Low 8-oxo-7,8-dihydro-2'-deoxyguanosine levels and influence of genetic background in an Andean population exposed to high levels of arsenic.
BACKGROUND
Arsenic (As) causes oxidative stress through generation of reactive oxygen species. 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a sensitive marker of oxidative DNA damage, has been associated with As exposure in some studies, but not in others, possibly due to population-specific genetic factors.


OBJECTIVE
To evaluate the association between As and 8-oxodG in urine in a population with a low urinary monomethylated As (%MMA) and high dimethylated As (%DMA), as well as the genetic impact on (a) 8-oxodG concentrations and (b) the association between As and 8-oxodG.


METHODS
Women (N=108) in the Argentinean Andes were interviewed and urine was analyzed for arsenic metabolites (ICPMS) and 8-oxodG (LC-MS/MS). Twenty-seven polymorphisms in genes related to oxidative stress and one in As(+III)methyltransferase (AS3MT) were studied.


RESULTS
Median concentration of 8-oxodG was 4.7 nmol/L (adjusted for specific weight; range 1.6-13, corresponding to 1.7 microg/g creatinine, range 0.57-4.8) and of total urinary As metabolites (U-As) 290 microg/L (range 94-720; 380 microg/g creatinine, range 140-1100). Concentrations of 8-oxodG were positively associated with %MMA (strongest association, p=0.013), and weakly associated with U-As (positively) and %DMA (negatively). These associations were strengthened when taking ethnicity into account, possibly reflecting genetic differences in As metabolism and genes regulating oxidative stress and DNA maintenance. A genetic influence on 8-oxodG concentrations was seen for polymorphisms in apurinic/apyrimidinic endonuclease 1 (APEX1), DNA-methyltransferases 1 and 3b (DNMT1, DNMT3B), thioredoxin reductase 1 (TXNRD1) and 2 (TXNRD2) and glutaredoxin (GLRX).


CONCLUSIONS
Despite high As exposure, the concentrations of 8-oxodG in this population were low compared with other As-exposed populations studied. The strongest association was found for %MMA, stressing that some inconsistencies between As and 8-oxodG partly depend on population variations in As metabolism. We found evidence of genetic impact on 8-oxodG concentrations.
Engström
Karin S
KS
Department of Laboratory Medicine, Lund University Hospital, Lund, Sweden. Karin.engstrom@med.lu.se
Vahter
Marie
M
Lindh
Christian
C
Teichert
Friederike
F
Singh
Rajinder
R
Concha
Gabriela
G
Nermell
Barbro
B
Farmer
Peter B
PB
Strömberg
Ulf
U
Broberg
Karin
K
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000293:Adolescent; D000328:Adult; D000368:Aged; D001118:Argentina; D001151:Arsenic / Q000652:urine*; D020261:Arsenic Poisoning / Q000235:genetics* / Q000652:urine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000652:urine; D005260:Female; D005828:Genetics, Population; D005838:Genotype; D054477:Glutaredoxins / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000235:genetics; D054482:Thioredoxin Reductase 2 / Q000235:genetics; D055815:Young Adult; D000097584:DNA Methyltransferase 3B
D000080242:8-Hydroxy-2'-Deoxyguanosine; D001151:Arsenic; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D003849:Deoxyguanosine; D054477:Glutaredoxins; D017382:Reactive Oxygen Species; D054481:Thioredoxin Reductase 1; D054482:Thioredoxin Reductase 2; D000097584:DNA Methyltransferase 3B; C516124:TXNRD1 protein, human; C516127:TXNRD2 protein, human; C000619380:DNMT1 protein, human; C085108:APEX1 protein, human