Application of a systems biology approach to developmental neurotoxicology.
Systems biology can be applied to enhance the understanding of complex biological processes such as apoptosis in the developing brain. Systems biology, as applied to toxicology, provides a structure to arrange information in the form of a biological model. The approach allows for the subsequent and iterative perturbation of the initial model with the use of toxicants, and the comparison of the resulting data against the proposed biological model. It is postulated that the exposure of the developing rat to NMDA antagonists, e.g., ketamine or phencyclidine (PCP), causes a compensatory up-regulation of NMDA receptors, thereby making cells bearing these receptors more vulnerable to excitotoxic effects of endogenous glutamate. Although comprehensive gene expression/proteomic studies and mathematical modeling remain to be accomplished, a biological model has been established and perturbed in an iterative manner to allow confirmation of the biological pathway for NMDA antagonist-induced brain cell death in the developing rat.
Slikker
William
W
Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079-9502, USA. wslikker@nctr.fda.gov
Xu
Zengjun
Z
Wang
Cheng
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D008954:Models, Biological; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D020258:Neurotoxicity Syndromes / Q000235:genetics / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D040901:Proteomics; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D049490:Systems Biology; D015854:Up-Regulation
D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate