Metabolism of low-dose inorganic arsenic in a central European population: influence of sex and genetic polymorphisms.
BACKGROUND
There is a wide variation in susceptibility to health effects of arsenic, which, in part, may be due to differences in arsenic metabolism. Arsenic is metabolized by reduction and methylation reactions, catalyzed by reductases and methyltransferases.


OBJECTIVE
Our goal in this study was to elucidate the influence of various demographic and genetic factors on the metabolism of arsenic.


METHODS
We studied 415 individuals from Hungary, Romania, and Slovakia by measuring arsenic metabolites in urine using liquid chromatography with hydride generation and inductively coupled plasma mass spectrometry (HPLC-HG-ICPMS). We performed genotyping of arsenic (+III) methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), and methylene-tetrahydrofolate reductase (MTHFR).


RESULTS
The results show that the M287T (T-->C) polymorphism in the AS3MT gene, the A222V (C-->T) polymorphism in the MTHFR gene, body mass index, and sex are major factors that influence arsenic metabolism in this population, with a median of 8.0 microg/L arsenic in urine. Females < 60 years of age had, in general, higher methylation efficiency than males, indicating an influence of sex steroids. That might also explain the observed better methylation in overweight or obese women, compared with normal weight men. The influence of the M287T (T-->C) polymorphism in the AS3MT gene on the methylation capacity was much more pronounced in men than in women.


CONCLUSIONS
The factors investigated explained almost 20% of the variation seen in the metabolism of arsenic among men and only around 4% of the variation among women. The rest of the variation is probably explained by other methyltransferases backing up the methylation of arsenic.
Lindberg
Anna-Lena
AL
Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
Kumar
Rajiv
R
Goessler
Walter
W
Thirumaran
Ranjit
R
Gurzau
Eugen
E
Koppova
Kvetoslava
K
Rudnai
Peter
P
Leonardi
Giovanni
G
Fletcher
Tony
T
Vahter
Marie
M
D001151:Arsenic / Q000378:metabolism*; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012737:Sex Factors
D017931:DNA Primers; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D001151:Arsenic