Elisa Bustaffa

Genotoxic and epigenetic mechanisms in arsenic carcinogenicity

Arsenic is a human carcinogen with weak mutagenic properties that induces tumors through mechanisms not yet completely understood. People worldwide are exposed to arsenic-contaminated drinking water, and epidemiological studies showed a high percentage of lung, bladder, liver, and kidney cancer in these populations. Several mechanisms by which arsenical compounds induce tumorigenesis were proposed including genotoxic damage and chromosomal abnormalities. Over the past decade, a growing body of evidence indicated that epigenetic modifications have a role in arsenic-inducing adverse effects on human health. The main epigenetic mechanisms are DNA methylation in gene promoter regions that regulate gene expression, histone tail modifications that regulate the accessibility of transcriptional machinery to genes, and microRNA activity (noncoding RNA able to modulate mRNA translation). The “double capacity” of arsenic to induce mutations and epimutations could be the main cause of arsenic-induced carcinogenesis. The aim of this review is to better clarify the mechanisms of the initiation and/or the promotion of arsenic-induced carcinogenesis in order to understand the best way to perform an early diagnosis and a prompt prevention that is the key point for protecting arsenic-exposed population. Studies on arsenic-exposed population should be designed in order to examine more comprehensively the presence and consequences of these genetic/epigenetic alterations.

Arsenic exposure, genetic susceptibility and leukocyte telomere length in an Italian young adult population

Arsenic-induced health effects may be associated with critically shortened telomeres. However, few data are available on the effects of arsenic exposure on telomere length. The aim of this study was to investigate the effects of chronic arsenic exposure on leukocyte telomere length (LTL) as well as the contribution of common polymorphisms in genes implicated in arsenic metabolism (GSTT1 and GSTM1) and DNA repair (hOGG1 and XRCC1). A group of 241 healthy subjects was enrolled from four areas of Italy known to be affected by natural or anthropogenic arsenic pollution. Urine samples were tested for inorganic As (iAs), monomethylarsinic (MMA) and dimethylarsinic acid (DMA). LTL was evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Genotyping was carried out by PCR-RFLP on leukocyte DNA. In multiple linear regression analysis, LTL was significantly and inversely correlated with age (β = -0.231, P = 0.006) and showed a certain trend toward significance with iAs urinary concentration (log10 iAs, β = -0.106, P = 0.08). The genotype distribution showed significant associations between GSTT1 and the As concentration (log10 iAs, P = 0.01) and metabolite patterns (log10 DMA, P = 0.05) in the urine. However, GST genes did not interact with arsenic exposure in the modulation of LTL. Conversely, the combined presence of a higher level of iAs + MMA + DMA ≥ 19.3 μg/l (F = 6.0, P interaction = 0.01), Asi ≥ 3.86 (F = 3.9, P interaction = 0.04) μg/l, iAs + MMA + DMA ≥ 15 μg/l (F = 4.2, P interaction = 0.04) and hOGG1 Cys allele was associated with a significantly lower LTL. An interaction between XRCC1 Arg399Gln and arsenic exposure was also observed (all P interaction = 0.04). These findings suggest that telomere shortening may represent a mechanism that contributes to arsenic-related disease. The interaction of hOGG1 and XRCC1 DNA repair polymorphisms and exposure enhances telomeric DNA damage. Future studies are warranted to understand better the epidemiologic impact of arsenic on telomere function as well as to identify the subgroups of exposed subjects who need better health surveillance.

Risk perception and access to environmental information in four areas in Italy affected by natural or anthropogenic pollution

A human biomonitoring (HBM) survey in four areas affected by natural or anthropogenic arsenic pollution was conducted in Italy within the framework of the SEpiAs project. A questionnaire, including the exploration of risk perception (RP) regarding environmental hazards and access to and trust in information, was administered to 282 subjects stratified by area, gender and age. The survey was designed to investigate how populations living in polluted areas could adopt prevention-oriented habits, fostered by the awareness of existing risks and, in addition, how increased knowledge of RP and information flows could support researchers in identifying recommendations, and presenting and disseminating HBM results. This study characterizes the four areas in terms of RP and access to and trust in environmental information, and provides insights into the influence of RP and environmental information on food consumption. For the data analysis, a combined random forest (RF) and logistic regression approach was carried out. RF was applied to the variables derived from the questionnaire in order to identify the most important in terms of the aims defined. Associations were then tested using Fishers exact test and assessed with logistic regression in order to adjust for confounders. Results showed that the perception of and personal exposure to atmospheric and water pollution, hazardous industries and waste, hazardous material transportation and waste was higher in geographical areas characterized by anthropogenic pollution. Citizens living in industrial areas appeared to be aware of environmental risks and had more confidence in environmental non-governmental organizations (NGOs) than in public authorities. In addition, they reported an insufficient circulation of information. Concerning the influence of RP and environmental information on food consumption, a high perception of personal exposure to atmospheric pollution and hazardous industries was associated with a lower consumption of local fish. In conclusion, different RPs and information flow patterns were observed in areas with arsenic of natural origin or in industrial contexts. These findings may be useful for targeted risk communication plans in support of risk-management strategies.

Urinary Arsenic in Human Samples from Areas Characterized by Natural or Anthropogenic Pollution in Italy

Arsenic is ubiquitous and has a potentially adverse impact on human health. We compared the distribution of concentrations of urinary inorganic arsenic plus methylated forms (uc(iAs+MMA+DMA)) in four Italian areas with other international studies, and we assessed the relationship between uc(iAs+MMA+DMA) and various exposure factors. We conducted a human biomonitoring study on 271 subjects (132 men) aged 20–44, randomly sampled and stratified by area, gender, and age. Data on environmental and occupational exposure and dietary habits were collected through a questionnaire. Arsenic was speciated using chromatographic separation and inductively coupled mass spectrometry. Associations between uc(iAs+MMA+DMA) and exposure factors were evaluated using the geometric mean ratio (GMR) with a 90% confidence interval by stepwise multiple regression analysis. The 95th percentile value of uc(iAs+MMA+DMA) for the whole sample (86.28 µg/L) was higher than other national studies worldwide. A statistical significant correlation was found between uc(iAs+MMA+DMA) and occupational exposure (GMR: 2.68 [1.79–4.00]), GSTT gene (GMR: 0.68 [0.52–0.80]), consumption of tap water (GMR: 1.35 [1.02–1.77]), seafood (GMR: 1.44 [1.11–1.88]), whole milk (GMR: 1.34 [1.04–1.73]), and fruit/vegetables (GMR: 1.37 [1.03–1.82]). This study demonstrated the utility of uc(iAs+MMA+DMA) as a biomarker to assess environmental exposure. In a public health context, this information could be used to support remedial action, to prevent individuals from being further exposed to environmental arsenic sources.