Systems biology approaches for toxicology

Abstract

Systems biology/toxicology involves the iterative and integrative study of perturbations by chemicals and other stressors of gene and protein expression that are linked firmly to toxicological outcome. In this review, the value of systems biology to enhance the understanding of complex biological processes such as neurodegeneration in the developing brain is explored. Exposure of the developing mammal to NMDA (N-methyl-D-aspartate) receptor antagonists perturbs the endogenous NMDA receptor system and results in enhanced neuronal cell death. It is proposed that continuous blockade of NMDA receptors in the developing brain by NMDA antagonists such as ketamine (a dissociative anesthetic) causes a compensatory up-regulation of NMDA receptors, which makes the neurons bearing these receptors subsequently more vulnerable (e.g. after ketamine washout), to the excitotoxic effects of endogenous glutamate: the up-regulation of NMDA receptors allows for the accumulation of toxic levels of intracellular Ca(2+) under normal physiological conditions. Systems biology, as applied to toxicology, provides a framework in which information can be arranged in the form of a biological model. In our ketamine model, for example, blockade of NMDA receptor up-regulation by the co-administration of antisense oligonucleotides that specifically target NMDA receptor NR1 subunit mRNA, dramatically diminishes ketamine-induced cell death. Preliminary gene expression data support the role of apoptosis as a mode of action of ketamine-induced neurotoxicity. In addition, ketamine-induced cell death is also prevented by the inhibition of NF-kappaB translocation into the nucleus. This process is known to respond to changes in the redox state of the cytoplasm and has been shown to respond to NMDA-induced cellular stress. Although comprehensive gene expression/proteomic studies and mathematical modeling remain to be carried out, biological models have been established in an iterative manner to allow for the confirmation of biological pathways underlying NMDA antagonist-induced cell death in the developing nonhuman primate and rodent. Published in 2007 John Wiley& Sons, Ltd.

Repeated Administration of Ketamine can Induce Hippocampal Neurodegeneration and Long-Term Cognitive Impairment via the ROS/HIF-1a Pathway in Developing Rats

“…The resulting enhancement of the activation of the NMDA receptors causes excitotoxicity and an increase in calcium influx [11,12]. Because calcium is an important secondary messenger, a disturbance in its homeostasis leads to aberrant activation of downstream molecular pathways, including excessive mitochondrial ROS generation, which can activate apoptotic pathways [4,6,8,9,10,11,12,13,14]. However, the downstream molecular signals leading from excessive mitochondrial ROS generation to ketamine-induced apoptosis are not well understood.…”

“…Excessive stimulation of NMDA receptors causes the accumulation of intracellular calcium to toxic concentrations. Such an increase in calcium load, beyond the buffering capacity of the mitochondria, causes an increase in the generation of reactive oxygen species (ROS), depolarization of the mitochondrial membrane and activation of the apoptotic cascade [4,6,8,9,10,11,12,13,14]. Although neuroapoptosis might be the final outcome of an excitotoxic insult in the developing brain, the molecular pathways leading from mitochondrial dysfunction and ROS generation to apoptosis are not completely understood [11].…”

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

“…Reports also show that exposure of the developing brain to a clinically relevant cocktail of anesthetics that has both NMDA antagonist and GABA mimetic properties results in an extensive pattern of neuroapoptosis, and subsequent cognitive deficits (Olney et al, 2002b). Several reports have illustrated that ketamine can induce neuronal apoptosis when administered in high doses and/or for prolonged durations during susceptible periods of development in rodents (Maxwell et al, 2006;Olney et al, 2002a;Wang et al, 2005) and primates (Haberny et al, 2002;Slikker et al, 2007a;Wang et al, 2006) and these effects can manifest on later disruptions in cognitive function (Paule et al, 2011). To minimize risks to children exposed to anesthesia, it is paramount to understand how anesthetic drugs affect the developing nervous system and whether those effects can be ameliorated or prevented.…”

Consensus statement understanding health and malnutrition through a systems approach: the ENOUGH program for early life

“…We now understand that pathways interact with regulatory elements, with one another, and with systems critical to the endocrine, circulatory, digestive, nervous, and immune function (Afacan et al 2012;MacLellan et al 2012;Slikker et al 2007;van Ommen et al 2008a, b;Zhao et al 2012). As an example, a map of the central immunity pathway linking the toll-like receptor 4 to the transcription factor NFjB (a master regulator responsive to nutrients) contains only 20 core components, but adding just the main interacting elements of these 20 core proteins expands the network to more than 800 proteins (Gardy et al 2009).…”