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Study of adaptive response on renal tissue after chronic low doses exposure to uranium: identification of signaling pathways involved after in vivo or in vitro exposure

​Alice Bontemps has defended here thesis​ on 9th December 2019 in Fontenay-aux-Roses, France

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Research Unit > IRSN/PRP-HOM/SRBE/LRTOX

Authors > BONTEMPS Alice

Publication Date > 09/12/2019

Summary

Human population can be daily exposed to uranium (U) and fluoride (F) because of their natural and anthropogenic presence in the environment. Although U and F are known to be nephrotoxicant at high doses, their effects after low dose exposures are still unknown and previous studies suggested that chronic exposures to low doses of U or F could induce adaptive responses (AR). Therefore, a mouse in vivo study was designed and carried out to examine whether exposure to chronic low priming doses of U and F can induce AR in the kidney upon exposure to nephrotoxic challenge treatment.

A pilot dose-response study allowed selecting the nephrotoxic challenge treatments (5 mg/kg U and 7.5 mg/kg F), with a time of analysis of 72h post treatment. To study the AR, mice were exposed through drinking water for 6 months to priming doses of U (10, 20 and 40 mg/L) or F (15, 30 and 50 mg/L), and subsequently challenged. An AR was observed at the doses of 20 mg/L U and 50 mg/L F, with a return to normal gene expression and urinary levels of nephrotoxicity biomarkers KIM-1 and CLU in comparison with the non-pre-exposed mice. Apoptosis was reduced in animals pre-exposed to 20 mg/L U and a decrease of VCAM in situ expression was observed in animals pre-exposed to 50 mg/L F. These concentrations correspond to the appearance of AR. The unfolded protein response (UPR), autophagy and inflammatory cell recruitment were the mechanisms induced by U whereas only UPR was induced by F. However, these mechanisms were induced in challenged animals irrespective of pre-exposure.

Thus, our results do not allow us to identify these mechanisms as those involved in the AR. In summary, our data showed the existence of an AR to low doses of U and F delivered chronically to mice, with the induction of adaptive mechanisms such as apoptosis and inflammatory regulation. Results of this study allow for better understanding of the potential effects chronic low-dose exposures of U and F on human population, and provide new knowledge for informing the radioprotection system.

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