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

Grison, Stéphane; Kereselidze, Dimitri; Cohen, David; Gloaguen, C.; Elie, Christelle; Lestaevel, Philippe; Legendre, Audrey; Manens, Line; Habchi, Baninia; Benadjaoud, Mohamed Amine; Tarlet, Georges; Milliat, Fabien; Martin, Jean‐Charles; Lobaccaro, Jean-Marc A.; Souidi, Maâmar

doi:10.1080/09553002.2019.1577567

Cited by 11 publications

(13 citation statements)

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“…In addition, the targeted analysis of the annotated arrays confirmed the previous results for the nicotinate–nicotinamide pathway and reinforced those obtained for the tryptophan pathway [ 27 ].…”

Section: Discussionsupporting

confidence: 83%

“…While studies using targeted [ 25 , 26 ] and non-targeted [ 27 ] analyses have looked at the effects of high- and low-dose chronic exposure to uranium [ 12 , 28 , 29 ] to assess health risks [ 30 ], the effects of acute low-dose exposure to uranium are still poorly described, even though they are a part of the occupational exposure faced by nuclear workers. To fill this gap, identifying biological signatures that could be used to diagnose the sub-toxic effects of low-dose internal exposure would be relevant to improving the radiation protection and medical monitoring of nuclear workers.…”

Section: Discussionmentioning

confidence: 99%

“…As one of the main objectives of this study was to compare the effects of this acute NU exposure with those of chronic exposure, it is interesting to note that 1-methylnicotinamide (NMN), already identified as deregulated in urine by chronic NU contamination [ 20 ], was detected among these nine early markers of acute NU exposure. According to current knowledge and experimental observations, NMN increases in the renal cortex and plasma and decreases in the urine of rats exposed to a high toxic dose of uranium [ 21 , 37 ], also associated with the effects of chronic low-dose exposure in urine and renal tissue [ 27 ]. Others have also identified NMN in the salivary analyses of Kuwaiti adolescents living in an area contaminated by uranium during childhood [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…Regarding these 36 discriminating metabolites, it can be assumed that different metabolic pathways could be affected by uranium. The results showed that indoleacetic acid and tryptamine may be related to the tryptophan metabolism, which is also related to the nicotinate–nicotinamide pathway by quinolinic acid and 1-methylnicotinamide, as targeted by the early NU markers, as observed after chronic exposure [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

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Early Metabolomic Markers of Acute Low-Dose Exposure to Uranium in Rats

et al. 2022

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Changes in metabolomics over time were studied in rats to identify early biomarkers and highlight the main metabolic pathways that are significantly altered in the period immediately following acute low-dose uranium exposure. A dose response relationship study was established from urine and plasma samples collected periodically over 9 months after the exposure of young adult male rats to uranyl nitrate. LC-MS and biostatistical analysis were used to identify early discriminant metabolites. As expected, low doses of uranium lead to time-based non-toxic biological effects, which can be used to identify early and delayed markers of exposure in both urine and plasma samples. A combination of surrogate markers for uranium exposure was validated from the most discriminant early markers for making effective predictions. N-methyl-nicotinamide, kynurenic acid, serotonin, tryptophan, tryptamine, and indole acetic acid associated with the nicotinate–nicotinamide and tryptophan pathway seem to be one of the main biological targets, as shown previously for chronic contaminations and completed, among others, by betaine metabolism. This study can be considered as a proof of concept for the relevance of metabolomics in the field of low-dose internal contamination by uranium, for the development of predictive diagnostic tests usable for radiotoxicological monitoring.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Early Metabolomic Markers of Acute Low-Dose Exposure to Uranium in Rats

et al. 2022

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“…Levels of 2PY in renal tissues of healthy people are typically 1.37 mg/L (± 0.68), whereas concentrations in patients with uremia average 4.02 mg/L (± 3.28) with measurements as high as 7.80 mg/L (± 3.59) (13, 14). In rats, 2PY is one of a number of metabolites whose concentration in urine is associated with prolonged low-dose exposure to uranium (15, 16).…”

Section: Introductionmentioning

confidence: 99%

Salivary N1-Methyl-2-Pyridone-5-Carboxamide, a Biomarker for Uranium Uptake, in Kuwaiti Children Exhibiting Exceptional Weight Gain

et al. 2019

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In a longitudinal study of 6,158 Kuwaiti children, we selected 94 for salivary metabolomic analysis who were neither obese (by waist circumference) nor metabolic syndrome (MetS) positive (<3 diagnostic features). Half (43) remained healthy for 2 years. The other half (51) were selected because they became obese and MetS positive 2 years later. In the half becoming obese, metabolomic analysis revealed that the level of salivary N1-Methyl-2-pyridone-5-carboxamide (2PY) had the highest positive association with obesity ( p = 0.0003, AUC = 0.72) of 441 salivary biochemicals detected. 2PY is a recognized uremic toxin. Also, 2PY has been identified as a biomarker for uranium uptake. Considering that a relatively recent military conflict with documented uranium contamination of the area suggests that this weight gain could be a toxicological effect of long-time, low-level uranium ingestion. Comparison of salivary 2PY in samples from the USA and Kuwait found that only Kuwait samples were significantly related to obesity. Also, the geographic distribution of both reported soil radioactivity from 238 U and measured salivary 2PY was highest in the area where military activity was highest. The prevalence pattern of adult diabetes in Kuwait suggests that a transient diabetogenic factor has been introduced into the Kuwaiti population. Although we did not measure uranium in our study, the presence of a salivary biomarker for uranium consumption suggests potential toxicity related to obesity in children.

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