjects from northern Sweden had a high consumption of fish (lean/fat fish two to three times per week or more). We measured total Hg in erythrocytes (Ery-Hg) and long-chain n-3 polyunsaturated fatty acids in plasma (P-PUFA; an exposure marker for fish intake).


RESULTS
The GSTP1 genotype modified Ery-Hg; effects were seen for GSTP1-105 and -114 separately, and combining them resulted in stronger effects. We found evidence of effect modification: individuals with zero or one variant allele demonstrated a steeper regression slope for Ery-Hg (p=0.038) compared with individuals with two or more variant alleles. The GCLM-588 genotype also influenced Ery-Hg (p=0.035): Individuals with the GCLM-588 TT genotype demonstrated the highest Ery-Hg, but we saw no evidence of effect modification with increasing P-PUFA.


CONCLUSIONS
These results suggest a role of GSH-related polymorphisms in MeHg metabolism.
Schläwicke Engström
Karin
K
Department of Occupational and Environmental Medicine, Lund University Hospital, Lund, Sweden. karin.engstrom@med.lu.se
Strömberg
Ulf
U
Lundh
Thomas
T
Johansson
Ingegerd
I
Vessby
Bengt
B
Hallmans
Göran
G
Skerfving
Staffan
S
Broberg
Karin
K
D000328:Adult; D000818:Animals; D004912:Erythrocytes / Q000737:chemistry; D005231:Fatty Acids, Unsaturated / Q000097:blood; D005399:Fishes; D005506:Food Contamination / Q000032:analysis; D005787:Gene Frequency; D005838:Genotype; D005721:Glutamate-Cysteine Ligase / Q000235:genetics* / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism*; D051549:Glutathione S-Transferase pi / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008767:Methylmercury Compounds / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D013548:Sweden; D014874:Water Pollutants, Chemical / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics
D005231:Fatty Acids, Unsaturated; D008767:Methylmercury Compounds; D014874:Water Pollutants, Chemical; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione