The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis.

The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18-28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

Multigenerational Exposure to Uranium Changes Sperm Metabolome in Rats.

Male infertility is a major public health issue that can be induced by a host of lifestyle risk factors such as environment, nutrition, smoking, stress, and endocrine disruptors. Regarding the human population exposed to uranium, it is necessary to explore these effects on male reproduction in multigenerational studies. The sensitivity of mass spectrometry (MS)-based methods has already proved to be extremely useful in metabolite identification in rats exposed to low doses of uranium, but also in human sperm. We applied this method to rat sperm over three generations (F0, F1 and F2) with multigenerational uranium exposure. Our results show a significant content of uranium in generation F0, and a reduction in the pregnancy rate only in generation F1. Based on principal component analysis (PCA), we observed discriminant profiles between generations. The partial least squares discriminant analysis (PLS-DA) of the 48 annotated variables confirmed that parental exposure of generation F0 (during both the preconceptional and prenatal periods) can have metabolic effects on spermatozoa for the next two generations. Metabolomics applied to epididymal spermatozoa is a novel approach to detecting the multigenerational effects of uranium in an experimental model, but could be also recommended to identify potential biomarkers evaluating the impact of uranium on sperm in exposed infertile men.

Protection and safety of a repeated dosage of KI for iodine thyroid blocking during pregnancy.

In case of nuclear power plant accidents resulting in the release of radioactive iodine (131I) in large amounts, a single intake of stable iodine is recommended in order to prevent131I fixation to the thyroid gland. However, in situations of prolonged exposure to131I (e.g. Fukushima-Daiichi natural and nuclear disaster), repetitive administration of iodine may be necessary to ensure adequate protection, with acceptable safety in vulnerable populations including pregnant women. Here we conducted toxicological studies on adult rats progeny following prolonged exposure to potassium iodide (KI)in utero. Pregnant Wistar rats were treated with 1 mg kg d-1KI or saline water for 2 or 4 d either between gestation days gestational day (GD) GD 9-12, or GD13-16. Plasma samples from the progeny were tested 30 d post-weaning for clinical biochemistry, thyroid hormones, and anti-thyroid antibody levels. Thyroid and brain were collected for gene expression analysis. The hormonal status was similar for the mothers in all experimental conditions. In the offspring, while thyroid-stimulating hormone and anti-thyroid peroxidase (anti-TPO) antibody levels were similar in all groups, a significant increase of FT3 and FT4 levels was observed in GD9-GD10 and in GD13-GD14 animals treated for 2 d, respectively. In addition, FT4 levels were mildly decreased in 4 d treated GD13-16 individuals. Moreover, a significant decrease in the expression level of thyroid genes involved in iodide metabolism, TPO and apical iodide transporter, was observed in GD13-GD14 animals treated for 2 d. We conclude that repeated KI administration for 2-4 d during gestation did not induce strong thyroid toxicity.

Assessment of the effects of repeated doses of potassium iodide intake during pregnancy on male and female rat offspring using metabolomics and lipidomics.

Preparedness for nuclear accident responsiveness includes interventions to protect pregnancies against prolonged exposure to radioactive iodine. The aim of this study was to investigate a new design consisting of repeated administration of potassium iodide (KI, 1 mg/kg) for 8 days in late pregnancy gestational day 9-16 (GD9-GD16) in rats. The later-life effects of this early-life iodine thyroid blocking (ITB) strategy were assessed in offspring two months afterbirth. Functional behavioral tests including forced swimming test (FST) and rotarod test (RRT) in rats of both genders showed lower FST performance in KI-treated females and lower RRT performance in KI-treated male pups. This performance decline was associated with metabolic disruptions in cortex involving amino acid metabolism, tyrosine metabolism, as well as docosahexaenoic acid (DHA) lipids and signaling lipids in males and females. Beyond these behavior-associated metabolic changes, a portion of the captured metabolome (17-25%) and lipidome (3.7-7.35%) remained sensitive to in utero KI prophylactic treatment in both cortex and plasma of post-weaning rats, with some gender-related variance. Only part of these disruptions was attributed to lower levels of TSH and T4 (males only). The KI-induced metabolic shifts involved a broad spectrum of functions encompassing metabolic and cell homeostasis and cell signaling functions. Irrespective Regardless of gender and tissues, the predominant effects of KI affected neurotransmitters, amino acid metabolism, and omega-3 DHA metabolism. Taken together, data demonstrated that repeated daily KI administration at 1 mg/kg/day for 8 days during late pregnancy failed to protect the mother-fetus against nuclear accident radiation. Abbreviations: CV-ANOVA: Cross-validation analysis of variance; DHA: Docosahexaenoic acid; FST: Forced swimming test; FT3: plasma free triiodothyronine; FT4: plasma free thyroxine; GD: Gestational day; ITB: Iodine thyroid blocking; KI: potassium iodide; LC/MS: Liquid chromatography coupled with mass spectrometry; MTBE: Methyl tert-butyl ether; m/z: mass-to-charge ratio; PLS-DA: Partial least squares-discriminant analysis; PRIODAC: Repeated stable iodide prophylaxis in accidental radioactive releases; RRT: Rotarod test; TSH: Thyroid-stimulating hormone; VIP: Variable importance in projection.

EpiBrainRad: an epidemiologic study of the neurotoxicity induced by radiotherapy in high grade glioma patients.

BACKGROUND: Radiotherapy is one of the most important treatments of primary and metastatic brain tumors. Unfortunately, it can involve moderate to severe complications among which leukoencephalopathy is very frequent and implies cognitive deficits such as memory, attention and executive dysfunctions. However, the incidence of this complication is not well established and the risk factors and process are poorly understood. The main objective of the study is to improve knowledge on radio-induced leukoencephalopathy based on pluridisciplinar approaches combining cognitive, biologic, imagery and dosimetric investigations. METHOD/DESIGN: The EpiBrainRad study is a prospective cohort study including newly diagnosed high grade gliomas patients treated by radiotherapy and concomitant-adjuvant temozolomide chemotherapy. Patients are included between their surgery and first day of radio-chemotherapy, and the follow-up lasts for 3 years after treatment. Cognitive functioning assessments, specific blood biomarkers measures and magnetic resonance imagery are performed at different moment during the follow-up, and a specific dosimetric assessment of organs involved in the beam fields is performed. Firstly, leukoencephalopathy incidence rate will be estimated in this population. Secondly, correlations between cognitive impairments and dosimetry, biomarkers ranges and anomalies on imagery will be analyzed in order to better understand the onset and evolution of cognitive decrement associated with radiotherapy. Furthermore, a new cognitive test, quickly and easily performed, will be studied to determine its sensibility to detect leukoencephalopathy decrement. DISCUSSION: With an original multidisciplinary approach, the EpiBrainRad study aims to improve knowledge on radio-induced leukoencephalopathy in order to improve its early diagnosis and prevention. The main challenge is to preserve quality-of-life after cancer treatments which imply to study the incidence of radiation-induced complications and their associated risk factors. TRIAL REGISTRATION: NCT02544178.

Intranasal exposure to uranium results in direct transfer to the brain along olfactory nerve bundles.

AIMS: Uranium olfactory uptake after intranasal exposure raises some concerns for people potentially exposed to airborne radionuclide contamination as the brain could be a direct target for these contaminants. A model of nasal instillation was used to elucidate the transport mechanisms of uranium to the brain and to map its localization. METHODS: Increasing concentrations of depleted uranium containing solutions were instilled in the nasal cavity of adult male rats. Uranium concentrations were measured using inductively coupled plasma-mass spectrometry (ICP-MS) 4 h after instillation. Olfactory neuroepithelium cytoarchitecture was studied using immunohistochemistry experiments. Secondary ion mass spectrometry (SIMS) microscopy was performed to localize uranium in the olfactory system. RESULTS: ICP-MS analyses showed a frontal accumulation of uranium in the olfactory bulbs associated with a smaller increase in more caudal brain regions (frontal cortex, hippocampus and cerebellum). Uranium concentrations in the olfactory bulbs do not reach a saturation point. Olfactory nerve bundle integrity is not affected by uranium as revealed by immunohistochemistry. SIMS microscopy allowed us to show that uranium localization is mainly restricted to the olfactory neuroepithelium and around olfactory nerve bundles. It is subsequently detected in the olfactory nerve layer of the olfactory bulb. DISCUSSION: These results suggest the existence of a transcellular passage from the mucosa to the perineural space around axon bundles. Uranium bypasses the blood brain barrier and is conveyed to the brain via the cerebrospinal fluid along the olfactory nerve. Future studies might need to integrate this new contamination route to assess uranium neurotoxicity after nasal exposure.

Central nervous system tumours and occupational ionising radiation exposure: a nested case-control study among the ORICAMs cohort of healthcare workers in France.

OBJECTIVE: This study aimed at investigating the relationship between occupational exposure to external ionising radiation and central nervous system (CNS) tumours mortality in healthcare workers working in France. DESIGN AND SETTING: The Occupational Radiation-Induced Cancer in Medical staff (ORICAMs) nested case-control study was conducted based on the dosimetric records of the national register of occupational dosimetry (Système d'information de la surveillance de l'exposition aux rayonnements ionisants). PARTICIPANTS AND METHODS: 33 CNS tumour deaths occurred between 2002 and 2012 among the ORICAMs cohort composed of 164 015 healthcare workers. Each case was matched to five controls alive at the time of the corresponding case's death, based on sex, year of birth, date of enrolment in the cohort and duration of follow-up. All participants were badge monitored for external radiation exposure, expressed in Hp(10). Conditional logistic regression was used to analyse the dose-response relationship between radiation dose and CNS mortality. RESULTS: Cases were exposed to a mean cumulative career radiation dose of 5.8±13.7 (max: 54.3) millisievert (mSv) compared with 4.1±15.2 (142.2) mSv for controls. No statistically significant association was found between CNS tumour mortality and cumulative whole-body career dose (OR=1.00, 95% CI 0.98 to 1.03), duration of exposure (OR=1.03; 95% CI 0.95 to 1.12) or age at first exposure (OR=0.98; 95% CI 0.91 to 1.06). CONCLUSION: We found no evidence of an association between external radiation exposure and CNS tumour risk in healthcare workers. Limitations of the study include low statistical power and short duration of follow-up.

The effects of radionuclides on animal behavior.

Concomitant with the expansion of the nuclear industry, the concentrations of several pollutants, radioactive or otherwise, including uranium, caesium, cadmium and cobalt, have increased over the last few decades. These elemental pollutants do exist in the environment and are a threat to many organisms. Behavior represents the integration of all the anatomical adaptations and physiological processes that occur within an organism. Compared to other biological endpoints, the effects of pollutants on animal behavior have been the focus of only a few studies. However, behavioral changes appear to be ideal for assessing the effects of pollutants on animal populations, because behavior links physiological functions with ecological processes. The alteration of behavioral responses can have severe implications for survival of individuals and of population of some species. Behavioral disruptions may derive from several underlying mechanisms: disruption of neuro-sensorial activity and of endocrines, or oxidative and metabolic disruptions. In this review, we presented an overview of the current literature in which the effects of radioactive pollutants on behavior in humans, rodents, fish and wildlife species are addressed. When possible, we have also indicated the potential underlying mechanisms of the behavioral alterations and parameters measured. In fried, chronic uranium contamination is associated with behavior alterations and mental disorders in humans, and cognitive deficits in rats. Comparative studies on depleted and enriched uranium effects in rats showed that chemical and radiological activities of this metal induced negative effects on several behavioral parameters and also produced brain oxidative stress. Uranium exposure also modifies feeding behavior of bivalves and reproductive behavior of fish. Studies of the effects of the Chernobyl accident shows that chronic irradiation to 137Cs induces both nervous system diseases and mental disorders in humans leading to increased suicides, as well as modification of preferred nesting sites, reduced hatching success and fecundity in birds that live in the Chernobyl zone. No significant effect from caesium exposure was shown in laboratory experiments with rats, but few studies were conducted. Data on radioactive cadmium are not available in the literature, but the effects of its metallic form have been well studied. Cadmium induces mental retardation and psychomotor alterations in exposed populations and increases anxiety in rats, leading to depression. Cadmium exposure also results in well-documented effects on feeding and burrowing behavior in several invertebrate species (crustaceans, gastropods, annelids, bivalves) and on different kinds of fish behavior (swimming activity, fast-start response, antipredatory behavior). Cobalt induces memory deficits in humans and may be involved in Alzheimer's disease; gamma irradiation by cobalt also decreases fecundity and alters mating behavior in insects. Collectively, data are lacking or are meagre on radionuclide pollutants, and a better knowledge of their actions on the cellular and molecular mechanisms that control animal behavior is needed.

The Challenges of 21st Century Neurotoxicology: The Case of Neurotoxicology Applied to Nanomaterials.

After a short background discussing engineered nanomaterials (ENMs) and their physicochemical properties and applications, the present perspective paper highlights the main specific points that need to be considered when examining the question of neurotoxicity of nanomaterials. It underlines the necessity to integrate parameters, specific tools, and tests from multiple sources that make neurotoxicology when applied to nanomaterials particularly complex. Bringing together the knowledge of multiple disciplines e.g., nanotoxicology to neurotoxicology, is necessary to build integrated neurotoxicology for the third decade of the 21st Century. This article focuses on the greatest challenges and opportunities offered by this specific field. It highlights the scientific, methodological, political, regulatory, and educational issues. Scientific and methodological challenges include the determination of ENMs physicochemical parameters, the lack of information about protein corona modes of action, target organs, and cells and dose- response functions of ENMs. The need of standardization of data collection and harmonization of dedicated neurotoxicological protocols are also addressed. This article highlights how to address those challenges through innovative methods and tools, and our work also ventures to sketch the first list of substances that should be urgently prioritized for human modern neurotoxicology. Finally, political support with dedicated funding at the national and international levels must also be used to engage the communities concerned to set up dedicated educational program on this novel field.

Targeted Dorsal Dentate Gyrus or Whole Brain Irradiation in Juvenile Mice Differently Affects Spatial Memory and Adult Hippocampal Neurogenesis.

The cognitive consequences of postnatal brain exposure to ionizing radiation (IR) at low to moderate doses in the adult are not fully established. Because of the advent of pediatric computed tomography scans used for head exploration, improving our knowledge of these effects represents a major scientific challenge. To evaluate how IR may affect the developing brain, models of either whole brain (WB) or targeted dorsal dentate gyrus (DDG) irradiation in C57Bl/6J ten-day-old male mice were previously developed. Here, using these models, we assessed and compared the effect of IR (doses range: 0.25-2 Gy) on long-term spatial memory in adulthood using a spatial water maze task. We then evaluated the effects of IR exposure on adult hippocampal neurogenesis, a form of plasticity involved in spatial memory. Three months after WB exposure, none of the doses resulted in spatial memory impairment. In contrast, a deficit in memory retrieval was identified after DDG exposure for the dose of 1 Gy only, highlighting a non-monotonic dose-effect relationship in this model. At this dose, a brain irradiated volume effect was also observed when studying adult hippocampal neurogenesis in the two models. In particular, only DDG exposure caused alteration in cell differentiation. The most deleterious effect observed in adult hippocampal neurogenesis after targeted DDG exposure at 1 Gy may contribute to the memory retrieval deficit in this model. Altogether these results highlight the complexity of IR mechanisms in the brain that can lead or not to cognitive disorders and provide new knowledge of interest for the radiation protection of children.

Brain accumulation of inhaled uranium in the rat depends on aerosol concentration, exposure repetitions, particle size and solubility.

A rostro-caudal gradient of uranium (U) in the brain has been suggested after its inhalation. To study the factors influencing this mapping, we first used 30-min acute inhalation at 56 mg/m3 of the relatively soluble form UO4 in the rat. These exposure parameters were then used as a reference in comparison with the other experimental conditions. Other groups received acute inhalation at different concentrations, repeated low dose inhalation of UO4 (10 exposures) or acute low dose inhalation of the insoluble form UO2. At 24 h after the last exposure, all rats showed a brain U accumulation with a rostro-caudal gradient as compared to controls. However, the total concentration to the brain was greater after repeated exposure than acute exposure, demonstrating an accumulative effect. In comparison with the low dose soluble U exposure, a higher accumulation in the front of the brain was observed after exposure to higher dose, to insoluble particles and following repetition of exposures, thus demonstrating a dose effect and influences of solubility and repetition of exposures. In the last part, exposure to ultrafine U particles made it possible to show 24 h after exposure the presence of U in the brain according to a rostro-caudal gradient. Finally, the time-course after exposure to micronic or nanometric U particles has revealed greater residence times for nanoparticles.

Distribution of soluble uranium in the nuclear cell compartment at subtoxic concentrations.

Uranium is naturally found in the environment, and its extensive use results in an increased risk of human exposure. Kidney cells have mainly been used as in vitro models to study effects of uranium exposure, and very little about the effects on other cell types is known. The aim of this study was to assess the impact of depleted uranium exposure at the cellular level in human kidney (HEK-293), liver (HepG2), and neuronal (IMR-32) cell lines. Cytotoxicity studies showed that these cell lines reacted in a roughly similar manner to depleted uranium exposure, responding at a cytotoxicity threshold of 300-500 µM. Uranium was localized in cells with secondary ion mass spectrometry technology. Results showed that uranium precipitates at subtoxic concentrations (>100 µM). With this approach, we were able for the first time to observe the soluble form of uranium in the cell at low concentrations (10-100 µM). Moreover, this technique allows us to localize it mainly in the nucleus. These innovative results raise the question of how uranium penetrates into cells and open new perspectives for studying the mechanisms of uranium chemical toxicity.

Effect of repetitive potassium iodide on thyroid and cardiovascular functions in elderly rats.

BACKGROUND: To date, paediatric thyroid cancer has been the most severe health consequence of the Chernobyl accident, caused by radioactive iodine (131I) aerosol's dispersion. WHO recommends a single dose of potassium iodide (KI) to reduce this risk. Following the Fukushima accident, it became obvious that repetitive doses of KI may be necessary due to multiple exposures to 131I. Knowledge about the effects of repeated ITB (Iodine Thyroid Blocking) is scarce and controversial. KI may affect the thyroid hormones synthesis; which is crucial for the cardiovascular function. Furthermore, myocardial and vascular endothelial tissues are sensitizes to subtle changes at the concentration of circulating pituitary and/or thyroid hormones. OBJECTIVE: In this preclinical study, we aimed to assess the effects of repeated ITB in elderly male rats. METHODS: Twelve months old male Wistar rats were subjected to either KI or saline solution for eight days. Analyses were performed 24 h and 30 days after the treatment discontinuation. FINDINGS: We reported a significant increase (18%) in some urinary parameters related to renal function, a subtle decrease of plasma TSH level, a significant increase (379%) in renin and a significant decrease (50%) in aldosterone upon KI administration. At the molecular level, the expression of thyroid and cardiovascular genes was significantly affected by the treatment. However, in our experimental settlement, animal heart rate was not significantly affected thirty days after KI discontinuation. ECG patterns did not change after administration of KI, and arrhythmia was not observed in these conditions despite the PR-intervals decreased significantly. Cardiovascular physiology was preserved. CONCLUSION: Our results indicate that repeated ITB in elderly rats is characterized by molecular modifications of cardiovascular key actors, particularly the Renin-angiotensin-aldosterone axis with a preserved physiological homeostasis. This new scientific evidence may be useful for the maturation of ITB guidelines especially for elderly sub-population.

Evaluation of the Nose-to-Brain Transport of Different Physicochemical Forms of Uranium after Exposure via Inhalation of a UO4 Aerosol in the Rat.

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.

Repeated potassium iodide exposure during pregnancy impairs progeny's brain development.

Protracted radioiodine release may require repeated intake of potassium iodide (KI) to protect thyroid gland. It is well established that iodine excess inhibits transiently the thyroid function. As developing fetus depends on maternal thyroid hormones (TH) supply, more knowledge is needed about the plausible effects that repeated KI intake can cause in this sensitive population, especially that even subtle variation of maternal thyroid function may have persistent consequences on progeny brain processing. The aim of this study is to assess the consequences of repeated intake of KI during pregnancy on the progeny's thyroid function and brain development. To do so pregnant Wistar rats received KI over eight days, and then thirty days after the weaning, male progeny was subjected to behavior test. Pituitary and thyroid hormones level, anti-thyroid antibodies level, organs morphology, gene expression and global DNA methylation were assessed. Thirty days after the weaning, KI-exposed male progeny showed an uncommon hormonal status, characterized by a decrease of both thyroid-stimulating hormone (-28%) and free thyroxine (-7%) levels. Motor coordination was altered in KI-exposed male progeny. At the cerebellar level, we observed a decrease of mRNA expression of DCX (-42%) and RC3 (-85%); on the other hand, at the cortical level, mRNA expression of MBP (+71%), MOBP (+90%) and Kcna1 (+42%) was increased. To conclude, repeated KI prophylaxis is not adequate during pregnancy since it led to long-term irreversible neurotoxicity in the male progeny.

Applying a multiscale systems biology approach to study the effect of chronic low-dose exposure to uranium in rat kidneys.

Purpose: To examine the effects of low-dose exposure to uranium with a systems biology approach, a multiscale high-throughput multi-omics analysis was applied with a protocol for chronic exposure to the rat kidney. Methods: Male and female rats were contaminated for nine months through their drinking water with a nontoxic solution of uranyl nitrate. A multiscale approach enabled clinical monitoring associated with metabolomic and transcriptomic (mRNA and microRNA) analyses. Results: A sex-interaction effect was observed in the kidney, urine, and plasma metabolomes of contaminated rats. Moreover, urine and kidney metabolic profiles correlated and confirmed that the primary dysregulated metabolisms are those of nicotinate-nicotinamide and of unsaturated fatty acid biosynthesis. Upstream of the metabolic pathways, transcriptomic profiles of the kidney reveal gene activity focused on gene regulation mechanisms, cell signaling, cell structure, developmental processes, and cell proliferation. Examination of epigenetic post-transcriptional gene regulation processes showed significant dysregulation of 70 micro-RNAs. The multi-omics approach highlighted the activities of the cells' biological processes on multiple scales through analysis of gene expression, confirmed by changes observed in the metabolome. Conclusion: Our results showed changes in multi-omic profiles of rats exposed to low doses of uranium contamination, compared with controls. These changes involved gene expression as well as modifications in the transcriptome and the metabolome. The metabolomic profile confirmed that the main molecular targets of uranium in kidney cells are the metabolism of nicotinate-nicotinamide and the biosynthesis of unsaturated fatty acids. Additionally, gene expression analysis showed that the metabolism of fatty acids is targeted by processes associated with cell function. These results demonstrate that multiscale systems biology is useful in elucidating the most discriminative pathways from genomic to metabolomic levels for assessing the biological impact of this low-level environmental exposure, i.e. the exposome.

Neuro-inflammatory response in rats chronically exposed to (137)Cesium.

After the Chernobyl nuclear accident, behavioural disorders and central nervous system diseases were frequently observed in populations living in the areas contaminated by (137)Cs. Until now, these neurological disturbances were not elucidated, but the presence of a neuro-inflammatory response could be one explanation. Rats were exposed for 3 months to drinking water contaminated with (137)Cs at a dose of 400Bqkg(-1), which is similar to that ingested by the population living in contaminated areas in the former USSR countries. Pro-inflammatory and anti-inflammatory cytokine genes were assessed by real-time PCR in the frontal cortex and the hippocampus. At this level of exposure, gene expression of TNF-alpha and IL-6 increased in the hippocampus and gene expression of IL-10 increased in the frontal cortex. Concentration of TNF-alpha, measured by ELISA assays, was also increased in the hippocampus. The central NO-ergic pathway was also studied: iNOS gene expression and cNOS activity were significantly increased in the hippocampus. In conclusion, this study showed for the first time that sub-chronic exposure with post-accidental doses of (137)Cs leads to molecular modifications of pro- and anti-inflammatory cytokines and NO-ergic pathway in the brain. This neuro-inflammatory response could contribute to the electrophysiological and biochemical alterations observed after chronic exposure to (137)Cs.

Nano- and neurotoxicology: An emerging discipline.

The present critical review analyzes the question of how nanoparticles from continuously growing industrial production and use of nanomaterials may impact human brain health. Available evidence suggests incomplete effectiveness of protective barriers of the brain against nanoparticles translocation to the brain. This raises concerns of potential effects of manufactured nanoparticles on brain functions, given that nanoparticle's potential to induce oxidative stress, inflammation, death by apoptosis, or changes in the level of expression of certain neurotransmitters. Most concerns have not been studied sufficiently and many questions are still open: Are the findings in animals transposable to humans? What happens when exposure is chronic or protracted? What happens to the developing brain when exposure occurs in utero? Are some nanoparticles more deleterious, given their ability to alter protein conformations and aggregation? Aside from developments in nanomedicine, the evidence already available fully justifies the need to specifically evaluate the interactions between nanoparticles and the nervous system. The available data clearly indicates the need for original dedicated experimental models and tools for neurotoxicological research on the one hand, and the need for epidemiological studies of neurodegenerative diseases in manufactured nanoparticle-exposed populations, on the other. A combination of nanotoxicology with neurology in a novel discipline, with its specific tools and methods of investigation, should enable answering still unresolved questions.

Effects of repeated potassium iodide administration on genes involved in synthesis and secretion of thyroid hormone in adult male rat.

BACKGROUND: A single dose of potassium iodide (KI) is recommended to reduce the risk of thyroid cancer during nuclear accidents. However in case of prolonged radioiodine exposure, more than one dose of KI may be necessary. This work aims to evaluate the potential toxic effect of repeated administration of KI. METHODS: Adult Wistar rats received an optimal dose of KI 1 mg/kg over a period of 1, 4 or 8 days. RESULTS: hormonal status (TSH, FT4) of treated rats was unaffected. Contrariwise, a sequential Wolff-Chaikoff effect was observed, resulting in a prompt decrease of NIS and MCT8 mRNA expression (-58% and -26% respectively), followed by a delayed decrease of TPO mRNA expression (-33%) in conjunction with a stimulation of PDS mRNA expression (+62%). CONCLUSION: we show for the first time that repeated administration of KI at 1 mg/kg/24h doesn't cause modification of thyroid hormones level, but leads to a reversible modification of the expression of genes involved in the synthesis and secretion of thyroid hormones.

Low dose of uranium induces multigenerational epigenetic effects in rat kidney.

PURPOSE: A protocol of chronic exposure to low dose of uranium was established in order to distinguish the sexual differences and the developmental process that are critical windows for epigenetic effects over generations. METHODS: Both male and female rats were contaminated through their drinking water with a non-toxic solution of uranyl nitrate for 9 months. The exposed generation (F0) and the following two generations (F1 and F2) were examined. Clinical monitoring, global DNA methylation profile and DNA methyltransferases (DNMTs) gene expression were analyzed in kidneys. RESULTS: While the body weight of F1 males increased, a small decrease in kidney and body weight was observed in F2 males. In addition, global DNA hypermethylation profile in kidney cells was observed in F1 and F2 males. qPCR results reveal a significant increase of methyltransferase genes expression (DNMT1 and DNMT3a) for F2 females. CONCLUSIONS: 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.