Sostituire gli animali in tossicità dello sviluppo e neurotossicità dello sviluppo attraverso l’Epigenetica e la Trascrittomica

[Balmer NV, Leist M. Epigenetics and Transcriptomics to Detect Adverse Drug Effects in Model Systems of Human Development. Basic Clin Pharmacol Toxicol. 2014 Jan 30.]


Prenatal exposure to environmental chemicals or drugs has been associated with functional or structural deficits and the development of diseases in later life. For example, developmental neurotoxicity (DNT) is triggered by lead, and this compound may predispose to neurodegenerative disease in later life. The molecular memory for such late consequences of early exposure is not known, but epigenetic mechanisms (modification of the chromatin structure) could take this role. Examples and underlying mechanisms have been compiled here for the field of DNT. Moreover, we addressed the question what readout is suitable for addressing drug memory effects. We summarize how complex developmental processes can be modelled in vitro by using the differentiation of human stem cells. Although cellular models can never replicate the final human DNT phenotype, they can model the adverse effect that a chemical has on key biological processes essential for organ formation and function. Highly information-rich transcriptomics data may inform on these changes and form the bridge from in vitro models to human prediction. We compiled data showing that transcriptome analysis can indicate toxicity patterns of drugs. A crucial question to be answered in our systems is when and how transcriptome changes indicate adversity (as opposed to transient adaptive responses), and how drug-induced changes are perpetuated over time even after washout of the drug. We present evidence for the hypothesis that changes in the histone methylation pattern could represent the persistence detector of an early insult that is transformed to an adverse effect at later time points in life.

Nel testo:

”Developmental toxicity (DT) testing is one of the technically most challenging fields of toxicology. There is a huge demand for more cost-effective, faster and more accurate assays [1]. DT may be caused by chemicals, drugs, pesticides and other compounds that interfere with biological processes essential for reproduction. The hazard posed by reproductive toxicants is therefore a matter of great societal concern, and measures to avoid DT are highly demanding in resources, animals and time [2].
Evaluation of a single compound for DT can require hundreds to several thousand animals. More than 1000 rats/rabbits are required alone for a single study (OECD test guideline TG426 ‘developmental neurotoxicity’) that examines disturbances of the development of the nervous system (the focus of the current review). One problem of animal experiments in the whole area of DT is that there may be large species differences, and extrapolation to man can therefore fail. For instance, thalidomide effects are hard to detect in rats, while they are very pronounced in man [3]
(and references therein). Strong species differences can also be observed in cell culture test systems, and therefore human cell-based test systems appear most promising [4, 5]. Animal studies assessing developmental neurotoxicity (DNT) usually do not yield any mechanistic information or biological background data that would facilitate the extrapolation to man. This type of testing often only detects toxicity through indirect measures such as changed numbers of embryos per litter, altered foetal weight or the development of behavioural abnormalities. To significantly reduce the use of animals, to get further mechanistic insights, and to obtain data that can be used to predict hazard to man, in vitro systems modelling critical steps of the human foetal development are being explored as alternatives [6, 7]. The development of initial germ layers from pluripotent cells, and the specification of organ systems, such as the central nervous system (CNS), are such critical processes, and their disturbance would be a key event in DT. The CNS is considered to be one of the most frequent targets of systemic toxicity, with the developing nervous system being particularly susceptible”



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