The adrenal glands have striking morpho-biochemical features that render them vulnerable to the effects of
toxins. Aims: This study was conducted to explore the therapeutic utility of extracellular vesicles derived from
bone marrow mesenchymal stem cells (BMSC-EVs) against fluoride-induced adrenal toxicity. Materials and
methods: The work included isolation and further identification of BMSC-EVs by transmission electron microscopy
and flow cytometric analysis. Adrenal toxicity in rats was induced by oral administration of 300 ppm of
sodium fluoride (NaF) in drinking water for 60 days followed by a single dose injection of BMSC-EVs. The effects
of BMSC-EVs against NaF was evaluated by adrenal oxidant/antioxidant biomarkers, hormonal assay of plasma
adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) and mRNA gene expression quantitation for
adrenal cortical steroidogenic pathway-encoding genes. Histopathological examination of the adrenal tissue was
performed. Key findings: BMSC-EVs were effectively isolated and characterized. NaF exposure decreased adrenal
superoxide dismutase and catalase activities, increased adrenal malondialdehyde levels, elevated plasma ACTH,
diminished CORT concentrations and downregulated the adrenal cortical steroidogenic pathway-encoding genes.
In addition, NaF-induced marked adrenal histopathological lesions. Significance: BMSC-EVs treatment repaired
damaged adrenal tissue and recovered its function greatly following NaF consumption. BMSC-EVs reversed the
toxic effects of NaF and reprogramed injured adrenal cells by activating regenerative processes.