Imperial College London

Emeritus ProfessorNigelGooderham

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Emeritus Professor of Molecular Toxicology
 
 
 
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Contact

 

n.gooderham Website

 
 
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Location

 

Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

263 results found

S M N Mydin RB, Azlan A, Okekpa SI, Gooderham NJet al., 2024, Regulatory role of miRNAs in nasopharyngeal cancer involving PTEN/PI3K/AKT, TGFβ/SMAD, RAS/MAPK, Wnt/β-catenin and pRB-E2F signaling pathways: A review., Cell Biochem Funct, Vol: 42

MicroRNAs (miRNA) are small and conserved noncoding RNA molecules that regulate gene expression at the posttranscriptional level. These groups of RNAs are crucial in various cellular processes, especially in mediating disease pathogenesis, particularly cancer. The dysregulation of miRNAs was reported in many cancer types, including nasopharyngeal cancer (NPC), which is a malignant tumor of the nasopharynx. In this review, miRNAs involvement in crucial signaling pathways associated with NPC such as PTEN/PI3K/AKT, TGFβ/SMAD, RAS/MAPK, Wnt/β-catenin and pRB-E2F was investigated. miRNAs could function as tumor suppressor-miR or onco-miR in NPC profoundly influenced cell cycle, apoptosis, proliferation, migration, and metastasis. This comprehensive review of current literature provided a thorough profile of miRNAs and their interplay with the aforementioned signaling pathways in NPC. Understanding these molecular interactions could remarkably impact the diagnosis, prognosis, and therapeutic strategies for NPC.

Journal article

Davidsen JM, Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Rosol TJ, Harman CL, Ramanan D, Taylor SVet al., 2023, In response to the Letter to the Editor from Xiao regarding our article, "FEMA GRAS assessment of natural flavor complexes: Asafetida oil, garlic oil and onion oil", Food and Chemical Toxicology, Vol: 182, ISSN: 0278-6915

Journal article

Nor Mahiran SNS, Abd Kadir NH, Maulidiani M, Tengku Mohamad TR, Gooderham NJ, Alam Met al., 2023, Multivariate modelling analysis for prediction of glycidyl esters and 3-monochloropropane-1,2-diol (3-MCPD) formation in periodically heated palm oil, Heliyon, Vol: 9, ISSN: 2405-8440

Palm oil is a vegetable oil that is widely used for cooking and deep-frying because of its affordability. However, repeatedly heated palm oil is also prone to oxidation due to its significant content of unsaturated fatty acids and other chemical toxicants such as glycidyl esters and 3-monochloropropane-1,2-diol (3-MCPD). Initially, the physicochemical properties such as colour, viscosity, peroxide, p-anisidine and total oxidation (TOTOX) of periodically heated palm oil were investigated. Chemical profiling and fingerprinting of six different brands of palm cooking oil during heating cycles between 90 and 360 min were conducted using Fourier transform infrared (FTIR) and 1H Nuclear Magnetic Resonance (NMR) metabolomics. In addition, the multivariate analysis was employed to evaluate the 1H NMR spectroscopic pattern of repeatedly heated palm oil with the corresponding physicochemical properties. The FTIR metabolomics showed significant different of the chemical fingerprinting subjected to heating duration, which in agreement with the result of 1H NMR metabolomics. Partial least squares (PLS) model revealed that most of the physicochemical properties of periodically heated palm oil are positively correlated (R2 values of 0.98–0.99) to their spectroscopic pattern. Based on the findings, the color of the oils darkened with increased heating time. The peroxide value (PV), p-anisidine value (p-AnV), and total oxidation (TOTOX) values increased significantly due to degradation of unsaturated compounds and oxidation products formed. We identified targeted metabolites (probable carcinogens) such as 3-monochloropropane-1,2-diol (3-MCPD) and glycidyl ester (GE), indicating the conversion of 3-MCPD to GE in repeatedly heated oils based on PCA and OPLSDA models. Our correlation analysis of NMR and physicochemical properties has shown that the conversion of 3-MCPD to GE was significantly increased from 180 to 360 min cooking time. The combination spectroscopic techniques wit

Journal article

Gooderham NJ, Cohen SM, Eisenbrand G, Fukushima S, Guengerich FP, Hecht SS, Rietjens IMCM, Rosol TJ, Davidsen JM, Harman CL, Kelly SE, Taylor SVet al., 2023, FEMA GRAS assessment of natural flavor complexes: Sage oil, Orris Root Extract and Tagetes Oil and related flavoring ingredients, Food and Chemical Toxicology, Vol: 179, Pages: 1-31, ISSN: 0278-6915

In recent years, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) has conducted a program to re-evaluate the safety of natural flavor complexes (NFCs) used as flavor ingredients. This publication, twelfth in the series, details the re-evaluation of NFCs whose constituent profiles are characterized by alicyclic or linear ketones. In its re-evaluation, the Expert Panel applies a scientific constituent-based procedure for the safety evaluation of NFCs in commerce using a congeneric group approach. Estimated intakes of each congeneric group of the NFC are evaluated using the well-established and conservative Threshold of Toxicological Concern (TTC) approach. In addition, studies on the toxicity and genotoxicity of members of the congeneric groups and the NFCs under evaluation are reviewed. The scope of the safety evaluation of the NFCs contained herein does not include added use in dietary supplements or any products other than food. Thirteen (13) NFCs derived from the Boronia, Cinnamomum, Thuja, Ruta, Salvia, Tagetes, Hyssopus, Iris, Perilla and Artemisia genera are affirmed as generally recognized as safe (GRAS) under conditions of their intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.

Journal article

Davidsen JM, Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Rosol TJ, Harman CL, Taylor SVet al., 2023, FEMA GRAS assessment of derivatives of basil, nutmeg, parsley, tarragon and related allylalkoxybenzene-containing natural flavor complexes, Food and Chemical Toxicology, Vol: 175, Pages: 113646-113646, ISSN: 0278-6915

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavoring ingredients in food. In this publication, ninth in the series, NFCs containing a high percentage of least one naturally occurring allylalkoxybenzene constituent with a suspected concern for genotoxicity and/or carcinogenicity are evaluated. In a related paper, tenth in the series, NFCs containing anethole and/or eugenol and relatively low percentages of these allylalkoxybenzenes are evaluated. The Panel applies the threshold of toxicological concern (TTC) concept and evaluates relevant toxicology data on the NFCs and their respective constituent congeneric groups. For NFCs containing allylalkoxybenzene constituent(s), the estimated intake of the constituent is compared to the TTC for compounds with structural alerts for genotoxicity and when exceeded, a margin of exposure (MOE) is calculated. BMDL10 values are derived from benchmark dose analyses using Bayesian model averaging for safrole, estragole and methyl eugenol using EPA's BMDS software version 3.2. BMDL10 values for myristicin, elemicin and parsley apiole were estimated by read-across using relative potency factors. Margins of safety for each constituent congeneric group and MOEs for each allylalkoxybenzene constituent for each NFC were determined that indicate no safety concern. The scope of the safety evaluation contained herein does not include added use in dietary supplements or any products other than food. Ten NFCs, derived from basil, estragon (tarragon), mace, nutmeg, parsley and Canadian snakeroot were determined or affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.

Journal article

Rosol TJ, Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Davidsen JM, Harman CL, Kelly S, Ramanan D, Taylor SVet al., 2023, FEMA GRAS assessment of natural flavor complexes: lemongrass oil, chamomile oils, citronella oil and related flavoring ingredients., Food and Chemical Toxicology, Vol: 175, Pages: 1-30, ISSN: 0278-6915

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, eleventh in the series, evaluates the safety of NFCs characterized by primary alcohol, aldehyde, carboxylic acid, ester and lactone constituents derived from terpenoid biosynthetic pathways and/or lipid metabolism. The scientific-based evaluation procedure published in 2005 and updated in 2018 that relies on a complete constituent characterization of the NFC and organization of the constituents into congeneric groups. The safety of the NFCs is evaluated using the threshold of toxicological concern (TTC) concept in addition to data on estimated intake, metabolism and toxicology of members of the congeneric groups and for the NFC under evaluation. The scope of the safety evaluation does not include added use in dietary supplements or any products other than food. Twenty-three NFCs, derived from the Hibiscus, Melissa, Ricinus, Anthemis, Matricaria, Cymbopogon, Saussurea, Spartium, Pelargonium, Levisticum, Rosa, Santalum, Viola, Cryptocarya and Litsea genera were affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.

Journal article

Rietjens IMCM, Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rosol TJ, Davidsen JM, Harman CL, Taylor SVet al., 2023, FEMA GRAS assessment of natural flavor complexes: allspice, anise, fennel-derived and related flavoring ingredients, Food and Chemical Toxicology, Vol: 174, Pages: 1-26, ISSN: 0278-6915

The FEMA Expert Panel program to re-evaluate the safety of natural flavor complexes (NFCs) used as flavoring ingredients in food has resulted in the publication of an updated constituent-based procedure as well as publications on the safety evaluation of many botanical-derived NFCs. This publication, ninth in the series and related to the ninth publication, describes the affirmation of the generally recognized as safe (GRAS) status for NFCs with propenylhydroxybenzene and allylalkoxybenzene constituents under their conditions of intended use as flavoring ingredients added to food. The Panel's procedure applies the threshold of toxicological concern (TTC) concept and evaluates relevant data on absorption, metabolism, genotoxic potential and toxicology for the NFCs themselves and their respective constituent congeneric groups. For NFCs containing allylalkoxybenzene constituent(s) with suspected genotoxic potential, the estimated intake of the individual constituent is compared to the TTC for compounds with structural alerts for genotoxicity and if exceeded, a margin of exposure is calculated using BMDL10 values derived from benchmark dose analyses using Bayesian model averaging, as presented in the tenth article of the series. Safety evaluations for NFCs derived from allspice, anise seed, star anise, sweet fennel seed and pimento leaves were conducted and their GRAS status was affirmed for use as flavoring ingredients. The scope of the safety evaluation contained herein does not include added use in dietary supplements or any products other than food.

Journal article

Davidsen JM, Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Rosol TJ, Harman CL, Ramanan D, Taylor SVet al., 2023, FEMA GRAS assessment of natural flavor complexes: Asafetida oil, garlic oil and onion oil., Food and Chemical Toxicology, Vol: 173, Pages: 1-18, ISSN: 0278-6915

The Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) applies its procedure for the safety evaluation of natural flavor complexes (NFCs) to re-evaluate the safety of Asafetida Oil (Ferula assa-foetida L.) FEMA 2108, Garlic Oil (Allium sativum L.) FEMA 2503 and Onion Oil (Allium cepa L.) FEMA 2817 for use as flavoring in food. This safety evaluation is part of a series of evaluations of NFCs for use as flavoring ingredients conducted by the Expert Panel that applies a scientific procedure published in 2005 and updated in 2018. Using a group approach that relies on a complete chemical characterization of the NFC intended for commerce, the constituents of each NFC are organized into well-defined congeneric groups and the estimated intake of each constituent congeneric group is evaluated using the conservative threshold of toxicological concern (TTC) concept. Data on the metabolism, genotoxic potential and toxicology for each constituent congeneric group are reviewed as well as studies on each NFC. Based on the safety evaluation, Asafetida Oil (Ferula assa-foetida L.), Garlic Oil (Allium sativum L.) and Onion Oil (Allium cepa L.) were affirmed as generally recognized as safe (GRASa) under their conditions of intended use as flavor ingredients.

Journal article

Li J, Gooderham N, Alotaibi A, 2023, Tumour necrosis factor-alpha (TNF-α)-induced metastatic phenotype in colorectal cancer epithelial cells: mechanistic support for the role of microRNA-21, Cancers, Vol: 15, Pages: 1-19, ISSN: 2072-6694

The progression of colorectal cancer is promoted by changes in the genetic makeup of tumour cells giving them potential to leave the site of their origin to seed new metastatic tumours in other tissue; inflammation at the tumour site is a driver of these changes. Tumour necrosis factor-alpha is a pro-inflammatory molecule that is associated with the progression of metastatic cancer. Small biologically active RNAs, microRNAs, target the production of specific proteins and are proposed as agents of tumour change. One agent, microRNA-21, shown to be present in colorectal cancer, is known to target the formation of proteins involved in metastatic changes in cells. We investigated the relationship between TNF-α and microRNA-21 in colorectal cancer cells and show their involvement in promoting cell changes indicative of the metastatic state. In summary, we provide mechanistic support for a role of microRNA-21 in tumour necrosis factor-alpha promotion of cancer cell metastatic change.

Journal article

Rietjens IMCM, Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rosol TJ, Linman MJ, Harman CL, Taylor SVet al., 2022, Direct addition of flavors, including taste and flavor modifiers, Present Knowledge in Food Safety: A Risk-Based Approach through the Food Chain, Pages: 194-210, ISBN: 9780128231548

The addition of flavorings to food and beverages provides practically unlimited opportunities for innovation, for maintaining and enhancing palatability, and is one essential element of a stable supply of nutritious consumer products. A safety evaluation by the Flavor and Extract Manufacturers Association (FEMA) Expert Panel provides a pathway for flavor producers and users to achieve regulatory authority to use for substances under the conditions of intended use as a flavoring. This chapter describes the factors that contribute to the safety assessment process that is conducted by the Expert Panel, and provides examples of specific flavorings and types of flavorings that are considered. The chapter also describes future issues and opportunities likely to be encountered within the context of the FEMA generally recognized as safe assessment of flavorings.

Book chapter

Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Rosol TJ, Davidsen JM, Harman CL, Lu V, Taylor SVet al., 2021, FEMA GRAS assessment of natural flavor complexes: Origanum oil, thyme oil and related phenol derivative-containing flavoring ingredients., Food and Chemical Toxicology, Vol: 155, Pages: 1-18, ISSN: 0278-6915

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients, mostly consisting of a variety of essential oils and botanical extracts. This publication, seventh in the series, re-evaluates NFCs with constituent profiles dominated by phenolic derivatives including carvacrol, thymol and related compounds using a constituent-based procedure first published in 2005 and updated in 2018. The procedure is based on the chemical characterization of each NFC as intended for commerce and the estimated intake of the constituent congeneric groups. The procedure applies the threshold of toxicological concern (TTC) concept and evaluates relevant data on absorption, metabolism, genotoxic potential and toxicology of the constituent congeneric groups and the NFC under evaluation. Herein, the FEMA Expert Panel affirmed the generally recognized as safe (GRAS) status of seven phenolic derivative-based NFCs, Origanum Oil (Extractive) (FEMA 2828), Savory Summer Oil (FEMA 3013), Savory Summer Oleoresin (FEMA 3014), Savory Winter Oil (FEMA 3016), Savory Winter Oleoresin (FEMA 3017), Thyme Oil (FEMA 3064) and Thyme White Oil (FEMA 3065) under their conditions of intended use as flavor ingredients.

Journal article

Eisenbrand G, Cohen SM, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Rosol TJ, Davidsen JM, Harman CL, Taylor SVet al., 2021, FEMA GRAS assessment of natural flavor complexes: Eucalyptus oil and other cyclic ether-containing flavoring ingredients, Food and Chemical Toxicology, Vol: 155, ISSN: 0278-6915

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, the sixth in the series, will summarize the re-evaluation of eight NFCs whose constituent profiles are characterized by significant amounts of eucalyptol and/or other cyclic ethers. This re-evaluation was based on a procedure first published in 2005 and subsequently updated in 2018 that evaluates the safety of naturally occurring mixtures for their intended use as flavoring ingredients. The procedure relies on a complete chemical characterization of the NFC intended for commerce and the organization of its chemical constituents into well-defined congeneric groups. The safety of the NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism and toxicology of the constituents of the congeneric groups and the NFC under evaluation. Eight NFCs derived from the Eucalyptus, Melaleuca, Origanum, Laurus, Rosmarinus and Salvia genera were affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.

Journal article

Alotaibi A, Li J, Gooderham N, 2021, Tumour necrosis factor-α (TNF-α) enhances dietary carcinogen-induced DNA damage in colorectal cancer epithelial cells through activation of JNK signaling pathway, Toxicology, Vol: 457, ISSN: 0300-483X

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death. Benzo[a]pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazol [4,5-b] pyridine (PhIP) present in cooked meat are pro-carcinogens and considered to be potential risk factors for CRC. Their carcinogenic and mutagenic effects require metabolic activation primarily by cytochrome P450 1 family enzymes (CYPs); the expression of these enzymes can be modulated by aryl hydrocarbon receptor (AhR) activation and the tumour microenvironment, involving mediators of inflammation. In this study, we hypothesized that tumour necrosis factor-α (TNF-α), a key mediator of inflammation, modulates BaP- and PhIP-induced DNA damage in colon cancer epithelial cells. Importantly, we observed that TNF-α alone (0.1–100 pg/ml) induced DNA damage (micronuclei formation) in HCT-116 cells and co-treatment of TNF-α with BaP or PhIP showed higher levels of DNA damage compared to the individual single treatments. TNF-α alone or in combination with BaP or PhIP did not affect the expression levels of CYP1A1 and CYP1B1 (target genes of AhR signaling pathways). The DNA damage induced by TNF-α was elevated in p53 null HTC-116 cells compared to wild type cells, suggesting that TNF-α-induced DNA damage is suppressed by functional p53. In contrast, p53 status failed to affect BaP and PhIP induced micronucleus frequency. Furthermore, JNK and NF-κB signaling pathway were activated by TNF-α treatment but only inhibition of JNK significantly reduced TNF-α-induced DNA damage. Collectively, these findings suggest that TNF-α induced DNA damage involves JNK signaling pathway rather than AhR and NF-κB pathways in colon cancer epithelial cells.

Journal article

Li J, 2021, Roux-en-Y Gastric bypass-induced bacterial perturbation contributes to altered host-bacterial co-metabolic phenotype, Microbiome, Vol: 9, ISSN: 2049-2618

BACKGROUND: Bariatric surgery, used to achieve effective weight loss in individuals with severe obesity, modifies the gut microbiota and systemic metabolism in both humans and animal models. The aim of the current study was to understand better the metabolic functions of the altered gut microbiome by conducting deep phenotyping of bariatric surgery patients and bacterial culturing to investigate causality of the metabolic observations. METHODS: Three bariatric cohorts (n = 84, n = 14 and n = 9) with patients who had undergone Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or laparoscopic gastric banding (LGB), respectively, were enrolled. Metabolic and 16S rRNA bacterial profiles were compared between pre- and post-surgery. Faeces from RYGB patients and bacterial isolates were cultured to experimentally associate the observed metabolic changes in biofluids with the altered gut microbiome. RESULTS: Compared to SG and LGB, RYGB induced the greatest weight loss and most profound metabolic and bacterial changes. RYGB patients showed increased aromatic amino acids-based host-bacterial co-metabolism, resulting in increased urinary excretion of 4-hydroxyphenylacetate, phenylacetylglutamine, 4-cresyl sulphate and indoxyl sulphate, and increased faecal excretion of tyramine and phenylacetate. Bacterial degradation of choline was increased as evidenced by altered urinary trimethylamine-N-oxide and dimethylamine excretion and faecal concentrations of dimethylamine. RYGB patients' bacteria had a greater capacity to produce tyramine from tyrosine, phenylalanine to phenylacetate and tryptophan to indole and tryptamine, compared to the microbiota from non-surgery, normal weight individuals. 3-Hydroxydicarboxylic acid metabolism and urinary excretion of primary bile acids, serum BCAAs and dimethyl sulfone were also perturbed following bariatric surgery. CONCLUSION: Altered bacterial composition and metabolism contribute to metabolic observations in biofluid

Journal article

Fukushima S, Cohen SM, Eisenbrand G, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Rosol TJ, Davidsen JM, Harman CL, Lu V, Taylor SVet al., 2020, FEMA GRAS assessment of natural flavor complexes: Lavender, Guaiac Coriander-derived and related flavoring ingredients, Food and Chemical Toxicology, Vol: 145, Pages: 1-24, ISSN: 0278-6915

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, fifth in the series, evaluates the safety of NFCs containing linalool and/or other characteristic mono- and sesquiterpenoid tertiary alcohols and esters using the safety evaluation procedure published by the FEMA Expert Panel in 2005 and updated in 2018. The procedure relies on a complete chemical characterization of the NFC intended for commerce and organization of the chemical constituents of each NFC into well-defined congeneric groups. The safety of each NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism and toxicology of both the constituent congeneric groups and the NFCs. Sixteen NFCs, derived from the Lavandula, Aniba, Elettaria, Daucus, Salvia, Coriandrum, Ribes, Guaiacum/Bulnesia, Citrus, Pogostemon, Melaleuca and Michelia genera, were affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.

Journal article

Gooderham NJ, Cohen SM, Eisenbrand G, Fukushima S, Guengerich FP, Hecht SS, Rietjens IMCM, Rosol TJ, Davidsen JM, Harman CL, Murray IJ, Taylor SVet al., 2020, FEMA GRAS assessment of natural flavor complexes: Clove, Cinnamon leaf and West Indian bay leaf-derived flavoring ingredients, Food and Chemical Toxicology, Vol: 145, Pages: 1-16, ISSN: 0278-6915

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association initiated the safety re-evaluation of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, 4th in a series focusing on the safety evaluation of NFCs, presents an evaluation of NFCs rich in hydroxyallylbenzene and hydroxypropenylbenzene constituents using a procedure initially published in 2005 and updated in 2018 that evaluates the safety of naturally occurring mixtures for their intended use as flavoring ingredients. The procedure requires the characterization of the chemical composition for each NFC and subsequent organization of the constituents into defined congeneric groups. The safety of each NFC is evaluated using the conservative threshold of toxicological concern (TTC) approach together with studies on absorption, metabolism and toxicology of the NFC and its constituent congeneric groups. By the application of this procedure, seven NFCs, derived from clove, cinnamon leaf and West Indian bay leaf were affirmed as “generally recognized as safe (GRAS)” under their conditions of intended use as flavor ingredients. An eighth NFC, an oleoresin of West Indian bay leaf, was affirmed based on its estimated intake, which is below the TTC of 0.15 μg/person per day for compounds with structural alerts for genotoxicity.

Journal article

Butler A, Ramachandran V, Cunningham T, David R, Gooderham N, Benurwar M, Dargham S, Hayat S, Sathypalan T, Najafi-Shoushtari H, Atkin Set al., 2020, Increased MicroRNA levels in women with polycystic ovarian syndrome but without insulin resistance: a pilot prospective study, Frontiers in Endocrinology, Vol: 11, ISSN: 1664-2392

Background: Small noncoding microRNA (miRNA) have regulatory functions in polycystic ovary syndrome (PCOS) that differ to those in women without PCOS. However, little is known about miRNA expression in women with PCOS who are not insulin resistant (IR).Methods: Circulating miRNAs were measured using quantitative polymerase chain reaction (qPCR) in 24 non-obese BMI and age matched women with PCOS and 24 control women. A miRNA data set was used to determine miRNA levels.Results: Women with PCOS showed a higher free androgen index (FAI) and anti-mullerian hormone (AMH) but IR did not differ. Four miRNAs (miR-1260a, miR-18b-5p, miR-424-5p, and miR let-7b-3p) differed between control and PCOS women that passed the false discovery rate (FDR) out of a total of 177 circulating miRNAs that were detected. MiRNA let-7b-3p correlated with AMH in PCOS (p < 0.05). When the groups were combined, miR-1260a correlated with FAI and let-7b-3p correlated with body mass index (BMI) (p < 0.05). There was no correlation to androgen levels. Ingenuity pathway analysis showed that nine of the top 10 miRNAs reported were associated with inflammatory pathways.Conclusion: When IR did not differ between PCOS and control women, only four miRNA differed significantly suggesting that IR may be a driver for many of the miRNA changes reported. Let-7b-3p was related to AMH in PCOS, and to BMI as a group, whilst miR-1260a correlated with FAI. Androgen levels, however, had no effect upon circulating miRNA profiles. The expressed miRNAs were associated with the inflammatory pathway involving TNF and IL6.

Journal article

Butler AE, Ramachandran V, Sathyapalan T, David R, Gooderham NJ, Benurwar M, Dargham SR, Hayat S, Hani Najafi-Shoushtari S, Atkin SLet al., 2020, Corrigendum: microRNA Expression in Women With and Without Polycystic Ovarian Syndrome Matched for Body Mass Index, Frontiers in Endocrinology, Vol: 11, Pages: 1-1, ISSN: 1664-2392

Journal article

Butler AE, Ramachandran V, Sathypalan T, David R, Gooderham NJ, Benurwar M, Dargham SR, Hayat S, Hani Najafi-Shoushtari S, Atkin SLet al., 2020, microRNA expression in women with and without polycystic ovarian syndrome matched for body mass index, Frontiers in Endocrinology, Vol: 11, Pages: 1-8, ISSN: 1664-2392

Background: Despite several authors who have hypothesized that alterations of smallnoncoding RNAs (miR) are implicated in the etiopathogenesis of polycystic ovariansyndrome (PCOS), contrasting findings have been reported so far. Discrepancies in bodymass index (BMI) levels may account for these differences; therefore, the aim of thepresent study was to determine whether miR differed in serum samples collected fromage- and BMI-matched control and PCOS women.Methods: In a cross-sectional study, miR were measured using quantitative polymerasechain reaction in 29 women with anovulatory PCOS women and 29 control women whowere in the follicular phase of their menstrual cycle, from the local biobank.Results: One hundred seventy-six miR were detected, of which 15 miR passed the falsediscovery rate (FDR; p < 0.05) that differed between PCOS and control women. Therewas no association of the top 9 miR (p < 0.02) (miR-486-5p, miR-24-3p, miR-19b-3p,miR-22-3p, miR-19a-3p, miR-339-5p, miR-185-5p, miR-101-3p, miR-let-7i-5p) withBMI, androgen levels, insulin resistance, or antimullerian hormone (AMH) in eitherPCOS or normal women. Ingenuity pathway assessment showed the pathways wereinterrelated for abnormalities of the reproductive system.Conclusion: When the confounding influence of weight was accounted for, miR levelsdiffered between anovulatory PCOS women and control women in the follicular phase ofthe menstrual cycle. Interestingly, the differing miR were associated with the pathways ofreproductive abnormalities but did not associate with AMH or metabolic parameters.

Journal article

Gooderham NJ, Cohen SM, Eisenbrand G, Fukushima S, Guengerich FP, Hecht SS, Rietjens IMCM, Rosol TJ, Bastaki M, Linman MJ, Taylor SVet al., 2020, The safety evaluation of food flavoring substances: the role of genotoxicity studies, Critical Reviews in Toxicology, Vol: 50, Pages: 1-27, ISSN: 1040-8444

The Flavor and Extract Manufacturers Association (FEMA) Expert Panel relies on the weight of evidence from all available data in the safety evaluation of flavoring substances. This process includes data from genotoxicity studies designed to assess the potential of a chemical agent to react with DNA or otherwise cause changes to DNA, either in vitro or in vivo. The Panel has reviewed a large number of in vitro and in vivo genotoxicity studies during the course of its ongoing safety evaluations of flavorings. The adherence of genotoxicity studies to standardized protocols and guidelines, the biological relevance of the results from those studies, and the human relevance of these studies are all important considerations in assessing whether the results raise specific concerns for genotoxic potential. The Panel evaluates genotoxicity studies not only for evidence of genotoxicity hazard, but also for the probability of risk to the consumer in the context of exposure from their use as flavoring substances. The majority of flavoring substances have given no indication of genotoxic potential in studies evaluated by the FEMA Expert Panel. Examples illustrating the assessment of genotoxicity data for flavoring substances and the consideration of the factors noted above are provided. The weight of evidence approach adopted by the FEMA Expert Panel leads to a rational assessment of risk associated with consumer intake of flavoring substances under the conditions of use.

Journal article

Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Bastaki M, Davidsen JM, Harman CL, McGowen MM, Taylor SVet al., 2020, FEMA GRAS assessment of natural flavor complexes: Mint, buchu, dill and caraway derived flavoring ingredients, Food and Chemical Toxicology, Vol: 135, ISSN: 0278-6915

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. NFC flavor materials include a variety of essential oils and botanical extracts. The re-evaluation of NFCs is conducted based on a constituent-based procedure outlined in 2005 and updated in 2018 to evaluate the safety of NFCs for their intended use as flavor ingredients. This procedure is applied in the re-evaluation of the generally recognized as safe (GRAS) status of NFCs with constituent profiles that are dominated by alicyclic ketones such as menthone and carvone, secondary alcohols such as menthol and carveol, and related compounds. The FEMA Expert Panel affirmed the GRAS status of Peppermint Oil (FEMA 2848), Spearmint Oil (FEMA 3032), Spearmint Extract (FEMA 3031), Cornmint Oil (FEMA 4219), Erospicata Oil (FEMA 4777), Curly Mint Oil (FEMA 4778), Pennyroyal Oil (FEMA 2839), Buchu Leaves Oil (FEMA 2169), Caraway Oil (FEMA 2238) and Dill Oil (FEMA 2383) and determined FEMA GRAS status for Buchu Leaves Extract (FEMA 4923), Peppermint Oil, Terpeneless (FEMA 4924) and Spearmint Oil, Terpeneless (FEMA 4925).

Journal article

Rietjens IMCM, Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rosol TJ, Davidsen JM, Harman CL, Murray IJ, Taylor SVet al., 2020, FEMA GRAS assessment of natural flavor complexes: Cinnamomum and Myroxylon-derived flavoring ingredients, Food and Chemical Toxicology, Vol: 135, ISSN: 0278-6915

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, third in the series, considers NFCs composed primarily of constituents with the 3-phenyl-2-propenyl or a cinnamyl functional group, using the procedure outlined in 2005 and updated in 2018 to evaluate the safety of naturally-occurring mixtures for their intended use as flavor ingredients. The procedure relies on a complete chemical characterization of the NFC intended for commerce and organization of each NFC's chemical constituents into well-defined congeneric groups. The safety of the NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism, and toxicology of members of the congeneric groups and the NFC under evaluation. Six NFCs from the Myroxylon and Cinnamomum genera, Balsam Oil, Peru (FEMA 2117), Tolu Balsam Extract (FEMA 3069), Cassia Bark Extract (FEMA 2257), Cassia Bark Oil (FEMA 2258), Cinnamon Bark Extract (FEMA 2290) and Cinnamon Bark Oil (FEMA 2291) were evaluated and affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients.

Journal article

Malik D-E-S, David R, Gooderham N, 2019, Interleukin-6 selectively induces drug metabolism to potentiate the genotoxicity of dietary carcinogens in mammary cells, Archives of Toxicology, Vol: 93, Pages: 3005-3020, ISSN: 0340-5761

Breast cancer is the most commonly diagnosed malignancy in females, the aetiology beingmultifactorial and includes the role of lifestyle exposure to DNA damaging chemicals such asdietary carcinogens benzo (a) pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo [4, 5-b]pyridine (PhIP). Both compounds require cytochrome P450 (CYP) mediated metabolic activationto DNA damaging species, and both induce transcriptional responses through the nuclearreceptors Aryl hydrocarbon receptor (AhR) and estrogen receptor α (ERα). BaP and PhIP aremammary carcinogens in rodents. Clinically, circulating IL-6 expression is linked with poorprognosis of cancer and 35% of the deaths in breast cancer are linked with inflammation. Theobjective of this work was to investigate the molecular toxicology and local activation of BaP andPhIP in the presence of IL-6. Our laboratory has previously reported that miR27b can regulateCYP1B1 expression in colorectal cells, here we have investigated if this mechanism is working inmammary cell models, MCF-7 and MDA-MB-231 cells. Treatment (24h) of cells with BaP (10nM10µM) and PhIP (100nM-100µM) significantly induced genetic damage (micronuclei formation) ina dose dependent manner in both cell lines. This effect was potentiated in the presence humanIL-6 at concentrations reported to be expressed in clinical breast cancer. On its own, IL-6treatment failed to induce micronuclei frequency above control levels in these cells. Compared toBaP or PhIP treatment alone, IL-6 plus BaP or PhIP, selectively induced CYP1B1 significantly inboth cell lines. Additionally, miR27b expression was downregulated by IL-6 treatments andtransfection with miR27b inhibitor confirmed that miR27b is a regulator of CYP1B1 in both celllines. These data show that BaP- and PhIP-induced DNA damage in mammary cells is potentiatedby the inflammatory cytokine IL-6 and that inflammation-induced CYP expression, specificallyCYP1B1 via miR27b, is responsible for this effect.

Journal article

Gooderham N, Alkandari A, Ashrafian H, Sathyapalan T, Darzi A, Holmes E, Athanasiou T, Atkin Set al., 2019, Bariatric surgery modulates urinary levels of microRNAs involved in the regulation of renal function, Frontiers in Endocrinology, Vol: 10, ISSN: 1664-2392

Background: Obesity and diabetes cause chronic kidney disease with a common pathophysiology that is characterized by the accumulation of collagen in the extracellular matrix. Recent evidence has implicated the epithelial-to-mesenchymal transition (EMT) as a key step in this pathology with regulation by microRNAs. Weight loss leads to improvements in renal function; therefore, this study hypothesized that bariatric-surgery aided weight loss would lead to changes in urinary microRNAs involved in the regulation of renal function.Materials and methods: Twenty-four bariatric patients undergoing Roux-en-Y gastric bypass and sleeve gastrectomy donated urine pre-operatively and at 2–6 months and 1–2 years post-operatively. Urine samples were also obtained from 10 healthy weight and 7 morbidly obese non-surgical controls. Expression levels of kidney microRNAs were assessed in urine and the function of microRNAs was assessed through the in vitro transfection of HK-2 cells, a kidney proximal tubule cell line.Results: Levels of miR 192, miR 200a, and miR 200b were upregulated in urine following bariatric surgery. This increase was consistent across surgical type and diabetes status and was maintained and enhanced with time. Bariatric surgery alters urinary miR 192 expression from levels seen in morbidly obese patients to levels seen in healthy weight control patients. In mechanistic studies, the transfection of miR 192 in HK-2 cells increased miR 200a expression and decreased ZEB2, a key transcriptional promoter of kidney fibrosis.Conclusions: Bariatric surgery increased miR 192 and miR 200 urinary levels, key anti-fibrotic microRNAs that could contribute to a renal-protective mechanism and may be of value as urinary biomarkers following surgery. These findings suggest that urinary microRNAs may represent potential novel biomarkers for obesity-associated renal function.

Journal article

Abdul Rahim MBH, Chilloux J, Martinez-Gili L, Neves AL, Myridakis A, Gooderham N, Dumas M-Eet al., 2019, Diet-induced metabolic changes of the human gut microbiome: importance of short-chain fatty acids, methylamines and indoles, Acta Diabetologica, Vol: 56, Pages: 493-500, ISSN: 0940-5429

The human gut is a home for more than 100 trillion bacteria, far more than all other microbial populations resident on the body's surface. The human gut microbiome is considered as a microbial organ symbiotically operating within the host. It is a collection of different cell lineages that are capable of communicating with each other and the host and has an ability to undergo self-replication for its repair and maintenance. As the gut microbiota is involved in many host processes including growth and development, an imbalance in its ecological composition may lead to disease and dysfunction in the human. Gut microbial degradation of nutrients produces bioactive metabolites that bind target receptors, activating signalling cascades, and modulating host metabolism. This review covers current findings on the nutritional and pharmacological roles of selective gut microbial metabolites, short-chain fatty acids, methylamines and indoles, as well as discussing nutritional interventions to modulate the microbiome.

Journal article

Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Bastaki M, Davidsen JM, Harman CL, McGowen M, Taylor SVet al., 2019, FEMA GRAS assessment of natural flavor complexes: Citrus-derived flavoring ingredients, Food and Chemical Toxicology, Vol: 124, Pages: 192-218, ISSN: 0278-6915

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavoring ingredients. This publication is the first in a series and summarizes the evaluation of 54 Citrus-derived NFCs using the procedure outlined in Smith et al. (2005) and updated in Cohen et al. (2018) to evaluate the safety of naturally-occurring mixtures for their intended use as flavoring ingredients. The procedure relies on a complete chemical characterization of each NFC intended for commerce and organization of each NFC's chemical constituents into well-defined congeneric groups. The safety of the NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism and toxicology of members of the congeneric groups and the NFC under evaluation. As a result of the application of the procedure, 54 natural flavor complexes derived from botanicals of the Citrus genus were affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavoring ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.

Journal article

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, Archives of Toxicology, Vol: 92, Pages: 3459-3469, ISSN: 0340-5761

Cooking food at high temperatures produces genotoxic chemicals and there is concern about their impact on human health. DNA damage caused by individual chemicals has been investigated but few studies have examined the consequences of exposure to mixtures as found in food. The current study examined the mutagenic response to binary mixtures of benzo[a]pyrene (BaP) with glycidamide (GA), BaP with acrylamide (AC), or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) with GA at human-relevant concentrations (sub-nM). The metabolically competent human MCL-5 cells were exposed to these chemicals individually or in mixtures and mutagenicity was assessed at the thymidine kinase (TK) locus. Mixture exposures gave dose-responses that differed from those for the individual chemicals; for the BaP-containing mixtures, an increased mutation frequency (MF) at low concentration combinations that were not mutagenic individually, and decreased MF at higher concentration combinations, compared to the calculated predicted additive MF of the individual chemicals. In contrast, the mixture of PhIP with GA did not increase MF above background levels. These data suggest BaP is driving the mutation response and that metabolic activation plays a role; in mixtures with BaP the increased/decreased MF above/below the expected additive MF the order is PhIP > AC > GA. The increase in MF at some low concentration combinations that include BaP is interesting and supports our previous work showing a similar response for BaP with PhIP, confirming this response is not limited to the BaP/PhIP combination. Moreover, the lack of a mutation response for PhIP with GA relative to the response of the individual chemicals at equivalent doses is interesting and may represent a potential avenue for reducing the risk of exposure to environmental carcinogens; specifically, removal of BaP from the mixture may reduce the mutation effect, although in the context of food this wou

Journal article

Dumas M-E, Chilloux J, Myridakis A, Hoyles L, Everard A, Plovier H, Cani P, Brial F, Gauguier D, Smyth D, Zhang L, Liu Pet 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), Publisher: SPRINGER, Pages: S267-S268, ISSN: 0012-186X

Conference paper

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, Archives of Toxicology, Vol: 92, Pages: 3223-3239, ISSN: 0340-5761

Benzo[a]pyrene (B(a)P) is a major cancer-causing contaminant present in food such as cooked meats and cereals, and is ubiquitous in the environment in smoke derived from the combustion of organic material. Exposure to B(a)P is epidemiologically linked with the incidence of breast cancer. Although B(a)P is recognized as a complete genotoxic carcinogen, thought to act primarily via CYP-mediated metabolic activation to DNA-damaging species, there is also evidence that B(a)P exposure elicits other biological responses that promote development of the cancer phenotype. Here in mechanistic studies using human mammary cells MCF-7 and MDA-MB-231, we have explored mechanisms whereby B(a)P (10- 8 to 10- 5M) promotes inflammation pathways via TNF-α and NFκB leading to IL-6 upregulation, microRNA (Let7a, miR21 and miR29b) dysregulation and activation of VEGF. The miRNA dysregulation is associated with altered expression of inflammation mediators and increased migration and invasive potential of human mammary cancer cells. Our data suggest that mammary cell exposure to B(a)P results in perturbation of inflammation mediators and dysregulation of tumorigenic miRNAs, leading to an inflammation microenvironment that facilitates migration and invasion of mammary epithelial cells. These properties of B(a)P, together with its well-established metabolic activation to DNA-damaging species, offer mechanistic insights into its carcinogenic mode of action.

Journal article

Cohen SM, Eisenbrand G, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Harman C, Taylor SVet al., 2018, GRAS 28 FLAVORING SUBSTANCES, FOOD TECHNOLOGY, Vol: 72, Pages: 62-77, ISSN: 0015-6639

Journal article

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