Imperial College London

Dr Toby Athersuch

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3806toby.athersuch Website

 
 
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Location

 

101Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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60 results found

Kuhn LT, MotiramCorral K, Athersuch TJ, Parella T, PérezTrujillo Met al., 2020, Simultaner enantiospezifischer Nachweis mehrerer Verbindungen in Mischungen mittels NMR‐Spektroskopie, Angewandte Chemie, Vol: 132, Pages: 23821-23826, ISSN: 0044-8249

Journal article

Kuhn LT, Motiram-Corral K, Athersuch TJ, Parella T, Pérez-Trujillo Met al., 2020, Simultaneous enantiospecific detection of multiple compounds in mixtures using NMR spectroscopy., Angewandte Chemie International Edition, Vol: 59, Pages: 23615-23619, ISSN: 1433-7851

Chirality plays a fundamental role in nature, but its detection and quantification still face many limitations. To date, the enantiospecific analysis of mixtures necessarily requires prior separation of the individual components. The simultaneous enantiospecific detection of multiple chiral molecules in a mixture represents a major challenge, which would lead to a significantly better understanding of the underlying biological processes; for example, via enantiospecifically analysing metabolites in their native environment. Here, we report on the first in situ enantiospecific detection of a thirty-nine-component mixture. As a proof of concept, eighteen essential amino acids at physiological concentrations were simultaneously enantiospecifically detected using NMR spectroscopy and a chiral solvating agent. This work represents a first step towards the simultaneous multicomponent enantiospecific analysis of complex mixtures, a capability that will have substantial impact on metabolism studies, metabolic phenotyping, chemical reaction monitoring, and many other fields where complex mixtures containing chiral molecules require efficient characterisation.

Journal article

Wilson I, Athersuch T, Bradshaw P, stachulski Aet al., 2020, Acyl glucuronide reactivity in perspective, Drug Discovery Today, Vol: 25, Pages: 1639-1650, ISSN: 1359-6446

Acyl glucuronidation is a common metabolic fate for acidic drugs andtheir metabolites and, because these metabolites are reactive, they havebeen linked to adverse drug reactions (ADRs) and drug withdrawals.However, alternative routes of metabolism leading to reactive metabolites(e.g., oxidations and acyl-CoA thioesters) mean that unambiguous proofthat acyl glucuronides are toxic is lacking. Here, we review the synthesisand reactivity of these metabolites, and describe the use of molecularmodelling and in vitro and in vivo reactivity assessment of acyl glucuronidereactivity. Based on the emerging structure-dependent differences inreactivity and protein adduction methods for risk assessment for acylglucuronide-forming acid drugs or drug candidates in drug discovery/development are suggested.

Journal article

Selley L, Schuster L, Marbach H, Forsthuber T, Forbes B, Gant TW, Sandstrom T, Camina N, Athersuch TJ, Mudway I, Kumar Aet al., 2020, Brake dust exposure exacerbates inflammation and transiently compromises phagocytosis in macrophages, Metallomics: integrated biometal science, Vol: 12, Pages: 371-386, ISSN: 1756-5901

Studies have emphasised the importance of combustion-derived particles in eliciting adverse health effects, especially those produced by diesel vehicles. In contrast, few investigations have explored the potential toxicity of particles derived from tyre and brake wear, despite their significant contributions to total roadside particulate mass. The objective of this study was to compare the relative toxicity of compositionally distinct brake abrasion dust (BAD) and diesel exhaust particles (DEP) in a cellular model that is relevant to human airways. Although BAD contained considerably more metals/metalloids than DEP (as determined by inductively coupled plasma mass spectrometry) similar toxicological profiles were observed in U937 monocyte-derived macrophages following 24 h exposures to 4–25 μg ml−1 doses of either particle type. Responses to the particles were characterised by dose-dependent decreases in mitochondrial depolarisation (p ≤ 0.001), increased secretion of IL-8, IL-10 and TNF-α (p ≤ 0.05 to p ≤ 0.001) and decreased phagocytosis of S. aureus (p ≤ 0.001). This phagocytic deficit recovered, and the inflammatory response resolved when challenged cells were incubated for a further 24 h in particle-free media. These responses were abrogated by metal chelation using desferroxamine. At minimally cytotoxic doses both DEP and BAD perturbed bacterial clearance and promoted inflammatory responses in U937 cells with similar potency. These data emphasise the requirement to consider contributions of abrasion particles to traffic-related clinical health effects.

Journal article

Bradshaw P, Richards S, Wilson I, Stachulski A, Lindon J, Athersuch Tet al., 2020, Kinetic modelling of acyl glucuronide and glucoside reactivity and development of structure-property relationships, Organic and Biomolecular Chemistry, Vol: 18, Pages: 1389-1401, ISSN: 1477-0520

Acyl glucuronide metabolites have been implicated in the toxicity of several carboxylic acid-containing drugs, and the rate of their degradation via intramolecular transacylation and hydrolysis has been associated with the degree of protein adduct formation. Although not yet proven, the formation of protein adducts in vivo-and subsequent downstream effects -has been proposed as amechanism of toxicity for carboxylic acid-containing xenobiotics capable of forming acyl glucuronides. A structurally-related series of metabolites, the acyl glucosides, have also been shown to undergo similar degradation reactions and consequently the potential todisplay a similar mode of toxicity.Here we reportdetailedkinetic modelsof each transacylation and hydrolysis reaction for a series of phenylacetic acid acyl glucuronides and their analogous acyl glucosides. Differences in reactivity were observed for the individual transacylation steps between the compound series; our findings suggest that the chargedcarboxylateion and neutral hydroxyl group in the glucuronideand glucoside conjugates, respectively, are responsible for these differences. The transacylation reaction was modelled using density functional theory and the calculated activation energy for this reaction showed a close correlation with thedegradation rateof the 1-banomer.Comparison of optimised geometries between the two series of conjugates revealed differences in hydrogen bondingwhich may further explain the differencesin reactivity observed. Together, these models may find application in drug discovery for prediction ofacyl glucuronide and glucoside metabolitebehaviour.

Journal article

Georgiadis P, Gavriil M, Rantakokko P, Ladoukakis E, Botsivali M, Kelly RS, Bergdahl IA, Kiviranta H, Vermeulen RCH, Spaeth F, Hebbels DGAJ, Kleinjans JCS, de Kok TMCM, Palli D, Vineis P, Kyrtopoulos SA, EnviroGenomarkers consortiumet al., 2019, DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia, Environment International, Vol: 126, Pages: 24-36, ISSN: 0160-4120

OBJECTIVES: To characterize the impact of PCB exposure on DNA methylation in peripheral blood leucocytes and to evaluate the corresponding changes in relation to possible health effects, with a focus on B-cell lymphoma. METHODS: We conducted an epigenome-wide association study on 611 adults free of diagnosed disease, living in Italy and Sweden, in whom we also measured plasma concentrations of 6 PCB congeners, DDE and hexachlorobenzene. RESULTS: We identified 650 CpG sites whose methylation correlates strongly (FDR < 0.01) with plasma concentrations of at least one PCB congener. Stronger effects were observed in males and in Sweden. This epigenetic exposure profile shows extensive and highly statistically significant overlaps with published profiles associated with the risk of future B-cell chronic lymphocytic leukemia (CLL) as well as with clinical CLL (38 and 28 CpG sites, respectively). For all these sites, the methylation changes were in the same direction for increasing exposure and for higher disease risk or clinical disease status, suggesting an etiological link between exposure and CLL. Mediation analysis reinforced the suggestion of a causal link between exposure, changes in DNA methylation and disease. Disease connectivity analysis identified multiple additional diseases associated with differentially methylated genes, including melanoma for which an etiological link with PCB exposure is established, as well as developmental and neurological diseases for which there is corresponding epidemiological evidence. Differentially methylated genes include many homeobox genes, suggesting that PCBs target stem cells. Furthermore, numerous polycomb protein target genes were hypermethylated with increasing exposure, an effect known to constitute an early marker of carcinogenesis. CONCLUSIONS: This study provides mechanistic evidence in support of a link between exposure to PCBs and the etiology of CLL and underlines the utility of omic profiling in the evaluation o

Journal article

Lau CH, Siskos AP, Maitre L, Robinson O, Athersuch TJ, Want EJ, Urquiza J, Casas M, Vafeiadi M, Roumeliotaki T, McEachan RRC, Azad R, Haug LS, Meltzer HM, Andrusaityte S, Petraviciene I, Grazuleviciene R, Thomsen C, Wright J, Slama R, Chatzi L, Vrijheid M, Keun HC, Coen Met al., 2018, Determinants of the urinary and serum metabolome in children from six European populations, BMC Medicine, Vol: 16, ISSN: 1741-7015

BackgroundEnvironment and diet in early life can affect development and health throughout the life course. Metabolic phenotyping of urine and serum represents a complementary systems-wide approach to elucidate environment–health interactions. However, large-scale metabolome studies in children combining analyses of these biological fluids are lacking. Here, we sought to characterise the major determinants of the child metabolome and to define metabolite associations with age, sex, BMI and dietary habits in European children, by exploiting a unique biobank established as part of the Human Early-Life Exposome project (http://www.projecthelix.eu).MethodsMetabolic phenotypes of matched urine and serum samples from 1192 children (aged 6–11) recruited from birth cohorts in six European countries were measured using high-throughput 1H nuclear magnetic resonance (NMR) spectroscopy and a targeted LC-MS/MS metabolomic assay (Biocrates AbsoluteIDQ p180 kit).ResultsWe identified both urinary and serum creatinine to be positively associated with age. Metabolic associations to BMI z-score included a novel association with urinary 4-deoxyerythronic acid in addition to valine, serum carnitine, short-chain acylcarnitines (C3, C5), glutamate, BCAAs, lysophosphatidylcholines (lysoPC a C14:0, lysoPC a C16:1, lysoPC a C18:1, lysoPC a C18:2) and sphingolipids (SM C16:0, SM C16:1, SM C18:1). Dietary-metabolite associations included urinary creatine and serum phosphatidylcholines (4) with meat intake, serum phosphatidylcholines (12) with fish, urinary hippurate with vegetables, and urinary proline betaine and hippurate with fruit intake. Population-specific variance (age, sex, BMI, ethnicity, dietary and country of origin) was better captured in the serum than in the urine profile; these factors explained a median of 9.0% variance amongst serum metabolites versus a median of 5.1% amongst urinary metabolites. Metabolic pathway correlations were identified, and concentrations of

Journal article

Vermeulen R, Saberi Hosnijeh F, Bodinier B, Portengen L, Liquet B, Garrido Manriquez J, Lokhorst H, Bergdahl I, Kyrtopoulos S, Johansson A-S, Georgiadis P, Melin B, Palli D, Krogh V, Panico S, Sacerdote C, Tumino R, Vineis P, Castagne RS, Chadeau Met al., 2018, Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma; univariate and functionally-informed multivariate analyses, International Journal of Cancer, Vol: 143, Pages: 1335-1347, ISSN: 0020-7136

Recent prospective studies have shown that dysregulation of the immune system may precede the development of B-cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case-control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years prior to diagnosis (range, 2.01-15.97) in 268 incident cases of BCL (including multiple myeloma) and matched controls. Linear mixed models, and Partial Least Square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes, and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed modelIrrespective of the model, our analyses identified associations linking blood lower immune markerslevels of and BCL incidence. In particular, we identified growth factors, and within that family, fibroblast growth factor-2 (FGF-2,p=7.2x10-4), ) and transforming growth factor alpha (TGF-α, p=6.5x10-5) and BCL incidence.Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF-2 (p=7.8x10-7), TGF-α (p=4.08x10-5),fractalkine (p=1.12x10-3), monocyte chemotactic protein-3 (p=1.36x10-4), macrophage inflammatory protein 1-alpha (p=4.6x10-4), and vascular endothelial growth factor (p=4.23x10-5). , and vascular endothelial growth factor (VEGF), to be consistently (and inversely) associated with MM incidence. Our results also provided marginal support for already reported associations between chemokines and diffuse large B-Cell lymphoma (DLBCL), and cytokines and chronic lymphocytic leukemia (CLL). Case-only analyses showed that GM-CSF levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression.In conclusion, our study suggests a role of gr

Journal article

Berger E, Delpierre C, Hosnijeh FS, Kelly-Irving M, Portengen L, Bergdahl IA, Johansson A-S, Krogh V, Palli D, Panico S, Sacerdote C, Tumino R, Kyrtopoulos SA, Vineis P, Chadeau-Hyam M, Vermeulen R, Castagne Ret al., 2018, Association between low-grade inflammation and Breast cancer and B-cell Myeloma and Non-Hodgkin Lymphoma: findings from two prospective cohorts, Scientific Reports, Vol: 8, ISSN: 2045-2322

Chronic inflammation may be involved in cancer development and progression. Using 28 inflammatory-related proteins collected from prospective blood samples from two case-control studies nested in the Italian component of the European Prospective Investigation into Cancer and nutrition (n = 261) and in the Northern Sweden Health and Disease Study (n = 402), we tested the hypothesis that an inflammatory score is associated with breast cancer (BC) and Β-cell Non-Hodgkin Lymphoma (B-cell NHL, including 68 multiple myeloma cases) onset. We modelled the relationship between this inflammatory score and the two cancers studied: (BC and B-cell NHL) using generalised linear models, and assessed, through adjustments the role of behaviours and lifestyle factors. Analyses were performed by cancer types pooling both populations, and stratified by cohorts, and time to diagnosis. Our results suggested a lower inflammatory score in B-cell NHL cases (β = −1.28, p = 0.012), and, to lesser, extent with BC (β = −0.96, p = 0.33) compared to controls, mainly driven by cancer cases diagnosed less than 6 years after enrolment. These associations were not affected by subsequent adjustments for potential intermediate confounders, notably behaviours. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated. These observations call for further studies involving larger populations, larger variety of cancer types and repeated measures of larger panel of inflammatory markers.

Journal article

Carr A-JF, Swann C, Radeke MJ, Rudd T, Man J, Keun H, Athersuch T, Coffey PJet al., 2018, Using ARPE-19 cells to investigate pathways associated with retinal pigment epithelium differentiation., Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404

Conference paper

Chadeau M, Jain P, Vineis P, Liquet B, Vlaanderen J, Bodinier B, van Veldhoven C, Kogevinas M, Athersuch TJ, Font-Ribera L, Villanueva C, Vermeulen Ret al., 2018, A multivariate approach to investigate the combined biological effects of multiple exposures, Journal of Epidemiology and Community Health, Vol: 72, Pages: 564-571, ISSN: 0143-005X

Epidemiological studies provide evidence that environmental exposures may affect health through complex mixtures. Formal investigation of the effect of exposure mixtures is usually achieved by modelling interactions, which relies on strong assumptions relating to the identity and the number of the exposures involved in such interactions, and on the order and parametric form of these interactions. These hypotheses become difficult to formulate and justify in an exposome context, where influential exposures are numerous and heterogeneous. To capture both the complexity of the exposome, and its possibly pleiotropic effects, models handling multivariate predictors and responses, such as partial least squares (PLS) algorithms, can prove useful. As an illustrative example, we applied PLS models to data from a study investigating the inflammatory response (blood concentration of 13 immune markers) to the exposure to four disinfection by-products (one brominated and three chlorinated compounds), while swimming in a pool. To accommodate the multiple observations per participant (N=60; before and after the swim), we adopted a multi-level extension of the PLS algorithms, including sparse PLS models shrinking loadings coefficients of unimportant predictors (exposures), and/or responses (protein levels). Despite the strong correlation among co-occurring exposures, our approach identified a subset of exposures (N=3/4) affecting the exhaled levels of 8 (out of 13) immune markers. PLS algorithms can easily scale to high-dimensional exposures and responses, and prove useful for exposome research to identify sparse sets of exposures jointly affecting a set of (selected) biological markers. Our descriptive work may guide these extensions for higher dimensional data.

Journal article

Athersuch TJ, Antoine DJ, Boobis AR, Coen M, Daly AK, Possamai L, Nicholson JK, Wilson IDet al., 2018, Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective, Toxicology Research, Vol: 7, Pages: 347-357, ISSN: 2045-452X

After over 60 years of therapeutic use in the UK, paracetamol (acetaminophen, N-acetyl-p-aminophenol, APAP) remains the subject of considerable research into both its mode of action and toxicity. The pharmacological properties of APAP are the focus of some activity, with the role of the metabolite N-arachidonoylaminophenol (AM404) still a topic of debate. However, that the hepatotoxicity of APAP results from the production of the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI/NABQI) that can deplete glutathione, react with cellular macromolecules, and initiate cell death, is now beyond dispute. The disruption of cellular pathways that results from the production of NAPQI provides a source of potential biomarkers of the severity of the damage. Research in this area has provided new diagnostic markers such as the microRNA miR-122 as well as mechanistic biomarkers associated with apoptosis, mitochondrial dysfunction, inflammation and tissue regeneration. Additionally, biomarkers of, and systems biology models for, glutathione depletion have been developed. Furthermore, there have been significant advances in determining the role of both the innate immune system and genetic factors that might predispose individuals to APAP-mediated toxicity. This perspective highlights some of the progress in current APAP-related research.

Journal article

Bradshaw P, Wilson I, Upcott Gill R, Butler P, Dilworth C, Athersuch TJet al., 2018, Metabolic Hydrolysis of Aromatic Amides in Selected Rat, Minipig, and Human In Vitro Systems, Scientific Reports, Vol: 8, ISSN: 2045-2322

The release of aromatic amines from drugs and other xenobiotics resulting from the hydrolysis of metabolically labile amide bonds presents a safety risk through several mechanisms, including geno-, hepato- and nephrotoxicity. Whilst multiple in vitro systems used for studying metabolic stability display serine hydrolase activity, responsible for the hydrolysis of amide bonds, they vary in their efficiency and selectivity. Using a range of amide-containing probe compounds (0.5–10 µM), we have investigated the hydrolytic activity of several rat, minipig and human-derived in vitro systems - including Supersomes, microsomes, S9 fractions and hepatocytes - with respect to their previously observed human in vivo metabolism. In our hands, human carboxylesterase Supersomes and rat S9 fractions systems showed relatively poor prediction of human in vivo metabolism. Rat S9 fractions, which are commonly utilised in the Ames test to assess mutagenicity, may be limited in the detection of genotoxic metabolites from aromatic amides due to their poor concordance with human in vivo amide hydrolysis. In this study, human liver microsomes and minipig subcellular fractions provided more representative models of human in vivo hydrolytic metabolism of the aromatic amide compounds tested.

Journal article

Athersuch TJ, Lau CH, Behrends V, Keun HCet al., 2018, CHAPTER 13: NMR Spectroscopy of Cell Culture, Tissues, and Other Biofluids, New Developments in NMR, Pages: 324-359, ISBN: 9781788011044

NMR spectroscopy can provide a wealth of information on cellular metabolism and is frequently used in metabolomics application that use cultured cells, tissues, and whole organisms. Central to these analyses are the protocols for sample harvest, which incorporate procedures for quenching metabolic processes to preserve samples in a state that is representative of their source. In this chapter, the main considerations are discussed with reference to literature exemplars. In the latter half of the chapter, less commonly studied biofluids that also have specific sample preparation requirements are discussed, with a focus on cerebrospinal fluid, faeces, bile, seminal fluid, and milk.

Book chapter

Johnson CH, Athersuch TJ, Collman GW, Dhungana S, Grant DF, Jones DP, Patel CJ, Vasiliou Vet al., 2017, Yale school of public health symposium on lifetime exposures and human health: the exposome; summary and future reflections, Human Genomics, Vol: 11, ISSN: 1479-7364

The exposome is defined as "the totality of environmental exposures encountered from birth to death" and was developed to address the need for comprehensive environmental exposure assessment to better understand disease etiology. Due to the complexity of the exposome, significant efforts have been made to develop technologies for longitudinal, internal and external exposure monitoring, and bioinformatics to integrate and analyze datasets generated. Our objectives were to bring together leaders in the field of exposomics, at a recent Symposium on "Lifetime Exposures and Human Health: The Exposome," held at Yale School of Public Health. Our aim was to highlight the most recent technological advancements for measurement of the exposome, bioinformatics development, current limitations, and future needs in environmental health. In the discussions, an emphasis was placed on moving away from a one-chemical one-health outcome model toward a new paradigm of monitoring the totality of exposures that individuals may experience over their lifetime. This is critical to better understand the underlying biological impact on human health, particularly during windows of susceptibility. Recent advancements in metabolomics and bioinformatics are driving the field forward in biomonitoring and understanding the biological impact, and the technological and logistical challenges involved in the analyses were highlighted. In conclusion, further developments and support are needed for large-scale biomonitoring and management of big data, standardization for exposure and data analyses, bioinformatics tools for co-exposure or mixture analyses, and methods for data sharing.

Journal article

Georgiadis P, Liampa I, Hebels DG, Krauskopf J, Chatziioannou A, Valavanis I, de Kok TMCM, Kleinjans JCS, Bergdahl IA, Melin B, Spaeth F, Palli D, Vermeulen RCH, Vlaanderen J, Chadeau-Hyam M, Vineis P, Kyrtopoulos SA, EnviroGenomarkers consortiumet al., 2017, Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis., BMC Genomics, Vol: 18, ISSN: 1471-2164

BACKGROUND: B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance. RESULTS: We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0-15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while

Journal article

Ghezzi P, Floridi L, Boraschi D, Cuadrado A, Manda G, Levic S, D'Acquisto F, Hamilton A, Athersuch TJ, Selley Let al., 2017, Oxidative Stress and Inflammation Induced by Environmental and Psychological Stressors: A Biomarker Perspective., Antioxidants and Redox Signaling, Vol: 28, Pages: 852-872, ISSN: 1523-0864

SIGNIFICANCE: The environment can elicit biological responses such as oxidative stress (OS) and inflammation as a consequence of chemical, physical, or psychological changes. As population studies are essential for establishing these environment-organism interactions, biomarkers of OS or inflammation are critical in formulating mechanistic hypotheses. Recent Advances: By using examples of stress induced by various mechanisms, we focus on the biomarkers that have been used to assess OS and inflammation in these conditions. We discuss the difference between biomarkers that are the result of a chemical reaction (such as lipid peroxides or oxidized proteins that are a result of the reaction of molecules with reactive oxygen species) and those that represent the biological response to stress, such as the transcription factor NRF2 or inflammation and inflammatory cytokines. CRITICAL ISSUES: The high-throughput and holistic approaches to biomarker discovery used extensively in large-scale molecular epidemiological exposome are also discussed in the context of human exposure to environmental stressors. FUTURE DIRECTIONS: We propose to consider the role of biomarkers as signs and to distinguish between signs that are just indicators of biological processes and proxies that one can interact with and modify the disease process.

Journal article

Maitre L, Lau C-HE, Vizcaino E, Robinson O, Casas M, Siskos AP, Want EJ, Athersuch T, Slama R, Vrijheid M, Keun HC, Coen Met al., 2017, Assessment of metabolic phenotypic variability in children's urine using H-1 NMR spectroscopy, Scientific Reports, Vol: 7, ISSN: 2045-2322

The application of metabolic phenotyping in clinical and epidemiological studies is limited by a poor understanding of inter-individual, intra-individual and temporal variability in metabolic phenotypes. Using 1H NMR spectroscopy we characterised short-term variability in urinary metabolites measured from 20 children aged 8–9 years old. Daily spot morning, night-time and pooled (50:50 morning and night-time) urine samples across six days (18 samples per child) were analysed, and 44 metabolites quantified. Intraclass correlation coefficients (ICC) and mixed effect models were applied to assess the reproducibility and biological variance of metabolic phenotypes. Excellent analytical reproducibility and precision was demonstrated for the 1H NMR spectroscopic platform (median CV 7.2%). Pooled samples captured the best inter-individual variability with an ICC of 0.40 (median). Trimethylamine, N-acetyl neuraminic acid, 3-hydroxyisobutyrate, 3-hydroxybutyrate/3-aminoisobutyrate, tyrosine, valine and 3-hydroxyisovalerate exhibited the highest stability with over 50% of variance specific to the child. The pooled sample was shown to capture the most inter-individual variance in the metabolic phenotype, which is of importance for molecular epidemiology study design. A substantial proportion of the variation in the urinary metabolome of children is specific to the individual, underlining the potential of such data to inform clinical and exposome studies conducted early in life.

Journal article

Chatziioannou A, Georgiadis P, Hebels DG, Liampa I, Valavanis I, Bergdahl IA, Johansson A, Palli D, Chadeau-Hyam M, Siskos AP, Keun H, Botsivali M, de Kok TMCM, Perez AE, Kleinjans JCS, Vineis P, Kyrtopoulos SAet al., 2017, Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

We recently reported that differential gene expression and DNA methylation profiles in blood leukocytes of apparently healthy smokers predicts with remarkable efficiency diseases and conditions known to be causally associated with smoking, suggesting that blood-based omic profiling of human populations may be useful for linking environmental exposures to potential health effects. Here we report on the sex-specific effects of tobacco smoking on transcriptomic and epigenetic features derived from genome-wide profiling in white blood cells, identifying 26 expression probes and 92 CpG sites, almost all of which are affected only in female smokers. Strikingly, these features relate to numerous genes with a key role in the pathogenesis of cardiovascular disease, especially thrombin signaling, including the thrombin receptors on platelets F2R (coagulation factor II (thrombin) receptor; PAR1) and GP5 (glycoprotein 5), as well as HMOX1 (haem oxygenase 1) and BCL2L1 (BCL2-like 1) which are involved in protection against oxidative stress and apoptosis, respectively. These results are in concordance with epidemiological evidence of higher female susceptibility to tobacco-induced cardiovascular disease and underline the potential of blood-based omic profiling in hazard and risk assessment.

Journal article

Athersuch TJ, 2016, Emergence of new properties in the investigation of disease aetiology: The contribution of omics, 52nd Congress of the European-Societies-of-Toxicology (EUROTOX), Publisher: ELSEVIER IRELAND LTD, Pages: S33-S33, ISSN: 0378-4274

Conference paper

Georgiadis P, Hebels DG, Valavanis I, Liampa I, Bergdahl IA, Johansson A, Palli D, Chadeau-Hyam M, Chatziioannou A, Jennen DGJ, Krauskopf J, Jetten MJ, Kleinjans JCS, Vineis P, Kyrtopoulos SAet al., 2016, Omics for prediction of environmental health effects: blood leukocyte-based cross-omic profiling reliably predicts diseases associated with tobacco smoking, Scientific Reports, Vol: 6, ISSN: 2045-2322

The utility of blood-based omic profiles for linking environmental exposures to their potential health effects was evaluated in 649 individuals, drawn from the general population, in relation to tobacco smoking, an exposure with well-characterised health effects. Using disease connectivity analysis, we found that the combination of smoking-modified, genome-wide gene (including miRNA) expression and DNA methylation profiles predicts with remarkable reliability most diseases and conditions independently known to be causally associated with smoking (indicative estimates of sensitivity and positive predictive value 94% and 84%, respectively). Bioinformatics analysis reveals the importance of a small number of smoking-modified, master-regulatory genes and suggest a central role for altered ubiquitination. The smoking-induced gene expression profiles overlap significantly with profiles present in blood cells of patients with lung cancer or coronary heart disease, diseases strongly associated with tobacco smoking. These results provide proof-of-principle support to the suggestion that omic profiling in peripheral blood has the potential of identifying early, disease-related perturbations caused by toxic exposures and may be a useful tool in hazard and risk assessment.

Journal article

Athersuch T, 2016, Metabolome analyses in exposome studies: Profiling methods for a vast chemical space, Archives of Biochemistry and Biophysics, Vol: 589, Pages: 177-186, ISSN: 1096-0384

Metabolic profiling (metabonomics/metabolomics) is now used routinely as a tool to provide information-rich datasets for biomarker discovery, prompting and augmenting detailed mechanistic studies. The experimental design and focus of any individual study will be reflected in the types of biomarkers that can be detected; toxicological studies will likely focus on markers of response to insult, whereas clinical case-control studies may yield diagnostic markers of disease. Population studies can make use of omics analyses, including metabonomics, to provide mechanistically-relevant markers that link environmental exposures to chronic disease endpoints. In this article, examples of how metabolic profiling has played a key role in molecular epidemiological analyses of chronic disease are presented, and how these reflect different aspects of the causal pathway. A commentary on the nature of metabolome analysis as a complex mixture problem as opposed to a coded, sequence or template problem is provided, alongside an overview of current and future analytical platforms that are being applied to meet this analytical challenge. Epidemiological studies are an important nexus for integrating various measures of the human exposome, and the ubiquity, diversity and functions of small molecule metabolites, represent an important way to link individual exposures, genetics and phenotype.

Journal article

Athersuch TJ, Keun HC, 2015, Metabolic profiling in human exposome studies, MUTAGENESIS, Vol: 30, Pages: 755-762, ISSN: 0267-8357

Journal article

Athersuch T, 2014, The role of metabolomics in characterising the human exposome, MUTAGENESIS, Vol: 29, Pages: 501-501, ISSN: 0267-8357

Journal article

Maitre L, 2014, Urinary metabolic profiles in early pregnancy are associated with preterm birth and fetal growth restriction in the Rhea mother–child cohort study, BMC Medicine, Vol: 12, ISSN: 1741-7015

BackgroundPreterm birth (PB) and fetal growth restriction (FGR) convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. Identifying early in pregnancy the unfavourable maternal conditions that can predict poor birth outcomes could help their prevention and management. Here we used an exploratory metabolic profiling approach (metabolomics) to investigate the association between birth outcomes and metabolites in maternal urine collected early in pregnancy as part of the prospective mother–child cohort Rhea study. Metabolomic techniques can simultaneously capture information about genotype and its interaction with the accumulated exposures experienced by an individual from their diet, environment, physical activity or disease (the exposome). As metabolic syndrome has previously been shown to be associated with PB in this cohort, we sought to gain further insight into PB-linked metabolic phenotypes and to define new predictive biomarkers.MethodsOur study was a case–control study nested within the Rhea cohort. Major metabolites (n = 34) in maternal urine samples collected at the end of the first trimester (n = 438) were measured using proton nuclear magnetic resonance spectroscopy. In addition to PB, we used FGR in weight and small for gestational age as study endpoints.ResultsWe observed significant associations between FGR and decreased urinary acetate (interquartile odds ratio (IOR) = 0.18 CI 0.04 to 0.60), formate (IOR = 0.24 CI 0.07 to 0.71), tyrosine (IOR = 0.27 CI 0.08 to 0.81) and trimethylamine (IOR = 0.14 CI 0.04 to 0.40) adjusting for maternal education, maternal age, parity, and smoking during pregnancy. These metabolites were inversely correlated with blood insulin. Women with clinically induced PB (IPB) had a significant increase in a glycoprotein N-acetyl resonance (IOR =&

Journal article

Chadeau-Hyam M, Vermeulen RCH, Hebels DGAJ, Castagne R, Campanella G, Portengen L, Kelly RS, Bergdahl IA, Melin B, Hallmans G, Palli D, Krogh V, Tumino R, Sacerdote C, Panico S, de Kok TMCM, Smith MT, Kleinjans JCS, Vineis P, Kyrtopoulos SAet al., 2014, Prediagnostic transcriptomic markers of Chronic lymphocytic leukemia reveal perturbations 10 years before diagnosis, Annals of Oncology, Vol: 25, Pages: 1065-1072, ISSN: 0923-7534

BackgroundB-cell lymphomas are a diverse group of hematological neoplasms with differential etiology and clinical trajectories. Increased insights in the etiology and the discovery of prediagnostic markers have the potential to improve the clinical course of these neoplasms.MethodsWe investigated in a prospective study global gene expression in peripheral blood mononuclear cells of 263 incident B-cell lymphoma cases, diagnosed between 1 and 17 years after blood sample collection, and 439 controls, nested within two European cohorts.ResultsOur analyses identified only transcriptomic markers for specific lymphoma subtypes; few markers of multiple myeloma (N = 3), and 745 differentially expressed genes in relation to future risk of chronic lymphocytic leukemia (CLL). The strongest of these associations were consistently found in both cohorts and were related to (B-) cell signaling networks and immune system regulation pathways. CLL markers exhibited very high predictive abilities of disease onset even in cases diagnosed more than 10 years after blood collection.ConclusionsThis is the first investigation on blood cell global gene expression and future risk of B-cell lymphomas. We mainly identified genes in relation to future risk of CLL that are involved in biological pathways, which appear to be mechanistically involved in CLL pathogenesis. Many but not all of the top hits we identified have been reported previously in studies based on tumor tissues, therefore suggesting that a mixture of preclinical and early disease markers can be detected several years before CLL clinical diagnosis.

Journal article

Vrijheid M, Slama R, Robinson O, Chatzi L, Coen M, van den Hazel P, Thomsen C, Wright J, Athersuch TJ, Avellana N, Basagana X, Brochot C, Bucchini L, Bustamante M, Carracedo A, Casas M, Estivill X, Fairley L, van Gent D, Gonzalez JR, Granum B, Grazuleviciene R, Gutzkow KB, Julvez J, Keun HC, Kogevinas M, McEachan RR, Meltzer HM, Sabido E, Schwarze PE, Siroux V, Sunyer J, Want EJ, Zeman F, Nieuwenhuijsen MJet al., 2014, The human early-life exposome (HELIX): project rationale and design, Environ Health Perspect, Vol: 122, Pages: 535-544, ISSN: 0091-6765

BACKGROUND: Developmental periods in early life may be particularly vulnerable to impacts of environmental exposures. Human research on this topic has generally focused on single exposure-health effect relationships. The "exposome" concept encompasses the totality of exposures from conception onward, complementing the genome. OBJECTIVES: The Human Early-Life Exposome (HELIX) project is a new collaborative research project that aims to implement novel exposure assessment and biomarker methods to characterize early-life exposure to multiple environmental factors and associate these with omics biomarkers and child health outcomes, thus characterizing the "early-life exposome." Here we describe the general design of the project. METHODS: In six existing birth cohort studies in Europe, HELIX will estimate prenatal and postnatal exposure to a broad range of chemical and physical exposures. Exposure models will be developed for the full cohorts totaling 32,000 mother-child pairs, and biomarkers will be measured in a subset of 1,200 mother-child pairs. Nested repeat-sampling panel studies (n = 150) will collect data on biomarker variability, use smartphones to assess mobility and physical activity, and perform personal exposure monitoring. Omics techniques will determine molecular profiles (metabolome, proteome, transcriptome, epigenome) associated with exposures. Statistical methods for multiple exposures will provide exposure-response estimates for fetal and child growth, obesity, neurodevelopment, and respiratory outcomes. A health impact assessment exercise will evaluate risks and benefits of combined exposures. CONCLUSIONS: HELIX is one of the first attempts to describe the early-life exposome of European populations and unravel its relation to omics markers and health in childhood. As proof of concept, it will form an important first step toward the life-course exposome.

Journal article

Athersuch TJ, Wilson ID, Keun HC, Lindon JCet al., 2013, Development of quantitative structure-metabolism (QSMR) relationships for substituted anilines based on computational chemistry, XENOBIOTICA, Vol: 43, Pages: 792-802, ISSN: 0049-8254

Journal article

Vineis P, van Veldhoven K, Chadeau-Hyam M, Athersuch TJet al., 2013, Advancing the application of omics-based biomarkers in environmental epidemiology, ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Vol: 54, Pages: 461-467, ISSN: 0893-6692

Journal article

Athersuch TJ, Malik S, Weljie A, Newton J, Keun HCet al., 2013, Evaluation of H-1 NMR Metabolic Profiling Using Biofluid Mixture Design, ANALYTICAL CHEMISTRY, Vol: 85, Pages: 6674-6681, ISSN: 0003-2700

Journal article

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