Considering Epigenetics in Adverse Outcome Pathways

Willett, Kristine L.

doi:10.1007/978-3-319-66084-4_11

Cited by 4 publications

(3 citation statements)

References 103 publications

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“…The contributions to risk assessment that are expected of toxicoepigenetics range from insight into the mechanism of action to novel biomarkers of exposure prior to changes in gene expression, cell signaling, or pathological findings. 2 , 27 , 28 Potential future applications include measuring the long-term susceptibility of a population to a given environmental exposure; developing epigenetic tests to detect at-risk, sensitive populations; and intervening at the molecular level to reverse the epigenetic changes implicated in the toxicity response to exposure. 3 , 29 , 30 In the present, promoters of toxicoepigenetics support relatively humble goals, namely, to contribute to well-established risk assessment processes and complement existing methods when they harbor gaps.…”

Section: The Promise and Current Status Of Toxicoepigenetics For Risk...mentioning

confidence: 99%

“…The epigenome, that is, the collection of covalent chemical modifications to the DNA and histone proteins, and of non-coding RNAs that regulate gene expression in a heritable fashion, is increasingly recognized as a key mediator of environmental response and a target of toxicants. 1 Toxicoepigenetics leverages and combines advances in the fields of epigenetics and toxicology to elucidate molecular initiating events, 2 a molecular basis for delineating windows of environmental sensitivity, 3 , 4 a mechanism of transgenerational inheritance running parallel to that of DNA, 5 biomarkers of current or prior exposure, 3 and potential therapeutic avenues. 6 …”

Section: Introductionmentioning

confidence: 99%

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Toxicoepigenetics for Risk Assessment: Bridging the Gap Between Basic and Regulatory Science

et al. 2022

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Toxicoepigenetics examines the health effects of environmental exposure associated with, or mediated by, changes in the epigenome. Despite high expectations, toxicoepigenomic data and methods have yet to become significantly utilized in chemical risk assessment. This article draws on a social science framework to highlight hitherto overlooked structural barriers to the incorporation of toxicoepigenetics in risk assessment and to propose ways forward. The present barriers stem not only from the lack of maturity of the field but also from differences in constraints and standards between the data produced by toxicoepigenetics and the regulatory science data that risk assessment processes require. Criteria and strategies that frame the validation of knowledge used for regulatory purposes limit the application of basic research in toxicoepigenetics toward risk assessment. First, the need in regulatory toxicology for standardized methods that form a consensus between regulatory agencies, basic research, and the industry conflicts with the wealth of heterogeneous data in toxicoepigenetics. Second, molecular epigenetic data do not readily translate into typical toxicological endpoints. Third, toxicoepigenetics investigates new forms of toxicity, in particular low-dose and long-term effects, that do not align well with the traditional framework of regulatory toxicology. We propose that increasing the usefulness of epigenetic data for risk assessment will require deliberate efforts on the part of the toxicoepigenetics community in 4 areas: fostering the understanding of epigenetics among risk assessors, developing knowledge infrastructure to demonstrate applicability, facilitating the normalization and exchange of data, and opening the field to other stakeholders.

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Section: The Promise and Current Status Of Toxicoepigenetics For Risk...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toxicoepigenetics for Risk Assessment: Bridging the Gap Between Basic and Regulatory Science

et al. 2022

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“…In particular, this complex will consistently induce (or repress) expression of a collection of genes, deemed the ‘AHR-core’ battery of genes [15,16,19,20,21,22]. In addition to this canonical signaling pathway, the AHR can also influence gene expression by alternative pathways including epigenetic mechanisms (e.g., DNA methylation, histone modifications, miRNA, and noncoding long-RNA induction as reviewed in [23,24,25]), functioning as a nuclear E3 ubiquitin ligase, and cross-talk with other transcription factors [26,27,28,29].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

Prokopec

Pohjanvirta

Mahiout

et al. 2019

IJMS

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IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Both compounds are converted to the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, their functional resemblance to the highly toxic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) raises questions. Here, we characterize the hepatic transcriptomic changes induced by acute (single-dose) and subacute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to C2 in Sprague-Dawley rats. Exposure to C2 leads to activation of the AHR, as shown by altered transcription of Cyp1a1. We identify a heightened response early after exposure that drops off by day 10. Acute exposure to C2 leads to changes to transcription of genes involved in antiviral and antibacterial responses, which highlights the immunomodulator effects of this AHR agonist. Subacute exposure causes an oxidative stress response in the liver, the consequences of which require further study on target tissues such as the CNS and immune system, both of which may be compromised in this patient population.

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Epigenetic Inheritance

Fallet

2024

Epigenetics in Biological Communication

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Considering Epigenetics in Adverse Outcome Pathways

Cited by 4 publications

References 103 publications

Toxicoepigenetics for Risk Assessment: Bridging the Gap Between Basic and Regulatory Science

Toxicoepigenetics for Risk Assessment: Bridging the Gap Between Basic and Regulatory Science

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

Epigenetic Inheritance

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