Cell culture models for lead toxicity in neuronal and glial cells

Two goals of lead (Pb) neurotoxicity research are to identify molecular and cellular alterations that underlie behavioral deficits and to define mechanisms of Pb uptake and tolerance in cells that accumulate Pb. Cell and tissue cultures are practical tools with which to pursue these goals, offering such advantages over in vivo methods as defined cell types, an extracellular environment that can be precisely manipulated, and direct observation. On the other hand, toxicity studies with cultured cells also present new challenges of design and interpretation. If a living vertebrate is like an orchestra playing a Beethoven symphony, then tissue culture is like two of the violinists playing their part alone. Historically, Pb toxicity studies with cell and tissue culture can be divided into an exploratory phase, an expansion phase, and a newly emerging intensification phase. In the exploratory phase, gross cytotoxic effects from massive Pb exposure (50-500 microM) were characterized. The collective data suggest differential sensitivity to Pb toxicity among various types of cultured neural cells, ranked as follows from most to least sensitive: myelinating cells, neurons, and astroglia. In addition, astroglia were shown to take up and store large amounts of Pb intracellularly, a phenomenon resembling the Pb-sequestering ability hypothesized for mature astroglia in vivo. The mechanisms of Pb entry may involve an anion exchanger, Ca2+ channels, or some other transport process. Three ingrained problems concerning the use of cell cultures began to emerge: appropriate dose regimens, biologically relevant forms of Pb (i.e. ionized or complexed with other molecules), and suitable measurements of Pb effects. These problems received scrutiny in the expansion phase, during which subcellular targets of Pb-induced damage were examined, specifically membranes, enzymes, and Ca-mediated cellular processes. Investigators attempted to define a biologically relevant dose regimen in vitro, as well as a threshold dose below which Pb had no biological effect. Effects of Pb at nanomolar concentrations in intact cells and tissue homogenates stimulated the metamorphosis of Pb toxicity studies in cell culture into a new phase, the intensification phase. Alterations in discrete molecular targets, particularly those effects in the cell that may be metabolically amplified, will be a major focus of this phase. Critical molecular targets for Pb-induced injury appear to be present during neuritogenesis and/or synaptogenesis. With the availability of cell culture models for neurite extension and synapse formation, this area may be another focus for innovative Pb neurotoxicity research.(ABSTRACT TRUNCATED AT 400 WORDS)