Epigenetics

ToxStrategies professionals have extensive experience with the analysis and interpretation of epigenetic data, as well as in-depth knowledge of epigenetic mechanisms as they pertain to toxicant responses and potential health outcomes. Epigenetics (and epigenomics) is an important category of biological mechanisms involved in normal cellular processes as well as in disease progression, and is being increasingly considered in health and safety evaluations. ToxStrategies staff members are well-versed in epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA expression, as well as their potential modifications resulting from exposure to various pharmaceuticals, food, consumer products, and environmental compounds. ToxStrategies staff actively contribute to and follow current scientific literature, remaining at the fore-front of applying epigenetics data in toxicological assessments.

Epigenetic data are becoming increasingly recognized and incorporated into toxicological studies and assessments in a variety of settings. For example, “Induces epigenetic alterations” is one of ten key characteristics of carcinogens that are used by the International Agency for Research on Cancer as a framework to evaluate mechanistic data. Mechanistic data from compounds known to directly influence epigenetic programming are also influencing ongoing toxicological reviews and risk assessments by multiple government agencies. Epigenetic mediators involved in disease etiology are also being used as biomarkers of disease and targets for therapeutic purposes in the pharmaceutical setting. Epigenetic data can be generated, analyzed, and incorporated by ToxStrategies staff in a time- and cost-efficient manner, to contribute to therapeutic strategies, chemical mechanism of action / mode of action / adverse outcome pathway analyses, and overall risk assessments.

Areas of expertise in this field include the following:

 

Experimental design:

  • In vitro and in vivo studies designed to produce high quality DNA/RNA required for epigenetics analyses
  • Gene-specific analyses through quantitative PCR (methylation-specific, single miRNA, post-ChIP)
  • Genome-wide analyses through microarray technologies
  • Next generation sequencing through ATAC-seq, DNase-seq, ChIP-seq, FAIRE-seq, MeDIP-seq, Small-RNA-seq
  • High-throughput screening analyses (e.g. ToxCast/Tox21)
  • Experiments to anchor epigenetic alterations to functional endpoints (e.g. gene and/or protein expression, genotoxicity, phenotypic outcomes)
  • Development and implementation of other emerging methodologies

 

Human health and risk assessment integration of epigenetic data:

  • Dose-response modeling to estimate doses at which epigenetic alterations/perturbations occur
  • Implementation in chemical mode of action (MOA)
  • Integration into adverse outcome pathways (AOPs)

 

Systematic review of epigenetic data:

  • Development of tailored search strings to collect published epigenetics data
  • Implementation of inclusion/exclusion criteria to review epigenetics literature
  • Interpretation of published epigenetics data
  • Organization of mechanistic data in relation to the ten key characteristics of carcinogens (Key Characteristic #4: Induces epigenetic alterations)

 

Advanced tools to evaluate epigenetic data:

  • Encyclopedia of DNA Elements (ENCODE)
  • BMDExpress
  • Ingenuity Pathway Analysis (IPA)
  • Geneset Enrichment Analysis and Geneset Association Analysis (GSEA and GSAA)
  • MicroRNA target predictions with miRBase and TargetScan
  • R programming code and packages
  • Roadmap Epigenomics Project
  • The Cancer Genome Atlas (TCGA)
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