Inorganic arsenic is among the major contaminants of groundwater in the world. Worldwide population-based studies demonstrate that chronic arsenic exposure is associated with poor cognitive performance among children and adults, while research in animal models confirms learning and memory deficits after arsenic exposure. The aim of this study was to investigate the long-term effects of environmentally relevant arsenic exposure in the myelination process of the prefrontal cortex (PFC) and corpus callosum (CC). A longitudinal study with repeated follow-up assessments was performed in male Wistar rats exposed to 3 ppm sodium arsenite in drinking water. Animals received the treatment from gestation until 2, 4, 6, or 12 months of postnatal age. The levels of myelin basic protein (MBP) were evaluated by immunohistochemistry/histology and immunoblotting from the PFC and CC. As plausible alterations associated with demyelination, we considered mitochondrial mass (VDAC) and two axonal damage markers: amyloid precursor protein (APP) level and phosphorylated neurofilaments. To analyze the microstructure of the CC in vivo, we acquired diffusion-weighted images at the same ages, from which we derived metrics using the tensor model. Significantly decreased levels of MBP were found in both regions together with significant increases of mitochondrial mass and slight axonal damage at 12 months in the PFC. Ultrastructural imaging demonstrated arsenic-associated decreases of white matter volume, water diffusion anisotropy, and increases in radial diffusivity. This study indicates that arsenic exposure is associated with a significant and persistent negative impact on microstructural features of white matter tracts.
Keywords: Amyloid; Anisotropy; Arsenic; Axonal damage; DTI; Demyelination; Development; MRI; Microstructure; Mitochondria.
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