Molecular Epidemiology Group - UK

Committee

Dr Jill Ann McKay - Chairperson

Jill Ann McKay My research activities have centred upon the developmental origins of health and disease (DOHaD).  Increasing evidence supports the DOHaD hypothesis which argues for a causal relationship between early life events (i.e. environmental factors) and increased disease risk in later life.  Currently, the mechanisms behind these observed relationships are poorly understood.  However the modulation of epigenetic marks, e.g. DNA methylation and the consequential altered gene expression, has been proposed as a mechanism mediating these effects. 

In my appointed role as Lecturer in Molecular Epidemiology, I am developing a research programme to explore the DOHaD hypothesis in the context of childhood cancers. This will involve studies investigating the impact of environmental factors, such as folate nutrition during pregnancy, on epigenetic markers e.g. abnormal DNA methylation, associated with childhood cancers, the objective of which is to aid understanding of the causes of childhood cancer.

Memberships
United Kingdom Environmental Mutagen Society (UKEMS)
Children’s Cancer and Leukaemia Group (CCLG)
European Nutrigenomics Organisation (NuGO)

Links to own Institutes home pages
http://www.ncl.ac.uk/
http://www.ncl.ac.uk/ihs/about/
http://www.ncl.ac.uk/hnrc/about/

Latest publications

  • McKay, J.A., Groom, A., Potter, C., Coneyworth, L.J., Ford, D., Mathers, J.C., Relton, C.L. (2012) Genetic and non-genetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12. PLoS One. 7(3):e33290.
  • McKay, J.A., Wong, Y. Relton, C.L., Ford D., and Mathers, J.C. Maternal folate supply and sex influence gene-specific DNA methylation in the fetal gut. Molecular Nutrition and Food Research, 55(11), 1717-1723.
  • McKay, J.A., Williams E.A., and Mathers J.C. (2011) Effect of maternal and post weaning folate supply on gene-specific DNA methylation in the small intestine of weaning and adult Apc+/Min and wild type mice. Frontiers in Epigenomics, 2, 23.
  • McKay, J.A. and Mathers, J.C. (2011) Diet Induced Epigenetic Changes and their implications for Health. Acta Physiologica, 202(2), 103-118.
  • Palou, M., Picó, C., McKay, J.A., Sánchez, J., Priego, T., Mathers, J.C. and Palou, A. (2011) Protective effects of leptin during the suckling period against later obesity may be associated with changes in promoter methylation of the hypothalamic proopiomelanocortin gene. British Journal of Nutrition, 106(5), 769-778.
  • McKay, J.A., Xie, L., Harris, S., Wong, Y., Ford D., and Mathers, J.C. (2011) Blood as a surrogate marker for tissue specific methylation changes due to folate depletion in post-partum female mice. Molecular Nutrition and Food Research, 55(7)1026-1035.
  • McKay, J.A., Waltham K.J., Williams E.A., and Mathers, J.C. (2010) Folate depletion during pregnancy and lactation reduces genomic DNA methylation in murine adult offspring. Genes and Nutrition 6(2),189-196.
  • Mathers, J.C. and McKay J.A. (2009). Epigenetics – potential contribution to fetal programming. Adv Exp Med Biol. 646: 119-23.
  • McKay, J.A., Adriaens M.E., Ford D., Relton C.L., Evelo C.T. and Mathers, J.C. (2008). Bioinformatic interrogation of expression array data to identify nutritionally regulated genes potentially modulated by DNA methylation. Genes and Nutrition 3: 167-71.
  • McKay, J.A., Williams, E.A., and J.C. Mathers (2008) Gender-specific modulation of tumorigenesis by folic acid supply in the Apc mouse during early neonatal life. British Journal of Nutrition 99(3):550-8.

Dr Susan Duthie - Secretary

Susan DuthieMy research investigates how diet affects human health and particularly how nutrition influence cell function and genomic stability. I have determined mechanistically how specific phytochemicals influence DNA damage and DNA repair.  Dietary modulation of genomic stability is investigated at the level of the individual (human intervention and clinical studies) to alterations in specific cellular biomarkers (oxidised or altered DNA bases, sister chromatid exchanges, HPRT - mutant frequency and base excision repair (BER) capacity) in human and animal cells. The current focus of my research is to establish how folate influences DNA stability and DNA methylation in relation to CVD and colorectal cancer. I have established how folate status influences genomic stability, global protein expression (proteomics) and genome-wide DNA methylation in vitro, in rodent models and in human case-control and intervention studies. I am also interested in how gene-nutrient interactions influence risk of malignancy, specifically how polymorphisms in key folate metabolising enzymes influence genomic stability and incidence of colorectal cancer in humans. With regards to CVD, I have shown how folate status alters protein expression and DNA methylation status in aorta smooth muscle cells in culture and that long-term folate and/or B vitamin deficiency increases atherosclerosis by perturbing vascular lipid metabolism in transgenic ApoE mice. Poor folate status has also been implicated in the aetiology of low fertility, adverse pregnancy outcomes and fetal abnormalities in the newborn and poor cognitive function and dementia in the elderly. In collaboration with other research groups, I have examined the role of folic acid in colorectal cancer human trials, in ageing and cognitive function and in pregnancy and development.

Memberships
Advisory Committee on Novel Foods and Processes (FSA, UK)
European Nutrigenomics Organisation (NuGO)
British Nutrition Society (BNS)
Micronutrient Genomics Organisation (MICROGENNET)
UK Environmental Mutagen Society (UKEMS)
UKEMS Molecular Epidemiology Group (MEG)
Advisory Board of the European Journal of Nutrition
Editorial Advisor Clinical Science
Editorial Board British Journal of Nutrition
Editorial Board Journal of Nutritional Sciences
Editorial Board World Journal of Gastrointestinal Pharmacology and Therapeutics
EU COST Network on Epigenetics

Latest publications

  • 2012 Distinct effects of folate deficiency and hyperhomocysteinemia on atherosclerosis and vascular tissue protein expression in ApoE mice. McNeil CJ, Beattie JH, Gordon M-J, Pirie LP, Reid MD, Duncan GJ, Horgan G and Duthie SJ.Molecular Proteomics (submitted).
  • 2012 Homocysteine, antioxidant micronutrients and late onset dementia. Whalley LJ, Duthie SJ, Collins AR, Starr JM, Lemmon H, Duthie AC, Murray AD, Staff RT. Eur. J. Nutr., (in press).
  • 2012 Effect of a tomato-rich diet on markers of cardiovascular disease risk in moderately overweight, disease-free, middle-aged adults: a randomized controlled trial. Thies F, Masson LF, Rudd A, Vaughan, N, Tsang C, Brittenden J, Simpson WG, Duthie S, Horgan G, Duthie G. Am. J. Clin. Nutr., 96: 1013-1022.
  • 2012 Nutritional B vitamin deficiency disrupts lipid metabolism causing accumulation of proatherogenic lipoproteins in the aorta adventitia of ApoE null mice. McNeil CJ, Beattie JH, Gordon M-J, Pirie LP, and Duthie SJ.Molecular Nutrition and Food Research 56: 1097-1105.
  • 2012 Suboptimal dietary zinc intake promotes vascular inflammation and atherogenesis in a mouse model of atherosclerosis. Beattie JH, Gordon M-J, Duthie SJ, McNeil CJ, Horgan GW and Kwun I-S. Molecular Nutrition and Food Research 56: 1122-1130.
  • 2011 2D-electrophoresis and multiplex immunoassay proteomics analysis of different body fluids and cellular components reveal known and novel markers for prolonged fasting. Bouwman FG, de Roos B, Rubio-Aliaga I, Crosley LK, Duthie SJ, Mayer C, Horgan G, Polley AC, Heim C, Coort SLM, Evelo CT, Mulholland F, Johnson IT, Elliott RM, Daniel H & Mariman ECM. BMC Medical Genomics 4: 24.
  • 2011 Epigenetic modifications and human pathologies: cancer and cardiovascular disease. Duthie SJ. Proc. Nut. Soc., 70: 47-56.
  • 2011 Folate and cancer: how DNA damage and DNA repair impact on colon carcinogenesis. SJ Duthie. J. Inherited Metabolic Disease 34: 101-109.
  • 2011 Metabolomics of prolonged fasting in humans reveals new catabolic markers. Rubio-Aliaga I, de Roos B, Duthie SJ, Crosley LK, Mayer C, Horgan G, Colquhoun IJ, Le Gall G, Huber F, Kremer W, Rychlik M, Wopereis S, van Ommen B, Schmidt G, Heim C, Bouwman FG, Mariman EC, Mulholland F, Johnson IT, Polley IC, Elliott RC, Daniel H. Metabolomics 7: 375-387.
  • 2011 Differential effects of nutritional folic acid deficiency and moderate hyperhomocysteinemia on aortic plaque formation and DNA methylation in vascular tissue from ApoE -/- mice. McNeil CJ, Beattie JH, Gordon M-J, Pirie LP & Duthie SJ. Clinical Epigenetics 2: 361-368.

Dr Andy Povey - Treasurer

Andy PoveyMy research interests focus on the role that chemicals play in causing ill-health in human populations. To better characterise their role in the causation of human disease, my research spans the range from basic laboratory research to population studies. In the laboratory, my group work on biomarkers of exposure and susceptibility to chemical toxicants, particularly in relation to alkylating agents, known genotoxic agents to which exposure is unavoidable. We have focussed on the DNA repair protein, O6-methylguanine DNA methyltransferase1, and have identified SNPs2 and lifestyle factors3 that alter MGMT activity and potentially may alter cancer risk4. We have shown that MGMT repairs O6carboxymethylguanine, an adduct whose levels are increased by diets high in red meat5.  We have also measured levels of the DNA adducts, O6-methylguanine and N7-methylguanine and shown that such markers may be associated with disease risk6 or diet7. In addition, I also carry out population studies examining associations between adverse health outcomes and environmental exposures.  In the CHAPS-UK study, we identified a number of modifiable (e.g. type of underwear)  and non-modifiable  (e.g. history of testicular surgery) risk factors for poor semen quality8. In farming populations, we have identified patterns of ill-health in sheep farmers who use pesticides to treat their sheep for ectoparasites9 and have reported that both acute and chronic ill-health is associated with the PON1 genotype,  a gene associated with altered detoxification of pesticides10.

Memberships
American Association of Cancer Research.
British Association of Cancer Research.
U.K. Environmental Mutagen Society.
U.K. Molecular Epidemiology Group. 
Molecular Epidemiology Working Group  (AACR)
Advisory Committee on Pesticides
Carcinogenesis Editorial Board
Open biomarkers Journal Editorial Board

Latest publications

  • Margison, G.P., Povey, A.C., Kaina, B., and Santibanez Koref, M. F. (2003) Variability and regulation of  O6-alkylguanine-DNA alkyltransferase activity. Carcinogenesis, 24, 625-635.
  • Margison, G.P., Heighway, J., McGown, G., Thorncroft, M.R., Harrison, K.L., Watson, A.J., Barber, P.V.,  O'Donnell, P.N., Lewis, S.J., Povey, A.C.,  and Santibáñez Koref,  M.F. (2005)  Quantitative trait locus analysis reveals two intragenic sites that influence O6-alkylguanine-DNA alkyltransferase activity in peripheral blood mononuclear cells. Carcinogenesis , 26, 1473-1480.
  • Povey, A.C.,  O'Donnell, P. N .S., Barber,  P.V.,  Watson, A.J., Margison, G.P., and Santibáñez Koref, M. F.  (2006) Smoking is associated with a decrease of O6-alkylguanine-DNA alkyltransferase activity in bronchial epithelial cells. Int. J. Cancer 119, 463-466.
  • Crosbie, P.A.J.,  McGown,  G., Thorncroft, M.R., O'Donnell, P.N.S.,  Barber,  P.V.,  Lewis, S.J.,  Harrison, K.L.,  Agius,  R.M., Santibáñez-Koref, M.F.,  Margison, G.P., and Povey, A.C. (2008) Association between lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, O6-alkylguanine-DNA alkyltransferase. Int. J. Cancer , 122, 791-5.
  • Senthong, P., Millington, C.L., Wilkinson, O.J., Marriott, A.S., Watson, A.J., Reamtong, O., Eyers, C.E., Williams, D.M., Margison, G.P., Povey, A.C. (2013) The nitrosated bile acid DNA lesion O6-carboxymethylguanine is a substrate for the human DNA repair protein O6-methylguanine-DNA methyltransferase. Nucleic Acids Res.,  41, 3047-55.
  • Acladious, N.N., Harrison, K.L., Sutton, C.J., Povey, A.C., Mandal, D., and Kitchener, H. (2004) Levels of the DNA Adduct, N7-methyldeoxyguanosine, are associated with Increased Risk of Failure of Treatment of Cervical Intraepithelial Neoplasia. Gynecologic Oncology, 93, 605-609.
  • Billson, H., Harrison, K.L., Lees, N.P., Hall, C.N.,  Margison, G.P., and Povey, A.C. (2009) Dietary variables associated with DNA-N7 methylguanine  levels and O6-alkylguanine DNA-alkyltransferase  activity in human colorectal mucosa. Carcinogenesis, 30, 615-20.
  • Povey, A.C., Clyma, J.-A., McNamee, R., Moore, H.D., Baillie, H., Pacey, A.A., Cherry, N.M.,  and participating centres of Chaps-UK.  Modifiable and non-modifiable risk factors for poor semen quality: a case-referent study. Hum. Reprod., 27, 2799-2806.
  • Povey, A.C., Rees, H.G., Thompson, J.P., Watkins, G., Stocks, S.J., Karalliedde, L. (2012) Acute ill-health in sheep farmers following use of pesticides. Occup. Med., 62,541-8.
  • Cherry, N., Mackness, M., Mackness, B., Dippnall, M., and Povey, A. (2011) “Dippers’ flu” and its relation to PON1 polymorphisms. Occup. Environ. Med., 68, 211-7.

Links to own Institutes home pages
http://www.population-health.manchester.ac.uk/
http://www.population-health.manchester.ac.uk/research/epidemiology/
http://www.medicine.manchester.ac.uk/oeh/

Dr Andrew R. Collins - Committee member

Andrew CollinsResearch focus: From a background of research in DNA damage and repair in mammalian cells, I became interested in oxidative damage and antioxidant protection, in cells and in people, twenty years ago. We pioneered the application of the comet assay as a biomonitoring tool to measure endogenous DNA base oxidation in lymphocytes, and resistance of cells to oxidation in vitro (an index of antioxidant status). Numerous human intervention trials have shown the ability of antioxidant phytochemicals to protect against oxidation, but it is far from convincing that antioxidant supplementation per se is beneficial. Fruit and vegetable consumption are linked to lower cancer risk, but the antioxidant content of these foodstuffs is only one aspect of their biological activities. It is well known that micronutrients can affect phaseI/phase II metabolism, influence cell signalling pathways,  etc., and it was exciting to find that they can also modulate DNA repair; how they do this remains a mystery.

The ESCODD project, which I chaired, investigated different methods of measuring DNA base oxidation in human cells, and concluded that the comet assay is less prone to artefacts compared with chromatographic techniques. I am currently helping to set up the ComNet project; members are researchers using the comet assay in human studies, and the main aim is to collate data on DNA damage in order to carry out a pooled analysis and establish some basic information about DNA damage in humans, influences of genotype, effects of smoking, changes with age, sex differences, etc.

Memberships
UK Environmental Mutagen Society (past-president, and Jim Parry Award winner in 2011): Molecular Epidemiology Group: Nutrition Society: ComNet (founding committee member): International Comet Assay Workshop: Society for Free Radical Research (Europe).

Latest publications

  • Collins,A.R. and Azqueta,A. (2012) DNA repair as a biomarker in human biomonitoring studies; further applications of the comet assay. Mutation Res. 736,122-129
  • Collins,A.R., Azqueta,A., Langie,S.A.S. (2012) Effects of micronutrients on DNA repair. Eur. J. Nutr. 51, 261-279
  • Azqueta,A., Collins,A.R. (2012) Carotenoids and DNA damage. Mutat. Res. 733, 4-13.
  • Dusinska,M., Staruchova,M., Horska,A., Smolkova,B., Collins,A.R., Bonassi,S., Volkovova, K. (2012) Are glutathione S transferases involved in DNA damage signalling? Interactions with DNA damage and repair revealed from molecular epidemiology studies, Mutat. Res. 736, 130-137.
  • Dolara,P., Bigagli,E., Collins,A. (2012) Antioxidant vitamins and mineral supplementation, life span expansion and cancer incidence: a critical commentary, Eur. J. Nut. 51, 769-781.
  • Collins,A., Anderson,D., Coskun,E., Dhawan,A., Dusinska,M., Koppen,G., Kruszewski,M., Moretti,M., Rojas,E., Speit,G., Valverde,M., Bonassi,S. (2012) Launch of the ComNet (comet network) project on the comet assay in human population studies during the International Comet Assay Workshop meeting in Kusadasi, Turkey (September 13-16, 2011). Mutagenesis, 27, 385-386
  • Hudecova,A., Kusnierewicz,B., Runden-Pran,E., Magdolenova,Z., Hasplova,K., Rinna,A., Fjellsbø,L.M., Kruszewski,M., Lankoff,A., Sandberg,W.J., Refsnes,M., Skuland,T., Schwarze,P., Brunborg,G., Bjøras,M., Collins,A., Miadokova,E., Galova,E., Dusinska,M. (2012) Silver nanoparticles induce pre-mutagenic DNA oxidation that can be prevented by phytochemicals from Gentiana asclepiadea. Mutagenesis, 27, 759-769
  • Slyskova,J., Korenkova,V.,Collins,A.R., Prochazka,P., Vodickova,L., Svec,J., Lipska,L., Levy,M., Schneiderova,M., Liska,V., Holubec,L., Kumar,R., Soucek,P., Naccarati,A., Vodicka,P. (2012) Functional, genetic and epigenetic aspects of base and nucleotide excision repair in colorectal carcinomas. Clin. Cancer Res. doi: 10.1158/1078-0432.CCR-12-1380
  • Ringen, Ø., Azqueta, A., Moe, M.C., Zetterström, C., Røger, M., Nicolaissen, B., Collins, A.R. DNA damage in lens epithelium of cataract patients in vivo and ex vivo. Acta Ophthalm. (in press)
  • Azqueta,A., Arbillaga,L., Lopez de Cerain,A., Collins,A. Enhancing the sensitivity of the comet assay as a genotoxicity test, by combining it with bacterial repair enzyme FPG. Mutagenesis (in press)

Dr. Sabine A.S. Langie - Committee member

M_García-ClosasSabine Langie is interested in studying early-life exposures to xenobiotic agents and/or specific dietary compounds, and how these can influence the interaction between DNA methylation and oxidative stress/DNA damage plus predispose to pathological diseases later in life. Since November 2012 she has been working at VITO in Belgium as an AXA Research funded postdoctoral fellow on the topic "Allergy: environmental and nutritional programming in childhood". In 2013 she received the Cefic-LRI Innovative Science Award on the topic “Environmental programming of respiratory allergy in childhood: the applicability of saliva to study the effect of environmental exposures on DNA methylation”, which enabled her to expand her research on the developmental origin of respiratory allergy. The use of saliva will simplify the assessment of the impact of environmental exposures on DNA methylation patterns in human biomonitoring studies, especially for children where blood collection is often cumbersome. Prior to her position at VITO, she worked as a postdoctoral researcher at Newcastle University in the Centre for Brain Ageing and Vitality, focussing on the modulation of epigenetic modifications and DNA repair in the ageing brain in mice. Dr Langie's PhD-research on “Nutritional modulation of DNA repair” comprised the full range of studies with cells in vitro, experimental animals as well as human volunteers, and contributed to the field of genetic toxicology since she adapted a modified comet assay for DNA repair phenotyping purposes. She obtained her PhD in 2008.

Memberships of scientific societies

U.K. Environmental Mutagen Society (UKEMS)
U.K. Molecular Epidemiology Group (MEG)
Belgian Society of Toxicology and Ecotoxicology (BelTox)
Belgian Environmental Mutagen Society (BEMS)
The European Academy of Allergy and Cinical Immunology (EAACI)
European Nutrition Leadership Programme.(ENLP)
European Registered Toxicologist (ERT)
Former member of The Netherlands Society of Toxicology (NVT)

Links to own Institutes home pages

Latest publications

  • Sabine A.S. Langie. Predicting complex disease. In: International Innovation (Issue 171): A passion for progress; (2015) p86-89 (online: http://www.internationalinnovation.com/new-digital-editionissue-171-available-now/)
  • Book chapter: Jana Slyskova, Sabine A.S. Langie, Isabel Gaivão, Andrew R. Collins, Amaya Azqueta, “A standardized protocol for the in vitro comet-based DNA repair assay” In: L. María Sierra and Isabel Gaivão (eds.), Genotoxicity and DNA Repair: A Practical Approach, Methods in Pharmacology and Toxicology, DOI 10.1007/978-1-4939-1068-7_1, © Springer Science + Business Media New York 2014; pp. 377-395
  • Amaya Azqueta, Jana Slyskova, Sabine A.S. Langie, Isabel O'Neill Gaivão and Andrew R. Collins. Comet assay to measure DNA repair: approach and applications. Front Genet. (2014) 5;288
  • Jana Slyskova, Sabine A.S. Langie, Andrew R. Collins, Pavel Vodicka. Functional evaluation of DNA repair in human biopsies and their relation to other cellular biomarkers. Front Genet. (2014) 5;116
  • Sabine A.S. Langie, Pawel Kowalczyk, Bart Tomaszewski, Lou M. Maas, Edwin J. Moonen, Roger W.L. Godschalk, Barbara Tudek, Frederik J. van Schooten, Romuald Zabielski, John C. Mathers. Redox regulation and epigenetic regulation of the APE1 gene in the brain of young piglets: the effect of early life exposures. DNA Repair (Amst). (2014) 18;52-62
  • Jill A. McKay, Long Xie, Caroline Manus, Sabine A.S Langie, Ross J Maxwell, Dianne Ford, John C. Mathers. Maternal folate depletion during pregnancy and lactation influences susceptibility to the metabolic effects of a high-fat diet fed from weaning, without affecting adiposity, in adult offspring. Mol Nutr Food Res. (2014) 58;1087-97
  • Sofia Lisanti, Wan A.W. Omar, Bart Tomaszewski, Sofie De Prins, Griet Jacobs, Gudrun Koppen, John C. Mathers, Sabine A.S. Langie. Comparison of methods for quantification of global DNA methylation in human cells and tissues. PLoS One (2013) 8;e79044
  • Joanna P. Gorniak, Kerry M. Cameron, Kevin J. Waldron, Thomas von Zglinicki, John C. Mathers, Sabine A.S. Langie. Tissue specific differences in non-specific nuclease activity: an issue in the comet-based in vitro repair assay. Mutagenesis (2013) 28;673-81
  • Sabine A.S. Langie, Sebastian Achterfeldt, Joanna P. Gorniak, Kirstin J.A. Halley-Hogg, David Oxley, Frederik J. van Schooten, Roger W.L. Godschalk, Jill A. McKay, John C. Mathers. Maternal folate depletion and high-fat feeding from weaning affects DNA methylation and DNA repair in brain of adult offspring. FASEB J. (2013) 27;3323-34
  • Roger W. L. Godschalk, Clara Ersson, Patrizia Riso, Marisa Porrini, Sabine A.S. Langie, Frederik-Jan van Schooten, Amaya Azqueta, Andrew R. Collins, George D. D. Jones, Rachel W. L. Kwok, David H. Phillips, Osman Sozeri, Alessandra Allione, Giuseppe Matullo, Lennart Möller, Lykke Forchhammer, Steffen Loft, Peter Møller. DNA-repair measurements by use of the modified comet assay: An inter-laboratory comparison within the European Comet Assay Validation Group (ECVAG). Mutation research (2013) 757;60-7
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