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Gene-environment interactions for arsenic metabolism and metal-related oxidatively generated DNA damage

Engström, Karin LU (2010) In Lund University Faculty of Medicine Doctoral Dissertation Series 2010:101.
Abstract (Swedish)
Popular Abstract in Swedish

Arsenik (As) finns i grundvatten på många platser i världen, och mer än 100 miljoner människor världen över exponeras dagligen för As via dricksvatten. Kronisk exponering för As kan orsaka bl.a. cancer, hjärt-kärlsjukdom och diabetes. När As omsätts (metaboliseras) i kroppen bildas flera olika omsättningsprodukter (metaboliter) emellan vilka giftigheten skiljer sig åt. Oorganiskt As (iAs) metyleras till metaboliterna monometylerad As (MMA) och dimetylerad As (DMA), och dessa metaboliter utsöndras i urin. Allt As omvandlas inte till DMA, utan en del finns kvar som iAs och MMA. En hög andel MMA i urin har i åtskilliga studier sammankopplats med mer skadliga effekter på DNA- och cellnivå jämfört med... (More)
Popular Abstract in Swedish

Arsenik (As) finns i grundvatten på många platser i världen, och mer än 100 miljoner människor världen över exponeras dagligen för As via dricksvatten. Kronisk exponering för As kan orsaka bl.a. cancer, hjärt-kärlsjukdom och diabetes. När As omsätts (metaboliseras) i kroppen bildas flera olika omsättningsprodukter (metaboliter) emellan vilka giftigheten skiljer sig åt. Oorganiskt As (iAs) metyleras till metaboliterna monometylerad As (MMA) och dimetylerad As (DMA), och dessa metaboliter utsöndras i urin. Allt As omvandlas inte till DMA, utan en del finns kvar som iAs och MMA. En hög andel MMA i urin har i åtskilliga studier sammankopplats med mer skadliga effekter på DNA- och cellnivå jämfört med en låg andel MMA, och även en högre risk för vissa cancertyper. Fördelningen av de olika metaboliterna i urin varierar åtskilligt mellan olika individer och befolkningsgrupper. Miljöfaktorer kan vara en anledning till denna variation, men studier visar att även ärftliga faktorer har en stor betydelse. Enzymet As(3+)metyltransferas (AS3MT) omvandlar As i kroppen genom metylering av iAs till MMA och DMA. Polymorfier (d.v.s. varianter av en DNA-sekvens) i genen för AS3MT kan påverka funktionen eller mängden av enzymet AS3MT, vilket i sin tur kan påverka metabolismen av As, och därmed fördelningen av de olika metaboliterna.

As kan framkalla oxidativ stress, som betecknar en obalans av reaktiva syreradikaler (som kan oxidera DNA) och antioxidanter (som neutraliserar de reaktiva syreradikalerna), vilket kan leda till skador på DNA. Skadorna kan mätas genom förekomsten av 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) som uppstår vid DNA-skada och utsöndras i urin. Även samtidig kronisk exponering för vissa andra metaller kan generera oxidativ stress och därmed ökade halter av 8-oxodG. Exempel på sådana metaller är kadmium (Cd) och bly (Pb), två av de giftiga metaller som människor exponeras mest för via miljö och föda. Det kan även finnas en genetisk påverkan på nivåerna av 8-oxodG.

Syftet med dessa studier var att 1) utvärdera påverkan av genetiska faktorer på metabolismen av As, och att 2) utvärdera hur As och dess metaboliter, kronisk exponering för andra metaller, samt genetiska faktorer påverkar nivåerna av 8-oxodG i urin. Detta utvärderades i två befolkningsgrupper, en från de argentinska Anderna och en från Matlab, Bangladesh. Alla studiedeltagare var kvinnor. Båda befolkningsgrupperna hade en stor variation av As i urin. Dock fanns en mängd olikheter mellan dessa befolkningsgrupper, dels genetiskt, men även gällande matvanor, nutritionsstatus, livsstilsfaktorer och graviditet.

Sex polymorfier i AS3MT var starkt förknippade med en lägre andel av MMA i urin hos båda befolkningsgrupperna. Polymorfierna påverkade även hur mycket av genen AS3MT som uttrycktes. Polymorfier i ett antal andra gener påverkade också fördelningen av As-metaboliter, men effekten var inte lika dramatisk som för AS3MT. Högre halter av As i urin och högre andel MMA var associerat med högre koncentrationer av 8-oxodG. Högre koncentrationer av Cd var starkt associerat med högre koncentrationer av 8-oxodG. Cd och As en samverkande effekt på koncentrationerna av 8-oxodG. Det fanns även här en viss genetisk påverkan på nivåerna av 8-oxodG.

Denna forskning kan ge oss viktig information om mekanismerna bakom omsättning och skadliga effekter av As, samt öka kunskapen om individuella skillnader i metabolismen av As. Detta kan hjälpa till att identifiera känsliga grupper och förbättra riskbedömningen för As i dricksvatten. (Less)
Abstract
Over 100 million people around the world are exposed to high concentrations of arsenic (As) in drinking water, associated with a number of adverse health effects such as skin, lung and bladder cancer, vascular diseases and diabetes. In humans, As is metabolized via alternating reduction and methylation reactions, from inorganic As (iAs) into monomethylated (MMA) and dimethylated As (DMA). The most toxic metabolite is MMA, and the fraction of urinary MMA appears to be a marker for susceptibility to As-related toxic effects. The metabolism of As and thus the distribution of the As metabolites in urine demonstrate large inter-individual differences, which in part may be explained by genetic factors. A potential mechanism of the toxicity of As... (More)
Over 100 million people around the world are exposed to high concentrations of arsenic (As) in drinking water, associated with a number of adverse health effects such as skin, lung and bladder cancer, vascular diseases and diabetes. In humans, As is metabolized via alternating reduction and methylation reactions, from inorganic As (iAs) into monomethylated (MMA) and dimethylated As (DMA). The most toxic metabolite is MMA, and the fraction of urinary MMA appears to be a marker for susceptibility to As-related toxic effects. The metabolism of As and thus the distribution of the As metabolites in urine demonstrate large inter-individual differences, which in part may be explained by genetic factors. A potential mechanism of the toxicity of As is the induction of oxidative stress, which can result in oxidatively generated DNA damage. Oxidatively generated DNA damage can be assessed by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in urine. Concurrent chronic mixed exposure to other metals, such as cadmium (Cd) and lead (Pb), can also induce oxidative stress, and there may also be a genetic influence on oxidative stress. The aims of this thesis were 1) to evaluate the impact of genetic factors on As metabolism and 2) to evaluate the impact of As exposure and metabolism, chronic mixed metal exposure and genetic factors on oxidatively generated DNA damage, here assessed by 8-oxodG in urine. This was evaluated in two populations, one from the Argentinean Andes and one from rural Bangladesh. Six non-coding polymorphisms in As (3+ oxidation state) methyltransferase (AS3MT) had a strong impact on As metabolism in both populations, and it was demonstrated that one functional influence of the AS3MT polymorphisms was alternation of gene expression. Increasing concentrations of As in urine and increasing fractions of MMA were associated with higher 8-oxodG concentrations. Increasing concentrations of urinary Cd were strongly associated with higher 8-oxodG concentrations, and there was a joint effect of As and Cd on 8-oxodG concentrations. A polymorphism in apurinic/apyrimidinic endonuclease 1 (APEX1) had an impact on 8-oxodG concentrations. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Kumar, Rajiv, Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Tyskland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
AS3MT, methylation, polymorphism, 8-oxodG
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2010:101
pages
138 pages
publisher
Division of Occupational and Environmental Medicine
defense location
Föreläsningssal 3, Universitetssjukhuset, Lund
defense date
2010-11-12 09:15
ISSN
1652-8220
ISBN
978-91-86671-17-4
language
English
LU publication?
yes
id
ccbfe0f9-ce1f-4ee2-9905-db1106257105 (old id 1692616)
date added to LUP
2010-10-21 11:23:37
date last changed
2018-05-29 10:56:30
@phdthesis{ccbfe0f9-ce1f-4ee2-9905-db1106257105,
  abstract     = {Over 100 million people around the world are exposed to high concentrations of arsenic (As) in drinking water, associated with a number of adverse health effects such as skin, lung and bladder cancer, vascular diseases and diabetes. In humans, As is metabolized via alternating reduction and methylation reactions, from inorganic As (iAs) into monomethylated (MMA) and dimethylated As (DMA). The most toxic metabolite is MMA, and the fraction of urinary MMA appears to be a marker for susceptibility to As-related toxic effects. The metabolism of As and thus the distribution of the As metabolites in urine demonstrate large inter-individual differences, which in part may be explained by genetic factors. A potential mechanism of the toxicity of As is the induction of oxidative stress, which can result in oxidatively generated DNA damage. Oxidatively generated DNA damage can be assessed by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in urine. Concurrent chronic mixed exposure to other metals, such as cadmium (Cd) and lead (Pb), can also induce oxidative stress, and there may also be a genetic influence on oxidative stress. The aims of this thesis were 1) to evaluate the impact of genetic factors on As metabolism and 2) to evaluate the impact of As exposure and metabolism, chronic mixed metal exposure and genetic factors on oxidatively generated DNA damage, here assessed by 8-oxodG in urine. This was evaluated in two populations, one from the Argentinean Andes and one from rural Bangladesh. Six non-coding polymorphisms in As (3+ oxidation state) methyltransferase (AS3MT) had a strong impact on As metabolism in both populations, and it was demonstrated that one functional influence of the AS3MT polymorphisms was alternation of gene expression. Increasing concentrations of As in urine and increasing fractions of MMA were associated with higher 8-oxodG concentrations. Increasing concentrations of urinary Cd were strongly associated with higher 8-oxodG concentrations, and there was a joint effect of As and Cd on 8-oxodG concentrations. A polymorphism in apurinic/apyrimidinic endonuclease 1 (APEX1) had an impact on 8-oxodG concentrations.},
  author       = {Engström, Karin},
  isbn         = {978-91-86671-17-4},
  issn         = {1652-8220},
  keyword      = {AS3MT,methylation,polymorphism,8-oxodG},
  language     = {eng},
  pages        = {138},
  publisher    = {Division of Occupational and Environmental Medicine},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Gene-environment interactions for arsenic metabolism and metal-related oxidatively generated DNA damage},
  volume       = {2010:101},
  year         = {2010},
}