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Souidi (2019) Applying a multiscale systems biology approach to study the effect of chronic low-dose exposure to uranium in rat kidneys,

Altogether, our work demonstrates for the first time a sex-dependance and inheritance of epigenetic marks, DNA methylation, as a biological response to the exposure to low doses of uranium. However, it is not clear which type of reproductive cell type is more responsive in this context.

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Environmental toxicant exposure can induce disorders in sex steroidogenesis during fetal gonad development. Our previous study demonstrated that chronic adult exposure to a supra environmental concentration of depleted uranium (DU) does not impair testicular steroidogenesis in rats. In this study, we investigated the effects of lifelong exposure (embryo - adult) to low-dose DU (40 or 120mgL) on adult rat testicular steroidogenesis and spermatogenesis. A significant content of uranium was detected in testis and epididymis in the DU 120mgL group and the assay in epididymal spermatozoa showed a significant content in both groups. No major defect was observed in testicular histology except a decrease in the number of basal vacuoles in the DU groups. Moreover, plasma Follicle-Stimuling Hormone [FSH] and Luteinizing Hormone [LH] levels were increased only in the DU 120mgL group and intratesticular estradiol was decreased in both groups. Testosterone level was reduced in plasma and testis in the DU 40mgL group. These modulations could be explained by an observed decrease in gene expression of luteinizing hormone receptor (LHR), and enzymes involved in steroid production and associated signal transduction (StAR, cyp11a1, cyp17a1, 3βhsd, 17βhsd, TGFβ1, AR). Several genes specific to germ cells and cell junctions of the blood-testis barrier were also modulated. In conclusion, these data show that fetal life is a critical window for chronic uranium exposure and that the endocrine activities of low-dose uranium could disrupt steroidogenesis through the hypothalamic-pituitary-testicular axis. Further investigation should be so useful in subsequent generations to improve risk assessment of uranium exposure.

Background:Health-risk issues are raised concerning inhalation of particulate pollutants that are thought to have potential hazardous effects on the central nervous system. The brain is presented as a direct target of particulate matter (PM) exposure because of the nose-to-brain pathway involvement. The main cause of contamination in nuclear occupational activities is related to exposure to aerosols containing radionuclides, particularly uranium dust. It has been previously demonstrated that instilled solubilized uranium in the rat nasal cavity is conveyed to the brain via the olfactory nerve.Objective:The aim of this study was to analyze the anatomical localization of uranium compounds in the olfactory system after in vivo exposure to a polydisperse aerosol of uranium tetraoxide (UO4) particles.Methods:The olfactory neuroepithelium (OE) and selected brain structures—olfactory bulbs (OB), frontal cortex (FC), hippocampus (HIP), cerebellum (Cer), and brainstem (BS)—were microdissected 4 h after aerosol inhalation via a nose-only system in adult rats. Tissues were subjected to complementary analytical techniques.Results:Uranium concentrations measured by inductively coupled plasma mass spectrometry (ICP-MS) were significantly higher in all brain structures from exposed animals compared with their respective controls. We observed that cerebral uranium concentrations followed an anteroposterior gradient with typical accumulation in the OB, characteristic of a direct olfactory transfer of inhaled compounds. Secondary ion mass spectrometry (SIMS) microscopy and transmission electron microscopy coupled with energy-dispersive X-ray spectroscopy (TEM-EDX) were used in order to track elemental uranium in situ in the olfactory epithelium. Elemental uranium was detected in precise anatomical regions: olfactory neuron dendrites, paracellular junctions of neuroepithelial cells, and olfactory nerve tracts (around axons and endoneural spaces).Conclusion:These neuroanatomical observations in a rat model are consistent with the transport of elemental uranium in different physicochemical forms (solubilized, nanoparticles) along olfactory nerve bundles after inhalation of UO4 microparticles. This work contributes to knowledge of the mechanistic actions of particulate pollutants on the brain. https://doi.org/10.1289/EHP4927

In the field of public health policy and to raise attention to generational effects for the risk assessment of the environmental exposures, low doses of uranium do not imply clinical effects on adult exposed rats. However, our results confirm the importance of the developmental windows' sensitivity in addition to the sexual dimorphisms of the offspring.