Gene expression and cytosine DNA methylation alterations in induced pluripotent stem-cell-derived human hepatocytes treated with low doses of chemical carcinogens

Tryndyak, Volodymyr; Borowa-Mazgaj, Barbara; Beland, Frederick A.; Pogribny, Igor P.

doi:10.1007/s00204-019-02569-5

Cited by 11 publications

(7 citation statements)

References 37 publications

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“…For instance, enrichment of the P53 and DNA damage pathways herein reported is in large agreement with previous studies performed in human cell lines. In particular, the P53 pathway was significantly enriched in HepaRG cells exposed to 1 μM AFB1 for 24 h [ 126 ], in induced pluripotent stem-cell (iPSC)-derived human hepatocytes incubated with 0.2 μM AFB1 for 7 days [ 127 ], and in HepG2 and human primary hepatocytes (HPH) treated with 1 μM and 1.25/5 μM for 24 h, respectively [ 41 ]. Thus, we might hypothesize that activation of the P53 pathway also represents a key point in bovine response to AFB1.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, enrichment of the BP "inflammatory response" and the "NF-kappa B signaling pathway" is interesting evidence that highlights a distinctive transcriptional signature of the bovine cellular model here used. Indeed, in previous studies assessing the effects of AFB1 in human hepatic cells, these GO terms did not appear significantly enriched [40,41,126,127]. It is conceivable to hypothesize AFB1 modulates the expression of several genes implicated in cattle inflammatory processes (e.g., chemokine ligands, TNFα and INFγ pathways), which in part are modulated by the pivotal transcription factor NF-kB.…”

Section: Comparison With Data From Human In Vitro Modelsmentioning

confidence: 97%

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Insights into Aflatoxin B1 Toxicity in Cattle: An In Vitro Whole-Transcriptomic Approach

Pauletto

Tolosi²,

Giantin³

et al. 2020

Toxins

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Aflatoxins, and particularly aflatoxin B1 (AFB1), are toxic mycotoxins to humans and farm animal species, resulting in acute and chronic toxicities. At present, AFB1 is still considered a global concern with negative impacts on health, the economy, and social life. In farm animals, exposure to AFB1-contaminated feed may cause several untoward effects, liver damage being one of the most devastating ones. In the present study, we assessed in vitro the transcriptional changes caused by AFB1 in a bovine fetal hepatocyte-derived cell line (BFH12). To boost the cellular response to AFB1, cells were pre-treated with the co-planar PCB 3,3′,4,4′,5-pentachlorobiphenyl (PCB126), a known aryl hydrocarbon receptor agonist. Three experimental groups were considered: cells exposed to the vehicle only, to PCB126, and to PCB126 and AFB1. A total of nine RNA-seq libraries (three replicates/group) were constructed and sequenced. The differential expression analysis showed that PCB126 induced only small transcriptional changes. On the contrary, AFB1 deeply affected the cell transcriptome, the majority of significant genes being associated with cancer, cellular damage and apoptosis, inflammation, bioactivation, and detoxification pathways. Investigating mRNA perturbations induced by AFB1 in cattle BFH12 cells will help us to better understand AFB1 toxicodynamics in this susceptible and economically important food-producing species.

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Section: Discussionmentioning

confidence: 99%

Section: Comparison With Data From Human In Vitro Modelsmentioning

confidence: 97%

Insights into Aflatoxin B1 Toxicity in Cattle: An In Vitro Whole-Transcriptomic Approach

Pauletto

Tolosi²,

Giantin³

et al. 2020

Toxins

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show abstract

“…In addition, methapyrilene enhanced cell proliferation (Ito et al 2019). Overall, the effects of methapyrilene are believed to be mediated through alterations in transcription of multiple genes (Tryndyak et al 2019) and modulation of the DNA methylation footprint (Tryndyak et al 2018).…”

Section: Methapyrilenementioning

confidence: 99%

Targeting gap junctional intercellular communication by hepatocarcinogenic compounds

Leroy

Pieters

Tabernilla

et al. 2020

Journal of Toxicology and Environmental Health, Part B

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Gap junctions in liver, as in other organs, play a critical role in tissue homeostasis. Inherently, these cellular constituents are major targets for systemic toxicity and diseases, including cancer.This review provides an overview of chemicals that compromise liver gap junctions, in particular biological toxins, organic solvents, pesticides, pharmaceuticals, peroxides, metals and phthalates. The focus in this review is placed upon the mechanistic scenarios that underlie these adverse effects. Further, the potential use of gap junctional activity as an in vitro biomarker to identify non-genotoxic hepatocarcinogenic chemicals is discussed.

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“…A number of previous studies have reported changes in DNA methylation in relation to AFB1 treatment of human cells in vitro [50][51][52][53]. When primary human hepatocytes were treated with AFB1, Rieswijk et al found six genes that showed persistent hypomethylation associated with up-regulated gene expression.…”

Section: Discussionmentioning

confidence: 99%

Aflatoxin Exposure during Early Life Is Associated with Differential DNA Methylation in Two-Year-Old Gambian Children

Ghantous

Novoloaca

Bouaoun

et al. 2021

IJMS

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Background: DNA methylation is an epigenetic control mechanism that may be altered by environmental exposures. We have previously reported that in utero exposure to the mycotoxin and liver carcinogen aflatoxin B1 from the maternal diet, as measured using biomarkers in the mothers’ blood, was associated with differential DNA methylation in white blood cells of 6-month-old infants from The Gambia. Methods: Here we examined aflatoxin B1-associated differential DNA methylation in white blood cells of 24-month-old children from the same population (n = 244), in relation to the child’s dietary exposure assessed using aflatoxin albumin biomarkers in blood samples collected at 6, 12 and 18 months of age. HM450 BeadChip arrays were used to assess DNA methylation, with data compared to aflatoxin albumin adduct levels using two approaches; a continuous model comparing aflatoxin adducts measured in samples collected at 18 months to DNA methylation at 24 months, and a categorical time-dose model that took into account aflatoxin adduct levels at 6, 12 and 18 months, for comparison to DNA methylation at 24 months. Results: Geometric mean (95% confidence intervals) for aflatoxin albumin levels were 3.78 (3.29, 4.34) at 6 months, 25.1 (21.67, 29.13) at 12 months and 49.48 (43.34, 56.49) at 18 months of age. A number of differentially methylated CpG positions and regions were associated with aflatoxin exposure, some of which affected gene expression. Pathway analysis highlighted effects on genes involved with with inflammatory, signalling and growth pathways. Conclusions: This study provides further evidence that exposure to aflatoxin in early childhood may impact on DNA methylation.

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Gene expression and cytosine DNA methylation alterations in induced pluripotent stem-cell-derived human hepatocytes treated with low doses of chemical carcinogens

Cited by 11 publications

References 37 publications

Insights into Aflatoxin B1 Toxicity in Cattle: An In Vitro Whole-Transcriptomic Approach

Insights into Aflatoxin B1 Toxicity in Cattle: An In Vitro Whole-Transcriptomic Approach

Targeting gap junctional intercellular communication by hepatocarcinogenic compounds

Aflatoxin Exposure during Early Life Is Associated with Differential DNA Methylation in Two-Year-Old Gambian Children

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