All humans carry much more Pb2+ than our distant ancestors, and our bodies probably do not possess adequate means for sequestering or excreting Pb2+ so that there are no deleterious effects on our physiology. Recent epidemiological data indicate that there are significant effects on children's IQ at blood lead levels well below the CDC action level of 10 mug/dl. The cellular substrate(s) of such subtle effects remain elusive. Lead exerts multiple deleterious effects on cells; at low concentrations, these effects are usually relatively small. A major premise of this application is that Pb2+ exposure is seldom high enough to cause major physiological dysfunction by itself. However, low levels of Pb2+ may alter cellular metabolism in ways that exacerbate the toxic effects of other insults, including everyday metabolism (e.g., generation of reactive oxygen species [ROS] by mitochondria) and pathological conditions (e.g., ischemia caused by stroke). This application is based on two hypotheses: (1) Low-level Pb2+ exposures stimulates the production and/or reduces clearance of ROS and/or reactive nitrogen species (RNS). Therefore, events that stimulate the formation or retard the clearance of ROS or RNS will cause more damage to cells that are also exposed to Pb2+. (2) Cells of the nervous system differ in their responses to Pb2+. Cells that have intrinsic resistance or that mount an adaptive response to Pb2+ (astrocytes) will suffer fewer harmful effects when exposed to Pb2+. Cells with fewer defenses and/or that cannot mount an adaptive response to Pb2+ (neurons) wil be predisposed to damage from other insults. We further hypothesize that induction of heme oxygenase-1 (HO-1) in astrocytes confers protection against Pb2+; neurons, which do not induce HO-1 in response to Pb2+, lack this protection. We have the following specific aims: 1: To determine cell-specific effects of Pb2+ exposure on intracellular ROS and/or RNS, and on cellular damage from ROS/RNS. 2: To investigate whether Pb2+ exposure enhances cellular damage caused by other stresses. 3: To determine if Ho-1 provides protection against Pb2+-induced accumulation of ROS/RNS and against enhancement of cytotoxicity of other stresses of Pb2+/ 4: To determine if HO-1 expression by astrocytes provides protection to neurons from Pb2+-induced toxicity.
| Cabell, Leigh; Ferguson, Charles; Luginbill, Deana et al. (2004) Differential induction of heme oxygenase and other stress proteins in cultured hippocampal astrocytes and neurons by inorganic lead. Toxicol Appl Pharmacol 198:49-60 |
