Nigel Gooderham is Professor of Molecular Toxicology and the Assistant Provost (Academic Promotions) at Imperial College London. Nigel's research interests include mechanisms of chemical carcinogenesis and toxicity, the role of MiRNAs in chemical carcinogenesis and toxicity and the genetic toxicity of food-derived chemicals and oligonucleotides. Nigel's research contributions have been acknowledged through the 2018 Bo Holmstedt Memorial Award, by EUROTOX, the European Societies of Toxicology. Nigel has also been actively involved in toxicology education at Imperial College London and externally, contributing primarily to postgraduate programmes. He has recently stepped down as Director of the MRes in Biomedical Research at Imperial, but continues to contribute to the programme. He has trained more than ninety postgraduate and postdoctoral researchers at Imperial College. Nigel has served on the UK Government’s Advisory Committee on Mutagenicity, is a member of the MRC ITTP Steering Committee and funding panel and previously the NC3Rs Research Funding Assessment Panel. He has been a member of the UK’s MHRA Panel of Assessors and has participated in a number of expert advisory panels on toxicology including PIP breast implants, plastic pollution, hair dyes, agricultural chemicals and pharmaceuticals. Nigel is an Executive Member of the Flavour and Extract Manufacturer’s Association (USA) Expert Panel and a consultant for a number of commercial organisations involved in pharmaceuticals, agrochemicals, food production and the legal profession. He was the founding Editor-in-Chief of Toxicology Research (published by the Royal Society of Chemistry) and has served on the Editorial Boards of Mutagenesis, Toxicology, the Journal of Applied Toxicology and the Cancer Handbook. Nigel is a Gold Medal recipient and Fellow of the Royal Society of Chemistry and a Fellow of the British Toxicology Society (BTS), a member of the Society of Toxicology (USA), the Biochemical Society and the United Kingdom Environmental Mutagenicity Society. He has held several offices within the BTS including Chairman of the Scientific Committee and member of the BTS Executive. Nigel has also held the posts of Visiting Professor at the University of Malaysia, Terangganu, Malaysia and the Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
Nigel’s current research interests include:
- Mechanisms of chemical carcinogenesis
- Mechanisms of genotoxicity and mutation
- Molecular, cellular and genomic responses to toxicity
- Role of miRNA in chemical carcinogenesis and toxicity
- The genetic toxicology of food-derived chemicals and oligonucleotides
Our research programme attempts to understand and evaluate the hazard and risk to man of carcinogenic chemicals, especially food-borne molecules. The consumption of cooked meat, particularly when well done, is associated with a high incidence of colon, prostate, mammary and other cancers. One group of chemicals that have proved to be of particular interest are the food-derived heterocyclic amines that are formed during the cooking of food; these heterocyclic amines (Has) are metabolically activated to highly potent DNA damaging derivatives. Indeed, if these compounds were present in our environment as man-made contaminants, their toxicity would almost certainly have prompted regulatory legislation. Our programme explores exposure, bioavailablity, disposition, metabolism, activation and genotoxicity of the HAs in man using chemical, analytical and molecular technologies.
The metabolism of PhIP
About 20 genotoxic HAs have been shown to be formed at the parts per billion level during the normal cooking of food. Two of the most abundant HAs are 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Both compounds are highly DNA damaging and carcinogenic in rodent bioassays inducing tumours in a variety of tissues, including, in the case of PhIP, the colon, prostate and mammary glands. Daily human exposure to HAs is considerably less than the doses used in animal carcinogenicity studies, but species differences in metabolism and susceptibility to mutational effects suggests that their potency in rodent bioassays may be underestimated.
Our interest in DNA damage and mutation is underpinned by mechanistic research in a variety of in vitro models, using cell culture, molecular biology and biochemistry as well as high end analytical approaches such as metabonomics. Our programme explores not only small molecular weight chemicals but also oligonucleotide toxicity and genotoxicity and oligonucleotide mediated change in cell biology and phenotypic expression.
DNA damage and H2AX foci
This interest in the toxicology associated with oligonucleotides (antisense, siRNA and ability to influence quaternary DNA structure) compliments our interests in miRNA.
The consequence of toxicity is cell death and phenotypic change. Understanding the mechanisms whereby these phenotypic responses occur is important for recognising the toxicity of the molecules involved and for understanding the cellular responses to toxicity and identifying biomarkers of toxicity. The intention is to translate this research to in vivo models, particularly humans, in order to understand factors that predispose to, or protect against, toxicity. A major focus is to investigate the role of miRNAs in toxicity. These small (22 nucleotide length non coding RNAs) are post-transcriptional regulators of gene expression. Numerous studies have shown that these miRNAs are strongly associated with important biological processes such as development, homeostasis and pathology, including cancer. We believe that miRNAs are key mediators of both acute toxicity and more chronic events such as those associated with carcinogenesis. As such we are investigating the potential of miRNAs as biomarkers of toxicity and disease and understanding gene expression changes and dysregulation of miRNAs also offers clues to the mechanisms operating in toxicity and pathology.
Chemical induced miRNA differential expression
Active areas of research include the role of miRNAs in genotoxic and epigenetic chemical carcinogenesis, the role of miRNAs in hormonal disturbances, surgery-related pathology, metabolic surgery, obesity and nephropathy. Much of this work is translational, bridging in vitro based models with clinical research.
We also have active research in the area of inflammation and drug metabolism as it relates to toxicity and cancer. We have a focus on the colonic tumour microenvironment, which comprises epithelial and stromal cell populations that can manipulate the phenotypic expression of tumour tissue, compared to normal tissue, via cell to cell communication. We have found that important contributors to this crosstalk include inflammatory cytokines and more recently the role of microRNAs has emerged. These key players metabolically empower colon cancer cells, mediate intracellular communication and offer therapeutic opportunities to target the cancer microenvironment.
et al., 2018, FEMA GRAS assessment of natural flavor complexes: Citrus-derived flavoring ingredients., Food Chem Toxicol
Malik D-E-S, David RM, Gooderham NJ, 2018, Mechanistic evidence that benzo[a]pyrene promotes an inflammatory microenvironment that drives the metastatic potential of human mammary cells., Arch Toxicol, Vol:92, Pages:3223-3239
David RM, Gooderham NJ, 2018, Dose-dependent synergistic and antagonistic mutation responses of binary mixtures of the environmental carcinogen benzo[a]pyrene with food-derived carcinogens., Arch Toxicol
et al., 2018, The safety evaluation of food flavouring substances: the role of metabolic studies., Toxicol Res (camb), Vol:7, ISSN:2045-452X, Pages:618-646
et al., 2018, Microbiome inhibition of IRAK-4 by trimethylamine mediates metabolic and immune benefits in high fat diet-induced insulin resistance, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SPRINGER, Pages:S267-S268, ISSN:0012-186X