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Exposition précoce aux toxiques et déséquilibres nutritionnels : l’inflammation et les lésions précancéreuses de la prostate

Abstract : Non-communicable diseases (NCDs) including cardiovascular diseases, cancers, respiratory diseases and diabetes kill 38 million people worldwide every year, 16 million of them before the age of 70. Until the 1990s, the origin of these pathologies was associated with the lifestyle of the individual: consumption of tobacco, alcohol, physical inactivity and an unbalanced diet. Since the development of the concept of DOHaD, identifying the developmental origins of health and disease, number of evidence showed that NCDs have, in part, an early origin during the peri-conception period (in utero, first years of life). Exposure during this period to food imbalances, toxic chemicals, synthetic chemicals disrupting endogenous hormones (endocrine disruptors, EDCs) may impact the developing body through epigenetic changes imprinted by the environmental factors to which individuals are exposed. However, the phenotypes and mechanisms involved are still far from being decrypted. During this thesis, we focused on developmental effects on the prostate. In fact, prostate cancer (PCa) is the second leading cause of cancer and the fifth leading cause of death by cancer in the world. Data from the literature shows that dietary imbalances (High Fat Diet, HFD) and estrogen-like EDCs are risk factors for this cancer. We developed an experimental model of rats (young adults, 90 days postnatal) exposed during pregnancy until weaning to HFD (60% fat), or estrogen (estradiol benzoate, EB) during the neonatal period, or a combination of both, to explore the effects on the prostate (ventral lobe). Peri-natal exposure to EB or EB + HFD reduces the weight of the adult prostate. This abnormality is associated with low (HFD), moderate (EB) or massive (EB + HFD) prostate inflammation. The infiltrate is composed mainly of macrophages and T lymphocytes. This inflammation is associated with an increase in the prostate of pro-inflammatory cytokine TNFa, CCL2 / MCP1 (EB) but also IL-6 (EB + HFD) as well as a deregulation of the NLRP3 inflammasome. NLRP3 is chronically activated since its substrates IL1b and IL-18 were over expressed. In conclusion, we show that peri-conception exposure to an estrogen or HFD + EB combination programs prostatic lesions in adult animals. In men, it is suggested that chronic inflammatory lesions (proliferative inflammatory atrophy) would, as for other organs, be a first step towards the onset of carcinogenesis. Thus, our experimental model is relevant for the study of the early stages of prostatic tumorigenesis.
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Katia Gharieb. Exposition précoce aux toxiques et déséquilibres nutritionnels : l’inflammation et les lésions précancéreuses de la prostate. Biologie moléculaire. Université Côte d'Azur, 2017. Français. ⟨NNT : 2017AZUR4125⟩. ⟨tel-01728989⟩

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