Lead exposure activates nuclear factor kappa B, activator protein-1, c-Jun N-terminal kinase and caspases in the rat brain

How lead manifests its neurotoxicity is not well understood. The hypothesis that lead may activate nuclear transcription factors NF-kappaB, activator protein-1 (AP-1), c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase (MAPKK) and caspases in the rat brain leading to the manifestation of its neurotoxic effects, was tested in 21-day-old male Long-Evans rats exposed to 50 ppm Pb in drinking water for 90 days. After the 90-day exposure, blood lead levels of the rats in control group were 4 +/- 0.2 mug/dl, while those of the Pb-exposed group were 18 +/- 0.3 mug/dl (n = 50). Similarly, at the end of the exposure period, the Pb-exposed group showed significantly higher accumulation of Pb in brain regions such as, frontal cortex (FC), brain stem (BS), striatum (ST), and hippocampus (HIP) (338.6 +/- 7.7, 391.6 +/- 3.8, 288.3 +/- 6.7, and 382.3 +/- 3.3 ng/g wet tissue, respectively, in FC, BS, ST, and HIP) than the control group (126.6 +/- 2.7, 127.6 +/- 1.8, 201.3 +/- 9.4, and 180.3 +/- 4.4 ng/g wet tissue, respectively, in FC, BS, ST, and HIP). There was a 3-4-fold increase in NF-kappaB and AP-1 level in all the four regions of the brain of lead-treated animals. All four regions showed 4-10-fold activation of JNK and a 5-6-fold activation of MAPKK. As indicated by poly(ADP ribose) polymerase cleavage, lead exposure induced the activation of caspases in all four regions. Overall our results indicate that lead exposure induces the activation of NF-kappaB, AP-1, JNK, MAPKK, and caspases in the brain, which may contribute to its neurotoxic effects. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.