Musto, Giorgia (2025) Risk assessment of plant extracts obtained from organic food waste. [Tesi di dottorato]

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Abstract

In recent decades, there has been an increase in scientific attention for the valorization of agro-food waste, for the possibility of extracting bioactive compounds with potential application in the nutraceutical and functional fields. This approach represents a promising opportunity to reduce food waste, promote sustainability and develop innovative solutions for human health, favoring the circular economy. Although the natural origin of nutraceuticals and bioactive compounds may suggest risk-free use, it is crucial to remember that ‘natural’ is not synonymous with ‘safe’. Even products derived from natural sources, such as extracts obtained from agro-food waste, can interact in complex and unpredictable ways. The use of such extracts must therefore be subject to rigorous scientific evaluation to ensure their safety and confirm their efficacy. In parallel, a growing interest has emerged in epigenetics, that studies heritable modifications in gene expression not associated with changes in the DNA sequence. Epigenetic modifications include DNA methylation, histone modifications and non-coding RNAs. External factors, such as diet, exposure to natural and/or chemical substances or stress conditions, can induce stable epigenetic changes that can modulate long term cell function and, in some cases, be passed on to subsequent generations through epigenetic memory mechanism . In this context, this thesis aims to address two main objectives: 1. To assess the genotoxic safety of nutraceutical extracts obtained from agro- food waste 2. To study the epigenetic effects induced by environmental factors, such as paternal diet, nutraceutical use and exposure to environmental conditions with a focus on the cellular adaptation and epigenetic memory mechanisms. 8 The results of this thesis are organized in five sections, each of which covers a specific aspect of the research. Some of the results presented have already been subject of scientific publication, contributing to the validation of the methodologies adopted and the results obtained. The first part consists of a review article 1 that examines the current literature on the genotoxicity of bioactive compounds derived from agro-food by-products. Using well- established tests such as the bacterial reverse mutation assay (Ames test), the Micronucleus assay and the Comet assay, the absence of genotoxic effects and a significant antioxidant and protective activity against DNA damage, of the tested extracts is demonstrated. The second part presents an experimental study focused on the genotoxic assessment of extracts obtained from thinned nectarines and grape seed.2 Using methods, such as the bacterial reverse mutation assay (Ames test) and the Micronucleus assay, the study demonstrated that these extracts do not exhibit significant genotoxic effects. These findings, published in scientific journals, confirm the safe use of nectarine and grape-derived extracts and emphasize their potential as nutraceutical ingredients. The third part, already published, investigates the epigenetic effects of paternal diet on offspring.3 The study showed that imbalanced paternal nutrition induces changes in DNA methylation of genes associated with metabolic pathways, with potential consequences for offspring health. This work provides new insights into the role of paternal diet in epigenetic inheritance and adaptive responses in subsequent generations. The fourth part, also published, analyses the effects of N-acetylcysteine (NAC) treatment.4 The results highlighted NAC's potential to counteract epigenetic alterations induced by oxidative stress by modulating gene 9 expression and contributing to the restoration of cellular homeostasis. These results suggest a possible protective role of NAC in mitigating harmful environmental exposures. The fifth part, which results are preliminary and unpublished, explores the phenomenon of hypoxia-induced epigenetic memory in murine myoblasts. Exposure to hypoxic conditions causes stable changes in the regulation of H19 and IGF2 genes, which are involved in cellular growth and adaptation processes. These changes persisted during the recovery phase, indicating an epigenetic memory mechanism that allows cells to adapt to prolonged environmental stimuli. Taken together, the studies presented in this thesis provide a better understanding of the relationship between environmental factors, genetic stability and epigenetic regulation. While genotoxicity evaluation is necessary to ensure the safety of bioactive compounds derived from agro food waste, the analysis of epigenetic modifications highlights how external stimuli - including diet and oxidative stress - can induce stable changes in gene expression. By integrating genotoxicity safety with epigenetic mechanisms, this thesis emphasizes the importance of considering both genetic integrity and heritable regulatory changes when assessing environmental impact on human health. This multidisciplinary approach not only improves current risk assessment strategies, but also provides significant insights into the long-term effects of environmental stresses on gene regulation, Helping shape a more comprehensive and predictive models in the field of toxicology and epigenetics.

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