The risk of acquiring a chronic disease is influenced by a person's genetics (G) and exposures received during life (the 'exposome', E) plus their interactions (G×E). Yet, investigators use ...genome-wide association studies (GWAS) to characterize G while relying on self-reported information to classify E. If E and G×E dominate disease risks, this imbalance obscures important causal factors. To estimate proportions of disease risk attributable to G (plus shared exposures), published data from Western European monozygotic (MZ) twins were used to estimate population attributable fractions (PAFs) for 28 chronic diseases. Genetic PAFs ranged from 3.4% for leukemia to 48.6% for asthma with a median value of 18.5%. Cancers had the lowest PAFs (median = 8.26%) while neurological (median = 26.1%) and lung (median = 33.6%) diseases had the highest PAFs. These PAFs were then linked with Western European mortality statistics to estimate deaths attributable to G for heart disease and nine cancer types. Of 1.53 million Western European deaths in 2000, 0.25 million (16.4%) could be attributed to genetics plus shared exposures. Given the modest influences of G-related factors on the risks of chronic diseases in MZ twins, the disparity in coverage of G and E in etiological research is problematic. To discover causes of disease, GWAS should be complemented with exposome-wide association studies (EWAS) that profile chemicals in biospecimens from incident disease cases and matched controls.
During the 1920s, the forerunners of exposure science collaborated with health professionals to investigate the causes of occupational diseases. With the birth of U.S. regulatory agencies in the ...1970s, interest in the environmental origins of human diseases waned, and exposure scientists focused instead upon levels of selected contaminants in air and water. In fact, toxic chemicals enter the body not only from exogenous sources (air, water, diet, drugs, and radiation) but also from endogenous processes, including inflammation, lipid peroxidation, oxidative stress, existing diseases, infections, and gut flora. Thus, even though current evidence suggests that non-genetic factors contribute about 90% of the risks of chronic diseases, we have not explored the vast majority of human exposures that might initiate disease processes. The concept of the exposome, representing the totality of exposures received by a person during life, encompasses all sources of toxicants and, therefore, offers scientists an agnostic approach for investigating the environmental causes of chronic diseases. In this context, it is appropriate to regard the "environment" as the body's internal chemical environment and to define "exposures" as levels of biologically active chemicals in this internal environment. To explore the exposome, it makes sense to employ a top-down approach based upon biomonitoring (e.g. blood sampling) rather than a bottom-up approach that samples air, water, food, and so on. Because sources and levels of exposure change over time, exposomes can be constructed by analyzing toxicants in blood specimens obtained during critical stages of life. Initial investigations could use archived blood from prospective cohort studies to measure important classes of toxic chemicals, notably, reactive electrophiles, metals, metabolic products, hormone-like substances, and persistent organic compounds. The exposome offers health scientists an avenue for integrating research that is currently fractured along lines related to particular diseases and risk factors, and can thereby promote discovery of the key exposures responsible for chronic diseases. By embracing the exposome as its operational paradigm, exposure science can play a major role in discovering and mitigating these exposures.
Environment and Disease Risks Rappaport, Stephen M.; Smith, Martyn T.
Science,
10/2010, Letnik:
330, Številka:
6003
Journal Article
Recenzirano
Odprti dostop
A new paradigm is needed to assess how a lifetime of exposure to environmental factors affects the risk of developing chronic diseases.
Although the risks of developing chronic diseases are ...attributed to both genetic and environmental factors, 70 to 90% of disease risks are probably due to differences in environments (
1
–
3
). Yet, epidemiologists increasingly use genome-wide association studies (GWAS) to investigate diseases, while relying on questionnaires to characterize “environmental exposures.” This is because GWAS represent the only approach for exploring the totality of any risk factor (genes, in this case) associated with disease prevalence. Moreover, the value of costly genetic information is diminished when inaccurate and imprecise environmental data lead to biased inferences regarding gene-environment interactions (
4
). A more comprehensive and quantitative view of environmental exposure is needed if epidemiologists are to discover the major causes of chronic diseases.
Since 2001, researchers have examined the human genome (G) mainly to discover causes of disease, despite evidence that G explains relatively little risk. We posit that unexplained disease risks are ...caused by the exposome (E; representing all exposures) and G × E interactions. Thus, etiologic research has been hampered by scientists' continuing reliance on low-tech methods to characterize E compared with high-tech omics for characterizing G.
Because exposures are inherently chemical in nature and arise from both endogenous and exogenous sources, blood specimens can be used to characterize exposomes. To explore the "blood exposome" and its connection to disease, we sought human blood concentrations of many chemicals, along with their sources, evidence of chronic-disease risks, and numbers of metabolic pathways.
From the literature we obtained human blood concentrations of 1,561 small molecules and metals derived from foods, drugs, pollutants, and endogenous processes. We mapped chemical similarities after weighting by blood concentrations, disease-risk citations, and numbers of human metabolic pathways.
Blood concentrations spanned 11 orders of magnitude and were indistinguishable for endogenous and food chemicals and drugs, whereas those of pollutants were 1,000 times lower. Chemical similarities mapped by disease risks were equally distributed by source categories, but those mapped by metabolic pathways were dominated by endogenous molecules and essential nutrients.
For studies of disease etiology, the complexity of human exposures motivates characterization of the blood exposome, which includes all biologically active chemicals. Because most small molecules in blood are not human metabolites, investigations of causal pathways should expand beyond the endogenous metabolome.
There is increasing evidence that environmental, rather than genetic, factors are the major causes of most chronic diseases. By measuring entire classes of chemicals in archived biospecimens, ...exposome-wide association studies (EWAS) are being conducted to investigate associations between a myriad of exposures received during life and chronic diseases.
Because the intraindividual variability in biomarker levels, arising from changes in environmental exposures from conception onwards, leads to attenuation of exposure-disease associations, we posit that saliva can be collected repeatedly in longitudinal studies to reduce exposure-measurement errors in EWAS.
From the literature and an open-source saliva-metabolome database, we obtained concentrations of 1,233 chemicals that had been detected in saliva. We connected salivary metabolites with human metabolic pathways and PubMed Medical Subject Heading (MeSH) terms, and performed pathway enrichment and pathway topology analyses.
One hundred ninety-six salivary metabolites were mapped into 49 metabolic pathways and connected with human metabolic diseases, central nervous system diseases, and neoplasms. We found that the saliva exposome represents at least 14 metabolic pathways, including amino acid metabolism, TCA cycle, gluconeogenesis, glutathione metabolism, pantothenate and CoA biosynthesis, and butanoate metabolism.
Saliva contains molecular information worthy of interrogation via EWAS. The simplicity of specimen collection suggests that saliva offers a practical alternative to blood for measurements that can be used to characterize individual exposomes. https://doi.org/10.1289/EHP1011.
The feasibility of microwave breast cancer detection with a time-reversal (TR) algorithm is examined. This algorithm is based on the finite-difference time-domain method, and compensates for the wave ...decay and, therefore, is suitable for lossy media. In this paper, we consider a two-dimensional breast model based on magnetic resonance imaging data, and examine the focusing abilities of a TR mirror comprised of an array of receivers with a single ultra-wideband pulse excitation. In order to resolve small 3-mm-diameter tumors, a very short duration pulse is necessary, and this requirement may restrict the applicability of the system due to hardware limitations. We propose a way to overcome this obstacle based on the observation that the amplitude and phase information of the tumor response is sufficient to achieve focusing. The robustness of the TR algorithm with respect to breast inhomogeneities is demonstrated, and the good performance of the method suggests it is a promising technique for microwave breast cancer detection.
Etiological studies of human exposures to environmental factors typically rely on low-throughput methods that target only a few hundred chemicals or mixtures. In this Perspectives article, I outline ...how environmental exposure can be defined by the blood exposome-the totality of chemicals circulating in blood. The blood exposome consists of chemicals derived from both endogenous and exogenous sources. Endogenous chemicals are represented by the human proteome and metabolome, which establish homeostatic networks of functional molecules. Exogenous chemicals arise from diet, vitamins, drugs, pathogens, microbiota, pollution, and lifestyle factors, and can be measured in blood as subsets of the proteome, metabolome, metals, macromolecular adducts, and foreign DNA and RNA. To conduct 'exposome-wide association studies', blood samples should be obtained prospectively from subjects-preferably at critical stages of life-and then analyzed in incident disease cases and matched controls to find discriminating exposures. Results from recent metabolomic investigations of archived blood illustrate our ability to discover potentially causal exposures with current technologies.
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