Adaptive responses to low doses of radiation or chemicals: their cellular and molecular mechanisms.

This article reviews the current knowledge on the mechanisms of adaptive response to low doses of ionizing radiation or chemical exposure. A better knowledge of these mechanisms is needed to improve our understanding of health risks at low levels of environmental or occupational exposure and their involvement in cancer or non-cancer diseases. This response is orchestrated through a multifaceted cellular program involving the concerted action of diverse stress response pathways. These evolutionary highly conserved defense mechanisms determine the cellular response to chemical and physical aggression. They include DNA damage repair (p53, ATM, PARP pathways), antioxidant response (Nrf2 pathway), immune/inflammatory response (NF-κB pathway), cell survival/death pathway (apoptosis), endoplasmic response to stress (UPR response), and other cytoprotective processes including autophagy, cell cycle regulation, and the unfolded protein response. The coordinated action of these processes induced by low-dose radiation or chemicals produces biological effects that are currently estimated with the linear non-threshold model. These effects are controversial. They are difficult to detect because of their low magnitude, the scarcity of events in humans, and the difficulty of corroborating associations over the long term. Improving our understanding of these biological consequences should help humans and their environment by enabling better risk estimates, the revision of radiation protection standards, and possible therapeutic advances.

In Vivo Comparison of the Phenotypic Aspects and Molecular Mechanisms of Two Nephrotoxic Agents, Sodium Fluoride and Uranyl Nitrate.

Because of their nephrotoxicity and presence in the environment, uranium (U) and fluoride (F) represent risks to the global population. There is a general lack of knowledge regarding the mechanisms of U and F nephrotoxicity and the underlying molecular pathways. The present study aims to compare the threshold of the appearance of renal impairment and to study apoptosis and inflammation as mechanisms of nephrotoxicity. C57BL/6J male mice were intraperitoneally treated with a single dose of U (0, 2, 4 and 5 mg/kg) or F (0, 2, 5, 7.5 and 10 mg/kg) and euthanized 72 h after. Renal phenotypic characteristics and biological mechanisms were evaluated by urine biochemistry, gene/protein expression, enzyme activity, and (immuno)histological analyses. U and F exposures induced nephrotoxicity in a dose-dependent manner, and the highest concentrations induced severe histopathological alterations as well as increased gene expression and urinary excretion of nephrotoxicity biomarkers. KIM-1 gene expression was induced starting at 2 mg/kg U and 7.5 mg/kg F, and this increase in expression was confirmed through in situ detection of this biomarker of nephrotoxicity. Both treatments induced inflammation as evidenced by cell adhesion molecule expression and in situ levels, whereas caspase 3/7-dependent apoptosis was increased only after U treatment. Overall, a single dose of F or U induced histopathologic evidence of nephrotoxicity renal impairment and inflammation in mice with thresholds under 7.5 mg/kg and 4 mg/kg, respectively.