Arsenic exposure and early biomarkers of cardiovascular disease and cancer
Författare
Summary, in English
Abstract
Inorganic arsenic exposure through drinking water is a serious public health concern because of its association to cancer and non-cancer diseases. More than one hundred million people world-wide are exposed to elevated levels of arsenic on a regular basis. Arsenic is classified as class I carcinogen by International Agency for Research on Cancer (IARC). Recent report shows that arsenic exposure via drinking water is associated with increased risk of cardiovascular disease and diabetes. Several mechanisms of arsenic-related toxicity have been suggested, among those are genotoxicity and epigenetic modifications affecting gene expression. The aim of this thesis was to identify early biomarkers for arsenic-related cancer and cardiovascular disease, as well as, to analyse changes in gene expression and DNA methylation related to chronic arsenic exposure.
The study participants were from the Salta Province of northern Argentina, a region known to have areas with arsenic in drinking water. Two groups of study subjects, one residing in Puna area of Andes mountains (~4000 meters above the sea level) here called as Andes, and another residing in Salta plains (~300 meters above sea level) called Chaco, were studied. Arsenic exposure was assessed as the sum of inorganic arsenic and its metabolites, inorganic arsenic (iAs), methylarsonic acid (MMA) and dimethylarsinic acid (DMA) in urine, measured by high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry (HPLC-HG-ICPMS). The arsenic metabolism efficiency was assessed by the urinary fractions (%) of individual metabolites. To evaluate cardiovascular health, blood pressure was measured and homocysteine concentration and lipid profile were analysed in the plasma as early cardiovascular biomarkers in Andean women. To evaluate arenic realted DNA damage, telomere length and mitochondrial DNA copy number (mtDNAcn) were measured in peripheral blood in both Andes and Chaco study groups. Gene expression and DNA methylation were measured in peripheral blood in the Andes study group.
The arsenic concentrations in water had large ranges in both Andes and Chaco, and the median urinary arsenic concentrations for Andes and Chaco were 196 µg/L and 80 µg/L, respectively. The urinary arsenic metabolites differed significantly between the study groups, the median %iAs and %MMA were higher and the median %DMA was lower in Chaco population compared to the Andes, reflecting a less efficient arsenic metabolism in the Chaco study group. In women from Andes, increased urinary arsenic concentration was associated with decreased diastolic blood pressure and apoB/A, but there were no associations between urinary arsenic and homocysteine, triglycerides or cytokines, suggesting no evident cardiovascular toxicity. In men and women in Andes and Chaco, urinary arsenic was associated with longer telomere length and in Chaco with increased mtDNAcn. When the study groups were stratified according to fraction of inorganic arsenic in urine (%iAs), the associations remained significant in the above %iAs group, i.e. with less efficient arsenic metabolism capacity, for both Andes and Chaco. This suggests that individuals with less efficient arsenic metabolism are more prone to arsenic-related DNA damage and may be at high risk for arsenic-related future diseases. In Andes women, urinary arsenic was associated with decreased gene expression and increased DNA methylation in peripheral blood, indicating that arsenic exposure may have silenced gene expression by increasing DNA methylation. This thesis showed genotoxic and epigenetic, but no adverse cardiovascular, effects of arsenic exposure via drinking water. Future studies are needed to follow-up the study groups for future arsenic-related disease.
Inorganic arsenic exposure through drinking water is a serious public health concern because of its association to cancer and non-cancer diseases. More than one hundred million people world-wide are exposed to elevated levels of arsenic on a regular basis. Arsenic is classified as class I carcinogen by International Agency for Research on Cancer (IARC). Recent report shows that arsenic exposure via drinking water is associated with increased risk of cardiovascular disease and diabetes. Several mechanisms of arsenic-related toxicity have been suggested, among those are genotoxicity and epigenetic modifications affecting gene expression. The aim of this thesis was to identify early biomarkers for arsenic-related cancer and cardiovascular disease, as well as, to analyse changes in gene expression and DNA methylation related to chronic arsenic exposure.
The study participants were from the Salta Province of northern Argentina, a region known to have areas with arsenic in drinking water. Two groups of study subjects, one residing in Puna area of Andes mountains (~4000 meters above the sea level) here called as Andes, and another residing in Salta plains (~300 meters above sea level) called Chaco, were studied. Arsenic exposure was assessed as the sum of inorganic arsenic and its metabolites, inorganic arsenic (iAs), methylarsonic acid (MMA) and dimethylarsinic acid (DMA) in urine, measured by high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry (HPLC-HG-ICPMS). The arsenic metabolism efficiency was assessed by the urinary fractions (%) of individual metabolites. To evaluate cardiovascular health, blood pressure was measured and homocysteine concentration and lipid profile were analysed in the plasma as early cardiovascular biomarkers in Andean women. To evaluate arenic realted DNA damage, telomere length and mitochondrial DNA copy number (mtDNAcn) were measured in peripheral blood in both Andes and Chaco study groups. Gene expression and DNA methylation were measured in peripheral blood in the Andes study group.
The arsenic concentrations in water had large ranges in both Andes and Chaco, and the median urinary arsenic concentrations for Andes and Chaco were 196 µg/L and 80 µg/L, respectively. The urinary arsenic metabolites differed significantly between the study groups, the median %iAs and %MMA were higher and the median %DMA was lower in Chaco population compared to the Andes, reflecting a less efficient arsenic metabolism in the Chaco study group. In women from Andes, increased urinary arsenic concentration was associated with decreased diastolic blood pressure and apoB/A, but there were no associations between urinary arsenic and homocysteine, triglycerides or cytokines, suggesting no evident cardiovascular toxicity. In men and women in Andes and Chaco, urinary arsenic was associated with longer telomere length and in Chaco with increased mtDNAcn. When the study groups were stratified according to fraction of inorganic arsenic in urine (%iAs), the associations remained significant in the above %iAs group, i.e. with less efficient arsenic metabolism capacity, for both Andes and Chaco. This suggests that individuals with less efficient arsenic metabolism are more prone to arsenic-related DNA damage and may be at high risk for arsenic-related future diseases. In Andes women, urinary arsenic was associated with decreased gene expression and increased DNA methylation in peripheral blood, indicating that arsenic exposure may have silenced gene expression by increasing DNA methylation. This thesis showed genotoxic and epigenetic, but no adverse cardiovascular, effects of arsenic exposure via drinking water. Future studies are needed to follow-up the study groups for future arsenic-related disease.
Avdelning/ar
Publiceringsår
2016
Språk
Engelska
Fulltext
- Available as PDF - 12 MB
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Dokumenttyp
Doktorsavhandling
Förlag
Lund University: Faculty of Medicine
Ämne
- Medical and Health Sciences
Nyckelord
- Cardiovascular disease
- DNA methylation
- Telomere length
- MtDNAcn
- Gene expression
- Cancer
Status
Published
Handledare
ISBN/ISSN/Övrigt
- ISBN: 978-91-7619-334-1
Försvarsdatum
7 oktober 2016
Försvarstid
09:00
Försvarsplats
Pufendorfinstitutet, Biskopsgatan 3, Lund
Opponent
- Ulla Vogel (professor)