Proton Magnetic Resonance Spectroscopic Evidence of Glial Effects of Cumulative Lead Exposure in the Adult Human Hippocampus

BACKGROUND: Exposure to lead is known to have adverse effects on cognition in several different populations. Little is known about the underlying structural and functional correlates of such exposure in humans. OBJECTIVES: We assessed the association between cumulative exposure to lead and levels of different brain metabolite ratios in vivo using magnetic resonance spectroscopy (MRS). METHODS: We performed MRS on 15 men selected from the lowest quintile of patella bone lead within the Department of Veterans Affairs’ Normative Aging Study (NAS) and 16 from the highest to assess in the hippocampal levels of the metabolites N-acetylaspartate, myoinositol, and choline, each expressed as a ratio with creatine. Bone lead concentrations—indicators of cumulative lead exposure—were previously measured using K-X-ray fluorescence spectroscopy. MRS was performed on the men from 2002 to 2004. RESULTS: A 20-μg/g bone and 15-μg/g bone higher patella and tibia bone lead concentration—the respective interquartile ranges within the whole NAS—were associated with a 0.04 [95% confidence interval (CI), 0.00–0.08; p = 0.04] and 0.04 (95% CI, 0.00–0.08; p = 0.07) higher myoinositol-to-creatine ratio in the hippocampus. After accounting for patella bone lead declines over time, analyses adjusted for age showed that the effect of a 20-μg/g bone higher patella bone lead level doubled (0.09; 95% CI, 0.01–0.17; p = 0.03). CONCLUSIONS: Cumulative lead exposure is associated with an increase in the myinositol-to-creatine ratio. These data suggest that, as assessed with MRS, glial effects may be more sensitive than neuronal effects as an indicator of cumulative exposure to lead in adults

Feline immunodeficiency virus decreases cell-cell communication and mitochondrial membrane potential.

The in vitro effects of viral replication on mitochondrial membrane potential (MMP) and gap junctional intercellular communication (GJIC) were evaluated as two parameters of potential cellular injury. Two distinct cell types were infected with the Petaluma strain of feline immunodeficiency virus (FIV). Primary astroglia supported acute FIV infection, resulting in syncytia within 3 days of infection, whereas immortalized Crandell feline kidney (CRFK) cells of epithelial origin supported persistent FIV infection in the absence of an obvious cytopathic effect. An examination of cells under conditions that included an infection rate of more than 90% for either population revealed that the astroglia produced about four times more virus than the CRFK cells. The mitochondrial uptake of the cationic fluorescent dye rhodamine 123 in infected astroglia was less than 45% of that of normal control cells, whereas the MMP of the CRFK cells, which produced about one-fourth as much virus, was 80.8% of that of the normal cells. Cell-cell communication between adjacent cells was determined by the recovery of fluorescence following photobleaching of a single cell. In spite of the lower level of innate cell-cell communication among cultured CRFK cells than among astroglia, viral replication resulted in a 30% decrease in the GJIC of both astroglia and CRFK cells. These studies indicate that cell injury, as defined by an inhibition of MMP and GJIC, can occur as a result of persistent and acute infection with the Petaluma strain of FIV

Responses of Cultured Astrocytes, C6 Glioma and 1321NI Astrocytoma Cells to Amyloid β-Peptide Fragments

The effect of amyloid β-peptide (βAP), which can have both neurotrophic or neurotoxic effects on neurons and has been implicated in the pathogenesis of Alzheimer’s disease (AD), was studied on astrocytes using primary cultures and astrocyte cell lines (rat C6 glioma, human 1321NI astrocytoma cells). The cultures were exposed to 0.0005–50 μg/ml) βAP fragments 1–40, 25–35, 31–35, or 40–41 (control) for 24 hr. Some of the fragments were maintained at 37°C for 48 hr to induce aggregation and some of the cell cultures were pretreated with the differentiating agent dBcAMP before the experiments. The astrocyte responses were evaluated for lysosome activity (neutral red assay) and levels of structural proteins, glial fibrillary acidic protein, vimentin, and S-100, which are altered in the dystrophic plaques with associated astrogliosis in AD. The cells frequently responded with biphasic responses, with initial (low-dose) activation-type responses (i.e., increases of indicator compared to controls), before reductions with altered morphology (increased branching of cells) at higher concentrations. However, cell death (with EC50 values) was not observed, even at the maximum concentrations of βAP fragments. The findings suggest that the astrocytes have a relatively high resistance against the βAP toxicity

Bridging the gap between in vitro and in vivo models for neurotoxicology

In vitro systems are widely used for investigation of neurotoxicant-induced perturbations of cellular functions. A variety of systems exist that demonstrate certain similarities to neurotoxicant-induced events in the intact animal are discussed, including single-cell types, systems that consider endpoints relevant in toxicology, and systems that consider heterogeneous cell interactions. Relationships between the in vitro and in vivo systems are examined in which ethanol, lead, polychlorinated biphenyl compounds, and organophosphate insecticides are examples. Situations in which the in vitro systems have been used to advantage are provided, along with cautions associated with their use