Cytochrome P450 isoforms are differently up-regulated in aflatoxin B<sub>1</sub>-exposed human lymphocytes and monocytes

Bahari, Abbas; Mehrzad, Jalil; Mahmoudi, Mahmoud; Bassami, Mohammad Reza; Dehghani, Hesam

doi:10.3109/08923973.2013.850506

Cited by 46 publications

(32 citation statements)

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“…MYO1G was identified in whole blood samples of adult smokers [ 6 , 8 ] but not in PBMC [ 4 ] indicating granulocytes as the main source of this methylation change at this CpG. The enzyme of biotransformation CYP1A1 is rather expressed in metabolic active granulocytes or monocytes than in lymphocytes [ 33 , 34 ]. Additionally, it is of special interest that the smoking-induced hypomethylation at cg19859270 in GPR15+ T cells, representing the adaptive immunity, was never found in cord blood.…”

Section: Discussionmentioning

confidence: 99%

Tobacco smoking differently influences cell types of the innate and adaptive immune system—indications from CpG site methylation

et al. 2016

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BackgroundTobacco smoke is worldwide one of the main preventable lifestyle inhalative pollutants causing severe adverse health effects. Epidemiological studies revealed association of tobacco smoking with epigenetic changes at single CpGs in blood. However, the biological relevance of the often only marginal methylation changes remains unclear.ResultsComparing genome-wide changes in CpG methylation of three recently reported epidemiological datasets, two obtained on whole blood and one on peripheral blood mononuclear cells (PBMCs), it becomes evident that the majority of methylation changes (86.7 and 93.3 %) in whole blood account for changes in granulocytes. Analyzing, in more detail, seven highly significant reported smoking-induced methylation changes at single CpGs in different blood cell types of healthy volunteers (n = 32), we confirmatively found a strong cell-type specificity. Two CpGs in GFI1 and F2RL3 were significantly hypomethylated in granulocytes (−11.3 %, p = 0.001; −8.7 %, p = 0.001, respectively) but not in PBMCs of smokers while two CpGs in CPOX and GPR15 were found to be hypomethylated in PBMC (−4.3 %, p = 0.003; −4.2 %, P = 0.009, respectively) and their subtypes of GPR15 non-expressing (−3.2 %, p = 0.027; −2.5 %, p = 0.032, respectively) and smoking-evoked GPR15 expressing T cells (−15.8 %, p < 0.001; −13.8 %, p = 0.018, respectively) but not in granulocytes. In contrast, cg05575921 within AHRR was hypomethylated in every analyzed cell type of smokers, but with a different degree. Both, hypomethylation at cg05575921 in granulocytes (−55.2 % methylation change in smokers, p < 0.001) and the frequency of GPR15+ T cells (9.8–37.1 % in smokers), possessing a specific hypomethylation at cg19859270, were strongly associated with smoking behavior at individual level and could therefore serve as valuable biomarkers indicating a disturbed homeostasis in smokers.In contrast to the reported long-term persistent methylation changes in adult smokers after cessation, the hypomethylation at cg05575921 in prenatally tobacco smoke-exposed children (n = 13) from our LINA cohort was less stable and disappeared already within 2 years after birth.ConclusionsStudying cell type-specific methylation changes provides helpful information regarding the biological relevance of epigenetic modifications. Here, we could show that smoking differently affects both cells of the innate and adaptive immune systems.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0249-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Tobacco smoking differently influences cell types of the innate and adaptive immune system—indications from CpG site methylation

et al. 2016

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“…Hence, we aimed to evaluate the neuroimmunotoxic effects of low concentrations of the well-known and potent toxin at the cellular and molecular level in different tissues. We have shown active metabolism of the low level of aflatoxins and its immune dysregulatory effects on different types of human leucocytes [8, 21, 27]. We have also recently shown that murine microglial cells can be activated to produce free radicals and initiate inflammatory responses upon exposure to a low quantity of AFB 1 [9].…”

Section: Discussionmentioning

confidence: 99%

Human Microglial Cells Undergo Proapoptotic Induction and Inflammatory Activation upon in vitro Exposure to a Naturally Occurring Level of Aflatoxin B<sub>1</sub>

Mehrzad

Hosseinkhani

Malvandi

2018

Neuroimmunomodulation

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Objective: Knowledge regarding interactions of AFB₁ with the human nervous system and how a naturally occurring level of AFB₁ could potentially induce neuroimmune dysregulation is very limited. To assess the cellular effects of AFB₁ on the human brain, we used the human microglia cell line CHME5 as a model to pinpoint its potential in vivo translation. Methods: We used the CHME5 cell line culture system, multiplex qPCR, (chemi)bioluminescence, Luminex ELISA, and flow cytometry assays to evaluate the toxic effects of a naturally occurring level of AFB₁ on human microglia. Results: A low concentration of AFB₁ upregulates the mRNA expression of many proinflammatory molecules, such as TLRs, MyD88, NFκB, and CxCr4, induces intracellular ATP depletion, and increases caspase-3/7 activity at different time points following exposure to the toxin. Furthermore, AFB₁-exposed microglia secreted significantly higher levels of IFN-γ and GM-CSF after treatment. We also observed a slight increase in the percentage of apoptotic microglia (annexin V⁺/PI⁻) at 48 h posttreatment. Conclusion: Our work confirmed that the environmentally relevant level of AFB₁ could cause an inflammatory reaction in human microglial cells that is potentially harmful or toxic to the homeostasis of the human central nervous system and might increase susceptibility to neurodegenerative diseases.

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“…The results from this previous study revealed the overexpression of CYP2E1 in Kupffer cells, which induce TLR4 activation, produced inflammatory responses and may lead to liver damage ( 19 ). Under exposure to aflatoxin B1 (AFB1), the observed pronounced increase in TLR4 transcripts in monocytes may be partly attributed to higher expression of CYP1A1 and CYP1B1 caused by AFB1 peroxidation in monocytes ( 20 ). Extracellular signal-regulated kinase (ERK) is downstream of TLR4, and may also be involved in the regulation of DNA methylation patterns by regulating methyltransferase.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 1A1 and 1B1 promoter CpG island methylation regulates rat liver injury induced by isoniazid

Zheng

et al. 2017

Mol Med Report

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DNA methylation is an important component of epigenetics that is involved in the occurrence and development of a variety of diseases. The present study aimed to clarify the relationship between cytochrome P450 (CYP)1A1 and CYP1B1 promoter CpG island methylation and isoniazid-induced liver injury in rats, and to explore the possible mechanism, rats were given an intragastric dose of isoniazid (55 mg·kg−1·d−1). High performance liquid chromatography was used to analyze the DNA methylation level of the whole genome in liver tissue. Methylation-specific polymerase chain reaction (PCR) was used to detect the methylation level of CpG islands in the promoter region of CYP1A1 and CYP1B1. Reverse transcription-quantitative PCR was used to determine the mRNA expression levels of CYP1A1, CYP1B1, toll-like receptor 4 (TLR4), extracellular signal-regulated kinase (ERK) 2, peroxisome proliferator-activated receptor (PPAR) -γ, interleukin (IL)-6 and tumor necrosis factor (TNF)-α. The expression levels of CYP1A1 and CYP1B1 proteins were measured by ELISA, and malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were analyzed by colorimetric method. Liver tissue pathology, an indicator of liver function, indicated rat liver injury at 10 days following isoniazid treatment. Whole-genome methylation levels were gradually reduced, and methylation at day 7 post-treatment was significantly lower than the control group. CYP1A1 and CYP1B1 promoter CpG island methylation level was significantly increased at 3 days post-treatment. CYP1A1 and CYP1B1 mRNA expression levels were significantly reduced from day 7 and 10, respectively. These results suggested that CpG island hypermethylation of the CYP1A1 and CYP1B1 promoters regulate the low expression of genes involved in the occurrence of isoniazid-induced liver injury. With the alterations of CYP1A1 and CYP1B1 expression, the mRNA expression levels of TLR4, ERK, MDA, IL-6 and TNF-α were upregulated, and the expression of SOD and PPAR-γ were downregulated. These data demonstrated that alterations in methylation patterns may involve changes in the TLR4-ERK signaling pathway and PPAR-γ, which may alter the expression of MDA, SOD, IL-6 and TNF-α, leading to liver injury.

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Cytochrome P450 isoforms are differently up-regulated in aflatoxin B₁-exposed human lymphocytes and monocytes

Abstract: Our novel findings indicate that AFB₁ more intensively stimulates CYP genes expression in monocytes than in lymphocytes. Mechanistically, this could explain a more pronounced immunotoxicity of AFB₁ in myeloid than in lymphoid lineage cells in vitro/situ/vivo.

Cited by 46 publications

References 44 publications

Tobacco smoking differently influences cell types of the innate and adaptive immune system—indications from CpG site methylation

Tobacco smoking differently influences cell types of the innate and adaptive immune system—indications from CpG site methylation

Human Microglial Cells Undergo Proapoptotic Induction and Inflammatory Activation upon in vitro Exposure to a Naturally Occurring Level of Aflatoxin B<sub>1</sub>

Cytochrome P450 1A1 and 1B1 promoter CpG island methylation regulates rat liver injury induced by isoniazid

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Cytochrome P450 isoforms are differently up-regulated in aflatoxin B1-exposed human lymphocytes and monocytes

Abstract: Our novel findings indicate that AFB₁ more intensively stimulates CYP genes expression in monocytes than in lymphocytes. Mechanistically, this could explain a more pronounced immunotoxicity of AFB₁ in myeloid than in lymphoid lineage cells in vitro/situ/vivo.

Cited by 46 publications

References 44 publications

Tobacco smoking differently influences cell types of the innate and adaptive immune system—indications from CpG site methylation

Tobacco smoking differently influences cell types of the innate and adaptive immune system—indications from CpG site methylation

Human Microglial Cells Undergo Proapoptotic Induction and Inflammatory Activation upon in vitro Exposure to a Naturally Occurring Level of Aflatoxin B<sub>1</sub>

Cytochrome P450 1A1 and 1B1 promoter CpG island methylation regulates rat liver injury induced by isoniazid

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Cytochrome P450 isoforms are differently up-regulated in aflatoxin B₁-exposed human lymphocytes and monocytes