Participants
Publications
    Butera, Alessio; Smirnova, Lena; Ferrando-May, Elisa; Hartung, Thomas; Brunner, Thomas; Leist, Marcel; Amelio, Ivano (2023): Deconvoluting gene and environment interactions to develop an “epigenetic score meter” of disease EMBO Molecular Medicine. Wiley. 2023, 15(9), e18208. ISSN 1757-4676. eISSN 1757-4684. Available under: doi: 10.15252/emmm.202318208

Deconvoluting gene and environment interactions to develop an “epigenetic score meter” of disease

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Human health is determined both by genetics (G) and environment (E). This is clearly illustrated in groups of individuals who are exposed to the same environmental factor showing differential responses. A quantitative measure of the gene–environment interactions (GxE) effects has not been developed and in some instances, a clear consensus on the concept has not even been reached; for example, whether cancer is predominantly emerging from “bad luck” or “bad lifestyle” is still debated. In this article, we provide a panel of examples of GxE interaction as drivers of pathogenesis. We highlight how epigenetic regulations can represent a common connecting aspect of the molecular bases. Our argument converges on the concept that the GxE is recorded in the cellular epigenome, which might represent the key to deconvolute these multidimensional intricated layers of regulation. Developing a key to decode this epigenetic information would provide quantitative measures of disease risk. Analogously to the epigenetic clock introduced to estimate biological age, we provocatively propose the theoretical concept of an “epigenetic score‐meter” to estimate disease risk.

Origin (projects)

  Zobl, Walter; Bitsch, Annette; Blum, Jonathan; Boei, Jan J.W.A.; Capinha, Liliana; Carta, Giada; Castell, Jose V.; Davoli, Enrico; Drake, Christina; Leist, Marcel (2023): Protectiveness of NAM-based hazard assessment : which testing scope is required? Alternatives to Animal Experimentation : ALTEX. Springer Spektrum. ISSN 1868-596X. eISSN 1868-8551. Available under: doi: 10.14573/altex.2309081

Protectiveness of NAM-based hazard assessment : which testing scope is required?

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Hazard assessment (HA) requires toxicity tests to allow deriving protective points of departure (PoDs) for risk assessment irrespective of a compound’s mode of action (MoA). The scope of in vitro test batteries (ivTB) thereby necessitated for systemic toxicity is still unclear. We explored the protectiveness regarding systemic toxicity of an ivTB with a scope, which was guided by previous findings from rodent studies, where examining six main targets, including liver and kidney, was sufficient to predict the guideline scope-based PoD with high probability. The ivTB comprises human in vitro models representing liver, kidney, lung and the neuronal system covering transcriptome, mitochondrial dysfunction and neuronal outgrowth. Additionally, 32 CALUX®- and 10 HepG2 BAC-GFP reporters cover a broad range of disturbance mechanisms. Eight compounds were chosen for causing adverse effects such as immunotoxicity or anemia in vivo, i.e., effects not directly covered by assays in the ivTB. PoDs derived from the ivTB and from oral repeated dose studies in rodents were extrapolated to maximum unbound plasma concentrations for comparison. The ivTB-based PoDs were one to five orders of magnitude lower than in vivo PoDs for six of eight compounds, implying that they were protective. The extent of in vitro response varied across test compounds. Especially for hematotoxic substances, the ivTB showed either no response or only cytotoxicity. Assays better capturing this type of hazard would be needed to complement the ivTB. This study highlights the potentially broad applicability of ivTBs for deriving protective PoDs of compounds with unknown MoA.

Origin (projects)

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