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Article ; Online: Alterations in small RNA profiles in liver following a subchronic exposure to a low-dose pesticide mixture in Sprague-Dawley rats.

Mesnage, Robin / Mahmud, Nadiya / Mein, Charles A / Antoniou, Michael N

2021 Volume 353, Page(s) 20–26

Abstract: Small RNAs have emerged as a promising new type of biomarker to monitor health status and track the development of diseases. Here we report changes in the levels of small RNAs in the liver of rats exposed to a mixture of six pesticides frequently ... ...

Abstract	Small RNAs have emerged as a promising new type of biomarker to monitor health status and track the development of diseases. Here we report changes in the levels of small RNAs in the liver of rats exposed to a mixture of six pesticides frequently detected in foodstuffs (azoxystrobin, boscalid, chlorpyrifos, glyphosate, imidacloprid and thiabendazole). Multivariate analysis with OPLS-DA methods showed that small RNA profiles can discriminate samples from pesticide treated rats from their concurrent controls. A total of 9 miRNAs were found to have their levels altered in the liver of the pesticide-treated rats in comparison to the controls, which included 7 that were downregulated (miR-22-5p, miR-193a-3p, miR-32-5p, miR-33-5p, miR-122-5p, miR-22-3p, miR-130a-3p) and 2 that were upregulated (miR-486-5p, miR-146a-5p). These miRNAs were predicted to regulate genes, which were found to have their expression altered by the pesticide mixture and have known health implications in the regulation of hepatic metabolism. This supports and extends our recent conclusions that high- throughput 'omics' analyses can reveal molecular perturbations, which can potentially act as sensitive and accurate markers of health risks arising from exposure to environmental pollutants such as pesticides.
MeSH term(s)	Animals ; Female ; Gene Expression Regulation/drug effects ; Liver/drug effects ; Liver/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Pesticides/toxicity ; Phylogeny ; Rats ; Rats, Sprague-Dawley ; Transcriptome/drug effects
Chemical Substances	MicroRNAs ; Pesticides
Language	English
Publishing date	2021-10-06
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	433788-8
ISSN	1879-3169 ; 0378-4274
ISSN (online)	1879-3169
ISSN	0378-4274
DOI	10.1016/j.toxlet.2021.10.001
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Article ; Online: A DNA methylation signature in the stress driver gene Fkbp5 indicates a neuropathic component in chronic pain.

Maiarù, Maria / Acton, Richard J / Woźniak, Eva L / Mein, Charles A / Bell, Christopher G / Géranton, Sandrine M

Clinical epigenetics

2023 Volume 15, Issue 1, Page(s) 155

Abstract: Background: Epigenetic changes can bring insight into gene regulatory mechanisms associated with disease pathogenicity, including chronicity and increased vulnerability. To date, we are yet to identify genes sensitive to epigenetic regulation that ... ...

Abstract	Background: Epigenetic changes can bring insight into gene regulatory mechanisms associated with disease pathogenicity, including chronicity and increased vulnerability. To date, we are yet to identify genes sensitive to epigenetic regulation that contribute to the maintenance of chronic pain and with an epigenetic landscape indicative of the susceptibility to persistent pain. Such genes would provide a novel opportunity for better pain management, as their epigenetic profile could be targeted for the treatment of chronic pain or used as an indication of vulnerability for prevention strategies. Here, we investigated the epigenetic profile of the gene Fkbp5 for this potential, using targeted bisulphite sequencing in rodent pre-clinical models of chronic and latent hypersensitive states. Results: The Fkbp5 promoter DNA methylation (DNAm) signature in the CNS was significantly different between models of persistent pain, and there was a significant correlation between CNS and peripheral blood Fkbp5 DNAm, indicating that further exploration of Fkbp5 promoter DNAm as an indicator of chronic pain pathogenic origin is warranted. We also found that maternal separation, which promotes the persistency of inflammatory pain in adulthood, was accompanied by long-lasting reduction in Fkbp5 DNAm, suggesting that Fkbp5 DNAm profile may indicate the increased vulnerability to chronic pain in individuals exposed to trauma in early life. Conclusions: Overall, our data demonstrate that the Fkbp5 promoter DNAm landscape brings novel insight into the differing pathogenic origins of chronic pain, may be able to stratify patients and predict the susceptibility to chronic pain.
MeSH term(s)	Humans ; Chronic Pain/genetics ; DNA Methylation ; Epigenesis, Genetic ; Gene Expression Regulation ; Maternal Deprivation ; Tacrolimus Binding Proteins/genetics
Chemical Substances	tacrolimus binding protein 5 (EC 5.2.1.8) ; Tacrolimus Binding Proteins (EC 5.2.1.-)
Language	English
Publishing date	2023-09-30
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553921-8
ISSN	1868-7083 ; 1868-7075
ISSN (online)	1868-7083
ISSN	1868-7075
DOI	10.1186/s13148-023-01569-8
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Article ; Online: A DNA methylation signature in the stress driver gene Fkbp5 indicates a neuropathic component in chronic pain

Maria Maiarù / Richard J. Acton / Eva L. Woźniak / Charles A. Mein / Christopher G. Bell / Sandrine M. Géranton

Clinical Epigenetics, Vol 15, Iss 1, Pp 1-

2023 Volume 11

Abstract: Abstract Background Epigenetic changes can bring insight into gene regulatory mechanisms associated with disease pathogenicity, including chronicity and increased vulnerability. To date, we are yet to identify genes sensitive to epigenetic regulation ... ...

Abstract	Abstract Background Epigenetic changes can bring insight into gene regulatory mechanisms associated with disease pathogenicity, including chronicity and increased vulnerability. To date, we are yet to identify genes sensitive to epigenetic regulation that contribute to the maintenance of chronic pain and with an epigenetic landscape indicative of the susceptibility to persistent pain. Such genes would provide a novel opportunity for better pain management, as their epigenetic profile could be targeted for the treatment of chronic pain or used as an indication of vulnerability for prevention strategies. Here, we investigated the epigenetic profile of the gene Fkbp5 for this potential, using targeted bisulphite sequencing in rodent pre-clinical models of chronic and latent hypersensitive states. Results The Fkbp5 promoter DNA methylation (DNAm) signature in the CNS was significantly different between models of persistent pain, and there was a significant correlation between CNS and peripheral blood Fkbp5 DNAm, indicating that further exploration of Fkbp5 promoter DNAm as an indicator of chronic pain pathogenic origin is warranted. We also found that maternal separation, which promotes the persistency of inflammatory pain in adulthood, was accompanied by long-lasting reduction in Fkbp5 DNAm, suggesting that Fkbp5 DNAm profile may indicate the increased vulnerability to chronic pain in individuals exposed to trauma in early life. Conclusions Overall, our data demonstrate that the Fkbp5 promoter DNAm landscape brings novel insight into the differing pathogenic origins of chronic pain, may be able to stratify patients and predict the susceptibility to chronic pain.
Keywords	FKBP5 ; DNA methylation ; Chronic pain ; Preclinical models ; Vulnerability ; Medicine ; R ; Genetics ; QH426-470
Subject code	610
Language	English
Publishing date	2023-09-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Transcriptomic profiling reveals a pronociceptive role for angiotensin II in inflammatory bowel disease.

Higham, James P / Bhebhe, Charity N / Gupta, Rohit A / Tranter, Michael M / Barakat, Farah M / Dogra, Harween / Bab, Natalie / Wozniak, Eva / Barker, Katie H / Wilson, Catherine H / Mein, Charles A / Raine, Tim / Cox, James J / Wood, John N / Croft, Nicholas M / Wright, Paul D / Bulmer, David C

Pain

2024

Abstract: Abstract: Visceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side effects, driving the need for ...

Abstract	Abstract: Visceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side effects, driving the need for a more complete understanding of the mechanisms causing pain. Whole transcriptome gene expression analysis was performed by bulk RNA sequencing of colonic biopsies from patients with ulcerative colitis (UC) and Crohn's disease (CD) reporting abdominal pain and compared with noninflamed control biopsies. Potential pronociceptive mediators were identified based on gene upregulation in IBD biopsy tissue and cognate receptor expression in murine colonic sensory neurons. Pronociceptive activity of identified mediators was assessed in assays of sensory neuron and colonic afferent activity. RNA sequencing analysis highlighted a 7.6-fold increase in the expression of angiotensinogen transcripts, Agt , which encode the precursor to angiotensin II (Ang II), in samples from UC patients ( P = 3.2 × 10 -8 ). Consistent with the marked expression of the angiotensin AT 1 receptor in colonic sensory neurons, Ang II elicited an increase in intracellular Ca 2+ in capsaicin-sensitive, voltage-gated sodium channel subtype Na V 1.8-positive sensory neurons. Ang II also evoked action potential discharge in high-threshold colonic nociceptors. These effects were inhibited by the AT 1 receptor antagonist valsartan. Findings from our study identify AT 1 receptor-mediated colonic nociceptor activation as a novel pathway of visceral nociception in patients with UC. This work highlights the potential utility of angiotensin receptor blockers, such as valsartan, as treatments for pain in IBD.
Language	English
Publishing date	2024-01-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	193153-2
ISSN	1872-6623 ; 0304-3959
ISSN (online)	1872-6623
ISSN	0304-3959
DOI	10.1097/j.pain.0000000000003159
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Article ; Online: Areca catechu-(Betel-nut)-induced whole transcriptome changes in a human monocyte cell line that may have relevance to diabetes and obesity; a pilot study.

Cardosa, Shirleny R / Ogunkolade, B William / Lowe, Rob / Savage, Emanuel / Mein, Charles A / Boucher, Barbara J / Hitman, Graham A

BMC endocrine disorders

2021 Volume 21, Issue 1, Page(s) 165

Abstract: Background: Betel-nut consumption is the fourth most common addictive habit globally and there is good evidence linking the habit to obesity, type 2 diabetes (T2D) and the metabolic syndrome. The aim of our pilot study was to identify gene expression ... ...

Abstract	Background: Betel-nut consumption is the fourth most common addictive habit globally and there is good evidence linking the habit to obesity, type 2 diabetes (T2D) and the metabolic syndrome. The aim of our pilot study was to identify gene expression relevant to obesity, T2D and the metabolic syndrome using a genome-wide transcriptomic approach in a human monocyte cell line incubated with arecoline and its nitrosated products. Results: The THP1 monocyte cell line was incubated separately with arecoline and 3-methylnitrosaminopropionaldehyde (MNPA) in triplicate for 24 h and pooled cDNA indexed paired-end libraries were sequenced (Illumina NextSeq 500). After incubation with arecoline and MNPA, 15 and 39 genes respectively had significant changes in their expression (q < 0.05, log fold change 1.5). Eighteen of those genes have reported associations with T2D and obesity in humans; of these genes there was most marked evidence for CLEC10A, MAPK8IP1, NEGR1, NQ01 and INHBE genes. Conclusions: Our preliminary studies have identified a large number of genes relevant to obesity, T2D and metabolic syndrome whose expression was changed significantly in human TPH1 cells following incubation with betel-nut derived arecoline or with MNPA. These findings require validation by further cell-based work and investigation amongst betel-chewing communities.
MeSH term(s)	Areca/chemistry ; Arecoline/pharmacology ; Biomarkers/analysis ; Biomarkers/metabolism ; Diabetes Mellitus, Type 2/genetics ; Follow-Up Studies ; Gene Expression Regulation/drug effects ; Humans ; Metabolic Syndrome/genetics ; Monocytes/drug effects ; Monocytes/metabolism ; Monocytes/pathology ; Obesity/genetics ; Pilot Projects ; Prognosis ; Transcriptome/drug effects
Chemical Substances	Biomarkers ; Arecoline (4ALN5933BH)
Language	English
Publishing date	2021-08-14
Publishing country	England
Document type	Journal Article
ISSN	1472-6823
ISSN (online)	1472-6823
DOI	10.1186/s12902-021-00827-1
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Article: Glyphosate and its formulations Roundup Bioflow and RangerPro alter bacterial and fungal community composition in the rat caecum microbiome.

Mesnage, Robin / Panzacchi, Simona / Bourne, Emma / Mein, Charles A / Perry, Melissa J / Hu, Jianzhong / Chen, Jia / Mandrioli, Daniele / Belpoggi, Fiorella / Antoniou, Michael N

Frontiers in microbiology

2022 Volume 13, Page(s) 888853

Abstract: The potential health consequences of glyphosate-induced gut microbiome alterations have become a matter of intense debate. As part of a multifaceted study investigating toxicity, carcinogenicity and multigenerational effects of glyphosate and its ... ...

Abstract	The potential health consequences of glyphosate-induced gut microbiome alterations have become a matter of intense debate. As part of a multifaceted study investigating toxicity, carcinogenicity and multigenerational effects of glyphosate and its commercial herbicide formulations, we assessed changes in bacterial and fungal populations in the caecum microbiota of rats exposed prenatally until adulthood (13 weeks after weaning) to three doses of glyphosate (0.5, 5, 50 mg/kg body weight/day), or to the formulated herbicide products Roundup Bioflow and RangerPro at the same glyphosate-equivalent doses. Caecum bacterial microbiota were evaluated by 16S rRNA sequencing whilst the fungal population was determined by ITS2 amplicon sequencing. Results showed that both fungal and bacterial diversity were affected by the Roundup formulations in a dose-dependent manner, whilst glyphosate alone significantly altered only bacterial diversity. At taxa level, a reduction in Bacteroidota abundance, marked by alterations in the levels of
Language	English
Publishing date	2022-10-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2022.888853
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Article: Age- and quality-dependent DNA methylation correlate with melanin-based coloration in a wild bird.

Soulsbury, Carl D / Lipponen, Anssi / Wood, Kristie / Mein, Charles A / Hoffman, Joseph I / Lebigre, Christophe

Ecology and evolution

2018 Volume 8, Issue 13, Page(s) 6547–6557

Abstract: Secondary sexual trait expression can be influenced by fixed individual factors (such as genetic quality) as well as by dynamic factors (such as age and environmentally induced gene expression) that may be associated with variation in condition or ... ...

Abstract	Secondary sexual trait expression can be influenced by fixed individual factors (such as genetic quality) as well as by dynamic factors (such as age and environmentally induced gene expression) that may be associated with variation in condition or quality. In particular, melanin-based traits are known to relate to condition and there is a well-characterized genetic pathway underpinning their expression. However, the mechanisms linking variable trait expression to genetic quality remain unclear. One plausible mechanism is that genetic quality could influence trait expression via differential methylation and differential gene expression. We therefore conducted a pilot study examining DNA methylation at a candidate gene (agouti-related neuropeptide:
Language	English
Publishing date	2018-05-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2635675-2
ISSN	2045-7758
ISSN	2045-7758
DOI	10.1002/ece3.4132
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Article ; Online: Comparison of transcriptome responses to glyphosate, isoxaflutole, quizalofop-p-ethyl and mesotrione in the HepaRG cell line.

Mesnage, Robin / Biserni, Martina / Wozniak, Eva / Xenakis, Theodoros / Mein, Charles A / Antoniou, Michael N

Toxicology reports

2018 Volume 5, Page(s) 819–826

Abstract: Use and thus exposure to quizalofop-p-ethyl, isoxaflutole, mesotrione and glyphosate, which are declared as active principles in commercial formulations of herbicides, is predicted to rapidly increase in coming years in an effort to overcome the wide- ... ...

Abstract	Use and thus exposure to quizalofop-p-ethyl, isoxaflutole, mesotrione and glyphosate, which are declared as active principles in commercial formulations of herbicides, is predicted to rapidly increase in coming years in an effort to overcome the wide-spread appearance of glyphosate-resistant weeds, especially in fields where glyphosate-tolerant genetically modified crops are cultivated in the USA. Thus, there is an urgent need for an evaluation of metabolic effects of new pesticide ingredients used to replace glyphosate. As the liver is a primary target of chemical pollutant toxicity, we have used the HepaRG human liver cell line as a model system to assess the toxicological insult from quizalofop-p-ethyl, isoxaflutole, mesotrione and glyphosate by determining alterations in the transcriptome caused by exposure to three concentrations of each of these compounds, including a low environmentally relevant dose. RNA-seq data were analysed with HISAT2, StringTie and Ballgown. Quizalofop-p-ethyl was found to be the most toxic of the pesticide ingredients tested, causing alterations in gene expression that are associated with pathways involved in fatty acid degradation and response to alcoholism. Isoxaflutole was less toxic, but caused detectable changes in retinol metabolism and in the PPAR signalling pathway at a concentration of 1 mM. ToxCast data analysis revealed that isoxaflutole activated PPAR gamma receptor and pregnane X responsive elements in reporter gene assays. Glyphosate and mesotrione caused subtle changes in transcriptome profiles, with too few genes altered in their function to allow a reliable pathway analysis. In order to explore the effects of glyphosate in greater depth and detail, we undertook a global metabolome profiling. This revealed a decrease in free long chain fatty acids and polyunsaturated fatty acid levels at the lowest concentration (0.06 μM) of glyphosate, although no effects were detected at the two higher concentrations tested, perhaps suggesting a non-linear dose response. This surprising result will need to be confirmed by additional studies. Overall, our findings contribute to filling the knowledge gap regarding metabolic toxicity that can potentially arise from exposure to these four herbicide active principles.
Language	English
Publishing date	2018-08-11
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	2805786-7
ISSN	2214-7500 ; 2214-7500
ISSN (online)	2214-7500
ISSN	2214-7500
DOI	10.1016/j.toxrep.2018.08.005
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Article ; Online: Deep palmar phenotyping in atopic eczema: patterns associated with filaggrin variants, disease severity and barrier function in a South Asian population.

Thomas, Bjorn R / Tan, Xiang Li / Van Duijvenboden, Stefan / Hogan, Sarah C / Hughes, Aaron J / Tawfik, Soha S / Dhoat, Sasha / Atkar, Ravinder / Robinson, Elizabeth J / Rahman, Syedia R / Rahman, Samiha / Ahmed, Rehana A / Begum, Rubina / Khanam, Habiba / Bourne, Emma L / Wozniak, Eva L / Mein, Charles A / Kelsell, David P / O'Toole, Edel A

The British journal of dermatology

2023 Volume 188, Issue 6, Page(s) 785–792

Abstract: Background: Hyperlinear palms are described as a feature of loss-of-function (LoF) variants in filaggrin (FLG).: Objectives: To explore the phenotype of participants (age < 31 years) with atopic eczema of Bangladeshi ancestry from East London and ... ...

Abstract	Background: Hyperlinear palms are described as a feature of loss-of-function (LoF) variants in filaggrin (FLG). Objectives: To explore the phenotype of participants (age < 31 years) with atopic eczema of Bangladeshi ancestry from East London and investigate which factors best associate with LoF FLG variants. Methods: A cross-sectional study with participants recruited between May 2018 and December 2020. Patterns of palmar linearity were categorized and modelled with the Eczema Area and Severity Index (EASI), transepidermal water loss (TEWL), skin hydration (SH) and LoF FLG variants. Results: There were 506 complete cases available. Five palm patterns were noted. The 'prominent diamond' pattern associated best with EASI [marginal effects (ME) 2.53, 95% confidence interval (CI) 1.74-3.67], SH (ME 0.85, 95% CI 0.78-0.96) and TEWL (ME 1.32, 95% CI 1.11-1.62). Using five palm patterns had some ability to discriminate LoF FLG variants [area under the receiver operator characteristic (AUROC) 76.32%, 95% CI 71.91-80.73], improving to 77.99% (73.70-82.28) with the addition of SH. In subgroup analysis with only fine perpendicular/prominent diamond patterns the AUROC was 89.11% (95% CI 84.02-94.19). Conclusions: This was a single-centre study design with humans classifying clinical patterns. The stability of temperature and humidity was not guaranteed across TEWL and SH measurements despite using a climate-controlled room. Palm patterns associate with EASI and TEWL. The fine perpendicular/prominent diamond patterns are markers to detect the absence/presence of LoF FLG variants, respectively.
MeSH term(s)	Humans ; Adult ; Dermatitis, Atopic/genetics ; Filaggrin Proteins ; Cross-Sectional Studies ; Eczema/genetics ; Patient Acuity ; Intermediate Filament Proteins/genetics ; Intermediate Filament Proteins/metabolism ; Mutation/genetics ; Genetic Predisposition to Disease/genetics
Chemical Substances	Filaggrin Proteins ; Intermediate Filament Proteins
Language	English
Publishing date	2023-03-09
Publishing country	England
Document type	Journal Article
ZDB-ID	80076-4
ISSN	1365-2133 ; 0007-0963
ISSN (online)	1365-2133
ISSN	0007-0963
DOI	10.1093/bjd/ljad036
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Article ; Online: Multi-omics phenotyping of the gut-liver axis reveals metabolic perturbations from a low-dose pesticide mixture in rats.

Mesnage, Robin / Teixeira, Maxime / Mandrioli, Daniele / Falcioni, Laura / Ibragim, Mariam / Ducarmon, Quinten Raymond / Zwittink, Romy Daniëlle / Amiel, Caroline / Panoff, Jean-Michel / Bourne, Emma / Savage, Emanuel / Mein, Charles A / Belpoggi, Fiorella / Antoniou, Michael N

Communications biology

2021 Volume 4, Issue 1, Page(s) 471

Abstract: Health effects of pesticides are not always accurately detected using the current battery of regulatory toxicity tests. We compared standard histopathology and serum biochemistry measures and multi-omics analyses in a subchronic toxicity test of a ... ...

Abstract	Health effects of pesticides are not always accurately detected using the current battery of regulatory toxicity tests. We compared standard histopathology and serum biochemistry measures and multi-omics analyses in a subchronic toxicity test of a mixture of six pesticides frequently detected in foodstuffs (azoxystrobin, boscalid, chlorpyrifos, glyphosate, imidacloprid and thiabendazole) in Sprague-Dawley rats. Analysis of water and feed consumption, body weight, histopathology and serum biochemistry showed little effect. Contrastingly, serum and caecum metabolomics revealed that nicotinamide and tryptophan metabolism were affected, which suggested activation of an oxidative stress response. This was not reflected by gut microbial community composition changes evaluated by shotgun metagenomics. Transcriptomics of the liver showed that 257 genes had their expression changed. Gene functions affected included the regulation of response to steroid hormones and the activation of stress response pathways. Genome-wide DNA methylation analysis of the same liver samples showed that 4,255 CpG sites were differentially methylated. Overall, we demonstrated that in-depth molecular profiling in laboratory animals exposed to low concentrations of pesticides allows the detection of metabolic perturbations that would remain undetected by standard regulatory biochemical measures and which could thus improve the predictability of health risks from exposure to chemical pollutants.
MeSH term(s)	Animals ; Dose-Response Relationship, Drug ; Female ; Gastrointestinal Tract/drug effects ; Gastrointestinal Tract/metabolism ; Liver/drug effects ; Liver/metabolism ; Metabolomics ; Pesticides/toxicity ; Phenotype ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Pesticides
Language	English
Publishing date	2021-04-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-021-01990-w
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