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Stem Cells. 2019 Aug;37(8):1083-1094. doi: 10.1002/stem.3014. Epub 2019 Apr 17.

Low-Dose Pesticide Mixture Induces Accelerated Mesenchymal Stem Cell Aging In Vitro.

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CRCINA, INSERM U1232, Université de Nantes, Nantes, France.
LabEx Immunotherapy, Graft, Oncology, Nantes, France.
CHU de Nantes, Nantes, France.
Université de Nantes, UFR Sciences Biologiques et Pharmaceutiques, Nantes, France.
UMR1238 INSERM, Université de Nantes, PHY-OS, "Bone Sarcomas and Remodeling of Calcified Tissues," Medical School, Nantes, France.
LaBCT, Institut de Cancérologie de l'Ouest, St. Herblain Cedex, France.
Centre Hospitalier Régional Universitaire de Tours, Service d'Hématologie Biologique, Cedex 9 Tours, France.
National Center for Scientific Research ERL 7001 LNOx, Université de Tours, Tours, France.
National Center for Scientific Research GDR 3697, Paris, France.


The general population is chronically exposed to multiple environmental contaminants such as pesticides. We have previously demonstrated that human mesenchymal stem cells (MSCs) exposed in vitro to low doses of a mixture of seven common pesticides showed a permanent phenotype modification with a specific induction of an oxidative stress-related senescence. Pesticide mixture also induced a shift in MSC differentiation toward adipogenesis. Thus, we hypothesized that common combination of pesticides may induce a premature cellular aging of adult MSCs. Our goal was to evaluate if the prolonged exposure to pesticide mixture could accelerate aging-related markers and in particular deteriorate the immunosuppressive properties of MSCs. MSCs exposed to pesticide mixture, under long-term culture and obtained from aging donor, were compared by bulk RNA sequencing analysis. Aging, senescence, and immunomodulatory markers were compared. The protein expression of cellular aging-associated metabolic markers and immune function of MSCs were analyzed. Functional analysis of the secretome impacts on immunomodulatory properties of MSCs was realized after 21 days' exposure to pesticide mixture. The RNA sequencing analysis of MSCs exposed to pesticide showed some similarities with cells from prolonged culture, but also with the MSCs of an aged donor. Changes in the metabolic markers MDH1, GOT and SIRT3, as well as an alteration in the modulation of active T cells and modifications in cytokine production are all associated with cellular aging. A modified functional profile was found with similarities to aging process. Stem Cells 2019;37:1083-1094.


Aging cell; Immune response; Mesenchymal stem cells; Pesticide mixture; Senescence


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