Distribution of bismuth in the brain after intraperitoneal dosing of bismuth subnitrate in mice: Implications for routes of entry of xenobiotic metals into the brain

Abstract

Bismuth (Bi) can produce neurotoxic effects in both humans and animals under certain dosing conditions, but little else is known about the effects of Bi in the brain. In the present study we determined the distribution of Bi in the brains of adult female Swiss-Webster mice 4, 7, 14, 21 and 28 days after a single 2500 mg/kg i.p. injection of Bi subnitrate (BSN), which establishes a depot of absorbable Bi and produces morphological signs of neurotoxicity. Sections cf brains were processed by autometallographic (AMG) procedures that produced silver grains at the site of Bi localization (AMG Bi). Ventricular dilation was observed in all BSN-dosed mice. Among treated mice there were marked interanimal differences in the absolute amount of AMG Bi, but consistent regional and cellular patterns of AMG Bi were observed. AMG Bi was observed in many cell types in brain regions adjacent to fenestrated blood vessels of the circumventricular organs (CVOs) and olfactory epithelium. Prominent intrasomal AMG Bi was observed in nuclei containing large cell bodies, including cranial motor neurons innervating somatic muscle, lateral vestibular and red nucleus and pontine/medullary reticular nuclei. In the hypothalamus, the supraoptic and paraventricular nuclei demonstrated the densest AMG Bi. In the cerebellum, Purkinje and granule cell layers with the densest AMG Bi were in folia adjacent to the fourth ventricle. In the hippocampus, AMG Bi was densest in the fasciola cinerum, polymorph cells of the dentate gyrus, and pyramidal cell layer of the CA3 regions. Neuropil of subcortical auditory nuclei (cochlear nucleus, trapezoid body, lateral lemniscus and nucleus of lateral lemniscus, medial geniculate nucleus and inferior colliculus) had a high density of AMG Bi. Among nonneuronal cells, ependyma and meninges lining the ventricular and subarachnoid spaces were labeled extensively. Glial labeling was prominent adjacent to CVOs, in subependymal regions, and in fiber tracts. Presumptive perivascular cells lining large blood vessels had extremely dense AMG Bi as early as 4 days after dosing. Smaller blood vessels had moderate AMG Bi. However, in regions (e.g. cerebral cortex, striatum) known to have low brain Bi levels after i.p. dosing, vascular deposits accounted for most of the AMG Bi. Several animals had foci of AMG Bi which suggested that vascular or perivascular aberrations may have contributed to the unusually dense accumulations. The results of the present studies indicate that Bi accumulates predictably in certain regions and cell types. The pattern of regions and cells with the highest AMG Bi accumulations is very similar to pattern reported for other xenobiotic metals (i.e. mercury, silver, gold), and supports the hypothesis that these metals may share some mechanisms for entry, distribution and storage in the brain.