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

Abstract

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.

The Associations between Blood and Urinary Concentrations of Metal Metabolites, Obesity, Hypertension, Type 2 Diabetes, and Dyslipidemia among US Adults: NHANES 1999–2016

“…However, this study and a previous report [ 25 ] suggest there may also be positive associations between barium and body mass index. While there was no significant relationship between obesity and uranium exposure in this study, a longitudinal study of Kuwaiti children suggests the relationship between obesity and higher levels of 2PY, a potential biomarker of uranium uptake [ 46 ]. To date the research on antimony exposure and obesity is limited [ 47 ]; however, this study observed a curvilinear relationship between antimony and obesity with the moderate-concentration group having the highest risk of obesity.…”

“…While the nephrotoxicity of uranium is well known [ 57 ], this study supports the notion of a potential link between uranium exposure and type 2 diabetes. Uranium exposure could cause a potential positive feedback loop between the exposure, type 2 diabetes, and kidney disease particularly in areas of high environmental contamination and high type 2 diabetes prevalence such as the Navajo Nation in the United States [ 58 ] and countries like Kuwait [ 46 , 59 ] and thus increasing the healthcare burden of these communities. Conversely, this study demonstrates that high lead and cadmium were negatively associated with prevalent diabetes.…”

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

“…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 ]. Thus, these observations suggest that NMN metabolism could be impacted by uranium exposure and, in addition, could be a marker for renal sensitivity through membrane transporter interaction (OCT2) in tubular cells [ 21 , 39 , 40 ].…”

From metabolome to epigenome: example of multiscale analysis for studying the effects of low-dose uranium exposure

“…Impactées par ces nombreux facteurs de confusion, les résultats de ces études manquent de puissance statistique (taille insuffisante des cohortes suivies). Ils ne permettent ni de mettre en évidence un lien de causalité entre l'exposition environnementale à l'uranium et l'augmentation de la fréquence d'apparition de certaines maladies [25], ni de conclure en matière de risque sanitaire [23,[26][27][28]. analytiques très sensibles qui permettent de mesurer simultanément un très grand nombre de paramètres biologiques devient un atout majeur [29].…”

“…Sur ce dernier point, des études menées dans les années 70 et 80 sur l'insuffisance rénale, avaient observé une accumulation du N1-méthylnicotinamide dans le cortex rénal, accompagnée d'une diminution de sa clairance urinaire chez des rats ayant reçu une dose néphrotoxique d'uranium[40,41]. Une étude plus récente, a aussi fait un rapprochement entre la teneur salivaire en N1-Methyl-2-Pyridone-5-Carboxamide d'enfants koweitiens présentant une surcharge pondérale, et leur potentielle exposition juvénile à l'uranium par usage de munitions blindées durant la guerre de Golfe[25]. Dans ces différents cas, les études indiquent que la voie du nicotinate-nicotinamide semble être une cible biologique de l'uranium.Pour pouvoir disposer d'un outil utile à l'évaluation du risque d'une exposition à faible dose d'uranium, un prototype expérimental de test de diagnostic a pu être élaboré à partir des 11 marqueurs discriminant identifiés à toutes les doses d'uranium testées.…”