RESUMEN
Considering genetic variability in population studies focusing on the health risk assessment of exposure to environmental carcinogens may provide improved insights in individual environmental cancer risks. Therefore, the current study aims to determine the impact of genetic polymorphisms on the relationship between exposure and gene expression, by identifying exposure-dependently coregulated genes and genetic pathways. Statistical analysis based on mixed models, was performed to relate gene expression data from 134 subjects to exposure measurements of multiple carcinogens, 28 polymorphisms, age, sex and biomarkers of cancer risk. We evaluated the combined exposure to cadmium, lead, polychlorinated biphenyls, p,p'-dichlorodiphenyldichloroethylene, hexachlorobenzene and 1-OH-pyrene, and the outcome was biologically interpreted by using ConsensusPathDB, thereby focusing on carcinogenesis-related pathways. We found generic and carcinogenesis-related pathways deregulated in both sexes, but males showed a stronger transcriptome response than females. We highlighted NOTCH1, CBR1, ITGB3, ITGA4, ADI1, HES1, NCOA2 and SMARCA2 in view of their direct link with cancer development. Two of these, NOTCH1 and ITGB3, are also known to respond to PCBs and cadmium chloride exposure in rodents and to lead in humans. Subjects carrying a high number of risk alleles appear more responsive to combined carcinogen exposure with respect to the induced expression of some of these cancer-related genes, which may be indicative of increased cancer risk as a consequence of environmental factors.
Asunto(s)
Carcinógenos Ambientales/toxicidad , Proteínas de Neoplasias/biosíntesis , Neoplasias/genética , Transcriptoma/genética , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Exposición a Riesgos Ambientales , Monitoreo del Ambiente , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/genética , Neoplasias/inducido químicamente , Neoplasias/patología , Bifenilos Policlorados/toxicidad , Medición de RiesgoRESUMEN
A method to validate the relevance of the Total Diet Study (TDS) approach for different types of substances is described. As a first step, a list of >2800 chemicals classified into eight main groups of relevance for food safety (natural components, environmental contaminants, substances intentionally added to foods, residues, naturally occurring contaminants, process contaminants, contaminants from packaging and food contact materials, other substances) has been established. The appropriateness of the TDS approach for the different substance groups has then been considered with regard to the three essential principles of a TDS: representativeness of the whole diet, pooling of foods and food analyzed as consumed. Four criteria were considered for that purpose (i) the substance has to be present in a significant part of the diet or predominantly present in specific food groups, (ii) a robust analytical method has to be available to determine it in potential contributors to the dietary exposure of the population, and (iii) the dilution impact of pooling and (iv) the impact of everyday food preparation methods on the concentration of the substance are assessed. For most of the substances the TDS approach appeared to be relevant and any precautions to be taken are outlined.
Asunto(s)
Dieta , Exposición a Riesgos Ambientales , Residuos de Medicamentos/análisis , Contaminantes Ambientales/análisis , Humanos , Medicina VeterinariaRESUMEN
Due to possible health risks, quantification of mercury accumulation in humans was included in the Flemish biomonitoring programmes FLEHS I (2002-2006) and FLEHS II (2007-2011). The general objective of FLEHS I was to assess regional exposure levels in order to link possible differences in these internal exposure levels to different types of local environmental pressure. Therefore, Hg and MMHg (methylmercury) were only measured in pooled blood samples per region and per age class. In FLEHS II, mercury concentrations were measured in hair of each participant. About 200 adolescents and 250 mothers (reference group) and two times 200 adolescents (2 hotspots) were screened. The main objectives of the FLEHS II study were: (1) to determine reference levels of mercury in hair for Flanders; (2) to assess relations between mercury exposure and possible sources like fish consumption; (3) to assess dose-effect relations between mercury exposure and health effect markers. The results showed that mercury concentrations in the Flemish population were rather low compared to other studies. Mercury levels in the Flemish populations were strongly related to the age of the participants and consumption of fish. Significant negative associations were observed between mercury in hair and asthma, having received breast feeding as a newborn, age at menarche in girls, allergy for animals and free testosterone levels. Significant correlations were also observed between mercury in hair and genes JAK2, ARID4A, Hist1HA4L (boys) and HLAdrb5, PIAS2, MANN1B1, GIT and ABCA1 (girls).
Asunto(s)
Asma/etiología , Dieta , Exposición a Riesgos Ambientales/efectos adversos , Peces , Mercurio/efectos adversos , Compuestos de Metilmercurio/efectos adversos , Transcriptoma/efectos de los fármacos , Adolescente , Adulto , Animales , Asma/sangre , Asma/metabolismo , Bélgica , Lactancia Materna , Exposición a Riesgos Ambientales/análisis , Monitoreo del Ambiente , Contaminantes Ambientales/efectos adversos , Contaminantes Ambientales/sangre , Contaminantes Ambientales/metabolismo , Femenino , Cabello/metabolismo , Humanos , Hipersensibilidad/sangre , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Recién Nacido , Masculino , Menarquia , Mercurio/sangre , Mercurio/metabolismo , Mercurio/farmacología , Compuestos de Metilmercurio/sangre , Compuestos de Metilmercurio/metabolismo , Compuestos de Metilmercurio/farmacología , Embarazo , Testosterona/sangre , Adulto JovenRESUMEN
Flanders, Belgium, is one of the most densely populated areas in Europe. The Flemish Environment and Health Survey (2002-2006) aimed at determining exposure to pollutants of neonates, adolescents, and older adults and to assess associated biological and health effects. This study investigated genome wide gene expression changes associated with a range of environmental pollutants, including cadmium, lead, PCBs, dioxin, hexachlorobenzene, p,p'-DDE, benzene, and PAHs. Gene expression levels were measured in peripheral blood cells of 20 adults with relatively high and 20 adults with relatively low combined internal exposure levels, all non-smokers aged 50-65. Pearson correlation was used to analyze associations between pollutants and gene expression levels, separately for both genders. Pollutant- and gender-specific correlation analysis results were obtained. For organochlorine pollutants, analysis within genders revealed that genes were predominantly regulated in opposite directions in males and females. Significantly modulated pathways were found to be associated with each of the exposure biomarkers measured. Pathways and/or genes related to estrogen and STAT5 signaling were correlated to organochlorine exposures in both genders. Our work demonstrates that gene expression in peripheral blood is influenced by environmental pollutants. In particular, gender-specific changes are associated with organochlorine pollutants, including gender-specific modulation of endocrine related pathways and genes. These pathways and genes have previously been linked to endocrine disruption related disorders, which in turn have been associated with organochlorine exposure. Based on our results, we recommend that males and females be considered separately when analyzing gene expression changes associated with exposures that may include chemicals with endocrine disrupting properties.
Asunto(s)
Exposición a Riesgos Ambientales , Factores Sexuales , Transcriptoma , Anciano , Bélgica , Biomarcadores , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.
Asunto(s)
Disruptores Endocrinos/efectos adversos , Contaminantes Ambientales/efectos adversos , Disruptores Endocrinos/farmacología , Contaminantes Ambientales/farmacología , Humanos , Receptores de EstrógenosRESUMEN
Since 2002 a human biomonitoring network has been established in Flanders (Belgium) as part of a programme on environmental health surveillance. The human biomonitoring network should support environmental health policy by identifying priorities for further action. The first cycle of the programme (2002-2006) confirmed the hypotheses that living in areas with different environmental pressure is reflected in different loads of environmental chemicals in the residents. In the second cycle of the programme (2007-2011) the number of environmental chemicals for which human biomonitoring data were obtained was expanded substantially. The goal of the Flemish programme is to use and translate the scientific results into policy actions. Its further orientation in the second cycle to human biomonitoring in hot spots and sensitive age groups or susceptible persons with underlying complications (e.g. persons with diabetes) are linked to these goals. Interaction with stakeholders is embedded in the programme emphasizing transparency of the choices that are made and direct communication. The Flemish human biomonitoring programme is organized centrally with major involvement of research partners from different disciplines which allows engrafting environmental health research on the programme. One of the major focuses is the question whether combinations of pollutants in the general population are associated with biological effects. The objective of this paper is to review and discuss the options that were taken in the human biomonitoring programme in order to achieve its goals.
Asunto(s)
Exposición a Riesgos Ambientales , Monitoreo del Ambiente/métodos , Sustancias Peligrosas , Desarrollo de Programa , Adolescente , Adulto , Anciano , Bélgica , Biomarcadores/sangre , Biomarcadores/orina , Niño , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Exposición a Riesgos Ambientales/normas , Monitoreo del Ambiente/normas , Femenino , Sustancias Peligrosas/efectos adversos , Sustancias Peligrosas/sangre , Sustancias Peligrosas/orina , Política de Salud , Humanos , Recién Nacido , Comunicación Interdisciplinaria , Masculino , Persona de Mediana Edad , Valores de Referencia , Medición de Riesgo/métodos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: This study intended to investigate whether residence in areas polluted by heavy industry, waste incineration, a high density of traffic and housing or intensive use of pesticides, could contribute to the high incidence of cancer observed in Flanders. METHODS: Subjects were 1583 residents aged 50-65 from 9 areas with different types of pollution. Cadmium, lead, p,p'-DDE, hexachlorobenzene, PCBs and dioxin-like activity (Calux test) were measured in blood, and cadmium, t,t'-muconic acid and 1-hydroxypyrene in urine. Effect biomarkers were prostate specific antigen, carcinoembryonic antigen and p53 protein serum levels, number of micronuclei per 1000 binucleated peripheral blood cells, DNA damage (comet assay) in peripheral blood cells and 8-hydroxy-deoxyguanosine in urine. Confounding factors were taken into account. RESULTS: Overall significant differences between areas were found for carcinoembryonic antigen, micronuclei, 8-hydroxy-deoxyguanosine and DNA damage. Compared to a rural area with mainly fruit production, effect biomarkers were often significantly elevated around waste incinerators, in the cities of Antwerp and Ghent, in industrial areas and also in other rural areas. Within an industrial area DNA strand break levels were almost three times higher close to industrial installations than 5 kilometres upwind of the main industrial installations (p < 0.0001). Positive exposure-effect relationships were found for carcinoembryonic antigen (urinary cadmium, t,t'-muconic acid, 1-hydroxypyrene and blood lead), micronuclei (PCB118), DNA damage (PCB118) and 8-hydroxy-deoxyguanosine (t,t'-muconic acid, 1-hydroxypyrene). Also, we found significant associations between values of PSA above the p90 and higher values of urinary cadmium, between values of p53 above the p90 and higher serum levels of p,p'-DDE, hexachlorobenzene and marker PCBs (PCB 138, 153 and 180) and between serum levels of p,p'-DDE above the p90 and higher serum values of carcinoembryonic antigen. Significant associations were also found between effect biomarkers and occupational or lifestyle parameters. CONCLUSION: Levels of internal exposure, and residence near waste incinerators, in cities, or close to important industries, but not in areas with intensive use of pesticides, showed positive correlations with biomarkers associated with carcinogenesis and thus probably contribute to risk of cancer. In some rural areas, the levels of these biomarkers were not lower than in the rest of Flanders.