Nezli DOUMANDJI

Research team

Control of gene expression

Estrogenic endocrine disruptors and prostate cancer: Development of an in vitro model to study mechanisms of action

Abstract:

Epidemiological surveys and clinical studies have established a link between early-life environmental exposures and epigenetic modifications that influence long-term health. According to the DOHaD (Developmental Origins of Health and Disease) paradigm, perinatal exposure is a major factor in chronic diseases, primarily related to epigenetic mechanisms. Endocrine disruptors, present in various everyday products as well as in ambient air, to which we are continuously and chronically exposed, represent a significant risk factor, especially during the perinatal period. Lifestyle factors, such as an unbalanced diet (e.g., high-fat diet), are another contributor to the onset of chronic diseases in adulthood, including metabolic syndrome, obesity, and certain cancers. Endocrine disruptors on the one hand, and an unbalanced diet on the other, have each been associated with an increased risk of prostate cancer in adults. However, their combined action has not been evaluated. Yet, this combined exposure (endocrine disruptors, high-fat diet) represents a lifestyle pattern in contemporary societies. In this context, we have developed in vivo (perinatal exposure, observation of effects in adulthood) and in vitro experimental models to evaluate the effects on the prostate.
The in vivo model shows that the combination of endocrine disruptors and a high-fat diet has additive detrimental effects on the adult prostate, with lesions resembling chronic inflammatory atrophy linked to the activation of the NLRP3 inflammasome.
For the in vitro model, we assessed the role of EZH2 in LNCaP and PC-3 cell lines on the expression of certain long non-coding RNAs (PCA3, HOTAIR, and EGOT). Indeed, EZH2 is part of a complex regulating epigenetic marks and has been implicated in lesions programmed by perinatal exposure to endocrine disruptors. LNCaP cells incubated with an estrogenic endocrine disruptor exhibit increased expression of PCA3, HOTAIR, and EGOT, which is not observed in PC-3 cells. Inhibition of EZH2 with the molecule GSK343 inhibits the increase in PCA3, HOTAIR, and EGOT, suggesting a central role for EZH2 in their regulation and a potential mechanism for the epigenetic action of estrogenic endocrine disruptors.
In summary, by coupling in vivo and in vitro models, this study highlights the impact of deleterious exposures (estrogenic endocrine disruptors, high-fat diet) and their effects on the prostate. The identified lesions and mechanisms are precursor elements in the pathogenesis of prostate cancer.

Keywords: 

Cancer, prostate, endocrine disruptors, epigenetics, estrogen.