Impact of repeated dose of stable iodine in an in utero rat model using a metabolomic approach

The Fukushima nuclear power plant blast resulted in the release of 131Iodine for several weeks. This unexpected issue challenged the iodin doctrine [1], in which the counter-measure is to provide a unique iodine tablet to saturate thyroid during the radioactive contamination not expected to last more than several hours. A new doctrine must be implemented to take into account such case of extended exposure based on repeated iodine administration with adapted dosage. But repeated administration of iodine can block the thyroid [2] and few scientific evidences regarding repeated iodine administration (and its potential undesirable effect) are at our disposal [3]. Moreover, unborn and young children are at high risk during a nuclear incident: it is currently recognized that one of the risks of exposure to radioactive iodine is the development of thyroid cancer, especially when exposure occurred during childhood [4]. Their protection is a main priority. Our goal was to evaluate the potential undesirable effects of such repeated iodine administration in the offspring using an untargeted metabolomic approach on a rat reproductive model

Impact of repeated dose of stable iodine in an in utero rat model using a metabolomic approach

International audienceThe Fukushima nuclear power plant blast resulted in the release of 131 Iodine for several weeks. This unexpected issue challenged the iodin doctrine [1], in which the countermeasure is to provide a unique iodine tablet to saturate thyroid during the radioactive contamination not expected to last more than several hours. A new doctrine must be implemented to take into account such case of extended exposure based on repeated iodine administration with adapted dosage. But repeated administration of iodine can block the thyroid [2] and few scientific evidences regarding repeated iodine administration (and its potential undesirable effect) are at our disposal [3]. Moreover, unborn and young children are at high risk during a nuclear incident: it is currently recognized that one of the risks of exposure to radioactive iodine is the development of thyroid cancer, especially when exposure occurred during childhood [4]. Their protection is a main priority. Our goal was to evaluate the potential undesirable effects of such repeated iodine administration in the offspring using an untargeted metabolomic approach on a rat reproductive model. Pregnant rats received repeated doses of potassium iodine (KI group: 1mg/kg/24h) or water for injection (control group) for 8 days. The potential metabolic disruption was investigated in the offspring 30 days after weaning. Using LC-MS, we compared the blood's metabolite composition between KI and control male rats; using a high throughput annotation procedure with an in-house databank, 264 metabolites were annotated (based on retention time and exact mass), combined in 52 functional biological modules/pathways, and converted into corresponding scores using a PLS multiblock algorithm (see Fig. 1)

Metabolomics evaluation of repeated administration of potassium iodide on adult male rats

International audienceThe long-lasting consequence of a new iodine thyroid blocking strategy (ITB) to be used in case of nuclear accident is evaluated in male Wistar rats using a metabolomics approach applied 30 days after ITB completion. The design used 1 mg/kg/day of KI over 8 days. Thyroid hormones remained unchanged, but there was a metabolic shift measured mainly in thyroid then in plasma and urine. In the thyroid, tyrosine metabolism associated to catecholamine metabolism was more clearly impacted than thyroid hormones pathway. It was accompanied by a peripheral metabolic shift including metabolic regulators, branched-chain amino acids, oxidant stress and inflammation-associated response. Our results suggested that iodide intake can impact gut microbiota metabolism, which was related to host metabolic regulations including in the thyroid. As there were no clear clinical signs of dysfunction or toxicity, we concluded that the measured metabolomics response to the new ITB strategy, especially in thyroid, is unlikely to reveal a pathological condition but a shift towards a new adaptive homeostatic state, called 'allostatic regulation'. The question now is whether or not the shift is permanent and if so at what cost for long-term health. We anticipate our data as a start point for further regulatory toxicity studies

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

International audiencePreparedness 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

The Brassica napus (oilseed rape) seeds bioactive health effects are modulated by agronomical traits as assessed by a multi-scale omics approach in the metabolically impaired ob-mouse

International audienceBeside oil, oilseed rape (Brassica napus) seeds contains nutritional bioactives such as polyphenols and glucosinolates. However, to date their nutritional properties have been overlooked in the new "double zero" breeds. Seed alcoholic extracts from two B. napus cultivars most contrasting in their phytochemical contents as measured by mass-spectrometry were given to ob-mice. Biological outcomes including clinical metrics, gut and plasma metabolomes, liver transcriptome and metabolome were compared to ob-mice given a similar broccoli extract (Brassica oleracea). One B. napus extract induced a reduction of the oxidative stress indicated by the decrease of plasma isoprostanoids. This was associated to the regulation of the antioxidant stress defense Nrf2 pathway, to 'omic' oxidative stress functions, metabolic and cell process regulations, and the metabolomics microbiota profile. Extracts of B. napus seeds demonstrated health effects that may be improved by selecting appropriate agronomical traits, highlighting the potential benefits of better utilizing agronomy for improved human and animal nutritio

Review of the PRIODAC project on thyroid protection from radioactive iodine by repeated iodide intake in individuals aged 12+

International audienceBackground Intake of potassium iodide (KI) reduces the accumulation of radioactive iodine in the thyroid gland in the event of possible contamination by radioactive iodine released from a nuclear facility. The World Health Organization (WHO) has stated the need for research for optimal timing, appropriate dosing regimen, and safety for repetitive iodine thyroid blocking (ITB). The French PRIODAC project, addressed all these issues, involving prolonged or repeated releases of radioactive iodine. Preclinical studies established an effective dose through pharmacokinetic modeling, demonstrating the safety of repetitive KI treatment without toxicity. Summary Recent preclinical studies have determined an optimal effective dose for repetitive administration, associated with pharmacokinetic modeling. The results show the safety and absence of toxicity of repetitive treatment with KI. Good laboratory practice level preclinical studies corresponding to individuals >12 years have shown a safety margin established between animal doses without toxic effect. After approval from the French health authorities, the market authorization of the two tablets of KI, 65 mg/day, was defined with a new dosing scheme of a daily repetitive intake of the treatment up to 7 days unless otherwise instructed by the competent authorities for all categories of population except pregnant women and children under the age of 12 years. Conclusion This new marketed authorization resulting from scientific-based evidence obtained as part of the PRIODAC project may serve as an example to further harmonize the application of KI for repetitive ITB in situations of prolonged radioactive release at the European and international levels, under the umbrella of the WHO .(C2VN), Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE)