Epigenetic screening in product safety assessment: are we there yet?

Rasoulpour, Reza J.; LeBaron, Matthew J.; Ellis-Hutchings, Robert G.; Klapacz, Joanna; Gollapudi, B. Bhaskar

doi:10.3109/15376516.2011.557883

Cited by 33 publications

(17 citation statements)

References 55 publications

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“…More importantly, the reversibility of epigenetic alterations opens novel mechanism-based approaches not only to cancer treatment but also to the timely prevention of cancer [142]. However, despite a very promising outlook on the benefits of epigenetic biomarkers, additional studies are still needed to better define the nature and mechanisms of epigenetic abnormalities in respect to carcinogenic processes [60,143,144]. Although extensive studies have identified a number of cancer-related epigenetic abnormalities that are associated with carcinogen exposure, there is no consensus on the role of changes in tumorigenesis.…”

Section: Epigenetic Alterations and The Evaluation Of Cancer Riskmentioning

confidence: 99%

Environmental Toxicants, Epigenetics, and Cancer

Pogribny

Rusyn

2012

Advances in Experimental Medicine and Biology

104

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Tumorigenesis, a complex and multifactorial progressive process of transformation of normal cells into malignant cells, is characterized by the accumulation of multiple cancer-specific heritable phenotypes triggered by the mutational and/or non-mutational (i.e., epigenetic) events. Accumulating evidence suggests that environmental and occupational exposures to natural substances, as well as man-made chemical and physical agents, play a causative role in human cancer. In a broad sense, carcinogenesis may be induced through either genotoxic or non-genotoxic mechanisms; however, both genotoxic and non-genotoxic carcinogens also cause prominent epigenetic changes. This review presents current evidence of the epigenetic alterations induced by various chemical carcinogens, including arsenic, 1,3-butadine, and pharmaceutical and biological agents, and highlights the potential for epigenetic changes to serve as markers for carcinogen exposure and cancer risk assessment.

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Section: Epigenetic Alterations and The Evaluation Of Cancer Riskmentioning

confidence: 99%

Environmental Toxicants, Epigenetics, and Cancer

Pogribny

Rusyn

2012

Advances in Experimental Medicine and Biology

104

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“…Toxicological studies incorporating epigenetic endpoints are typically conducted at a single high-dose level of exposure and do not contain appropriate concurrent assessment of apical toxicity endpoints such as histopathology and clinical chemistry to correlate epigenetic changes to apical endpoints (Alyea et al, 2012; Miousse et al, 2015b; Rasoulpour et al, 2011). In addition, few studies have utilized multiple doses to investigate a dose-response relationship between apical effects, specific genes associated with alteration in epigenetic regulation, and metabolism and metabolite profiling.…”

Section: Introductionmentioning

confidence: 99%

Dose-response analysis of epigenetic, metabolic, and apical endpoints after short-term exposure to experimental hepatotoxicants

Miousse

Murphy

Lin

et al. 2017

Food and Chemical Toxicology

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Identification of sensitive and novel biomarkers or endpoints associated with toxicity and carcinogenesis is of a high priority. There is increasing interest in the incorporation of epigenetic and metabolic biomarkers to complement apical data; however, a number of questions, including the tissue specificity, dose-response patterns, early detection of those endpoints, and the added value need to be addressed. In this study, we investigated the dose-response relationship between apical, epigenetic, and metabolomics endpoints following short-term exposure to experimental hepatotoxicants, clofibrate (CF) and phenobarbital (PB). Male F344 rats were exposed to PB (0, 5, 25, and 100 mg/kg/day) or CF (0, 10, 50, and 250 mg/kg/day) for seven days. Exposure to PB or CF resulted in dose-dependent increases in relative liver weights, hepatocellular hypertrophy and proliferation, and increases in Cyp2b1 and Cyp4a1 transcripts. These changes were associated with altered histone modifications within the regulatory units of cytochrome genes, LINE-1 DNA hypomethylation, and altered microRNA profiles. Metabolomics data indicated alterations in the metabolism of bile acids. This study provides the first comprehensive analysis of the apical, epigenetic and metabolic alterations, and suggests that the latter two occur within or near the dose response curve of apical endpoint alterations following exposure to experimental hepatotoxicants.

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“…They are insufficient in themselves as indicators of an adverse response without connection with phenotype, for example diseaseassociated aberrant gene expression (Rasoulpour et al, 2011). Our current lack of knowledge about the interplay between individual members of the epigenetic machinery and the precise participation of each in the regulation of gene expression is the main reason that no hazard assessment test for epigenetic toxicity of NMs is available.…”

Section: Model Systems For Testing Nm-induced Epigenetic Toxicitymentioning

confidence: 99%

Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: New strategies for toxicity testing?

Dušinská

Tulinská

Yamani

et al. 2017

Food and Chemical Toxicology

116

101

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a b s t r a c tThe unique properties of nanomaterials (NMs) are beneficial in numerous industrial and medical applications. However, they could also induce unintended effects. Thus, a proper strategy for toxicity testing is essential in human hazard and risk assessment. Toxicity can be tested in vivo and in vitro; in compliance with the 3Rs, alternative strategies for in vitro testing should be further developed for NMs. Robust, standardized methods are of great importance in nanotoxicology, with comprehensive material characterization and uptake as an integral part of the testing strategy. Oxidative stress has been shown to be an underlying mechanism of possible toxicity of NMs, causing both immunotoxicity and genotoxicity. For testing NMs in vitro, a battery of tests should be performed on cells of human origin, either cell lines or primary cells, in conditions as close as possible to an in vivo situation. Novel toxicity pathways, particularly epigenetic modification, should be assessed along with conventional toxicity testing methods. However, to initiate epigenetic toxicity screens for NM exposure, there is a need to better understand their adverse effects on the epigenome, to identify robust and reproducible causal links between exposure, epigenetic changes and adverse phenotypic endpoints, and to develop improved assays to monitor epigenetic toxicity.

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Epigenetic screening in product safety assessment: are we there yet?

Cited by 33 publications

References 55 publications

Environmental Toxicants, Epigenetics, and Cancer

Environmental Toxicants, Epigenetics, and Cancer

Dose-response analysis of epigenetic, metabolic, and apical endpoints after short-term exposure to experimental hepatotoxicants

Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: New strategies for toxicity testing?

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