DS04 - Vie, santé et bien-être

Mitochondrial probes for investigating the impact of inhaling ultrafine pesticides particles on oxidative stress, cardiometabolic dysfunction and insulin resistance, combined with new devices for atmosphere-mimicking aerosols generation – MITODIAPM

Submission summary

Many studies have evidenced that peaks of air pollution are a cause of mortality in humans by promoting cardiovascular and pulmonary diseases. While the many consequences of acute intoxication with high levels of pesticides, carbon particles or metal derivatives are well documented, the more subtle, long term effects caused by ambient air pollution remain difficult to evaluate. Among the major pollutants in air, soils and water, recent epidemiological studies have suggested a possible link between exposure to pesticides and type 2 diabetes. Thus, ingestion of food contaminated with pesticides has been associated to impaired glucose regulation, endocrine disruption and obesity. However, it has not been clearly established whether lower levels of pesticides found in aerial particulate matter (PM) may be a new risk factor for insulin resistance and progression of diabetes mellitus because reliable experimental models are still not available.
Ultrafine particles having diameter ranges < 2.5 µm (PM2.5) or even smaller are very active components of today's atmospheres and are practically non-removable once inhaled. PM25 have been shown to be responsible for a wide array of pathologies, including inflammation, endothelial and mitochondrial dysfunction, and cardiac diseases due to their deep penetration within the bronchial cells. Regarding the mechanisms of action at the molecular level, PM25 promote oxidative processes, leading to protein oxidation and/or causing genotoxicity. For instance, lipophilic toxicants in volatile form can accumulate within mitochondria to trigger redox cycles highly detrimental to the cardiorespiratory system. For decades, members of our Laboratory (ICR-SMBSO) have been involved in the study of the various facets of the pathophysiological effects of oxidative stress, from the design of sensitive, highly specific and targetable probes and improved analytical procedures for protein oxidation and inflammation assessment, and their use in animal studies and clinical trials.
In the present project encompassing chemistry, biology, environment and health fields Dr. Sophie Thétiot-Laurent will led a subgroup of ICR-SMBSO, with the cooperation of all other members of the Team. Together they will apply their know-how to investigate the chronic effects of low levels of pesticides aerosols on mitochondrial and cardiac dysfunction, oxidative stress and insulin and metabolic disorders in experimental animals. Central to the project are:
i)a unique atmosphere-mimicking exposure device recently developed in the Laboratory and adapted for animal housing to produce aerosols of nanosized (= 1 µm) and concentration-controlled particles. This will allow chronic exposure to environmentally-relevant pollutants (1-20 ng/m3).
ii)EPR measurements at low frequency (L-band). Combining this technology, already available at ICR-SMBSO, with a series of novel vectorized probes will define a new research axis aimed at monitoring the redox state and pH changes in vivo.
To summarize, new mitochondria targeted probes will be synthesized and applied to investigations of metabolic, oxidative stress and histological endpoints using EPR and improved analytical methods. Below, the chronology of the 2-years project:
1-design (subcellular targeting, pKa adjustment, search for low toxicity), synthesize and apply (test tube to in vivo) new probes with specific spectroscopic fingerprints for investigating pollution-induced redox dysfunction in vivo
2-expose animals to controlled atmospheres (size, composition, concentration) of selected pesticides under realistic conditions (e.g. 2 hours/day)
3-run a proof of principle in vivo experiment aiming to assess the effect of pesticide exposure on the course of symptoms and pathological features of metabolic, inflammatory, and cardiac disorders in animals. This step will include the set up of analytical assays, and designing molecular sensors to monitor oxidative stress and systemic inflammation at real-time.

Project coordination

Sophie Thétiot-Laurent (Institut de Chimie Radicalaire)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

ICR Institut de Chimie Radicalaire

Help of the ANR 285,360 euros
Beginning and duration of the scientific project: September 2017 - 24 Months

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