Astroglial cells are resistant to cell death and morphologic damage following lead (Pb) exposure at concentrations which elicit detrimental effects in neurons. A possible explanation may be that astroglial cells respond to Pb by increasing the expression of specific proteins, such as heat-shock proteins (HSPs), which confer resistance to low levels of Pb. However, there has been relatively limited information regarding the ability of Pb to evoke the synthesis of HSPs. In the current study, pulse-labeling of cultured astroglial proteins with [3H]-leucine was used to evaluate the nature of Pb-induced changes in protein expression. The effect of Pb on newly synthesized proteins was compared to the response elicited by heat-shock and oxidative injury. Immunoblot analysis was utilized to examine alterations in levels of various stress proteins including HSP27, HSP70, HSP90, and heme oxygenase-1 (HO-1). Even though Pb induced the synthesis of proteins with estimated molecular weights of 23 kDa, 32 kDa, 70 kDa, and 90 kDa, the accumulation of HSPs other than HO-1 was not observed. Hyperthermia and treatment with Na arsenite both resulted in enhanced expression of HSWO and HO-1. In addition, exposure to hydrogen peroxide (H202), cadmium (Cd), and lipopolysaccharide (LPS) stimulated a rise in HO-1 levels. Although cellular insult failed to elicit an increase in either HSP27 or HSP90, cultured astroglia expressed readily detectable levels of both these proteins. Furthermore, Pb exposure resulted in the development of crosstolerance to subsequent injury by treatment with either Cd or H202. The results of this study indicate that Pb triggers a less conventional stress response in astroglial cells, which may provide enhanced resistance to the toxic effects of Pb.