Systems Toxicology & Health Risk Assessment

Overview

Humans are exposed to many chemicals in the form of drugs but also through the environment. In order to understand the risk to human health of drug and chemical exposure, it is necessary to understand how these xenobiotics may affect normal cellular processes and so lead to toxicological consequence. The advent of high throughput genomic screens has led to the possibility of much greater breadth of understanding of the effect of xenobiotics in biological systems. Furthermore there has been interest in the possibility of using the output of these genomic assays as a signature of xenobiotic exposure, and thus as a test procedure for the recognition of toxicological hazard. Systems Toxicology and Health Risk Assessment aims to apply a system biology approach to describe and predict the effects of chemicals and other environmental stressors at different levels of biological organisation and identify key events leading to adverse health outcomes. The group aims to study the perturbation of biological systems by chemicals and stressors, monitoring changes in molecular expression and conventional toxicological parameters, iteratively integrating data to achieve a mechanistic understanding of the specific toxicity, and eventually develop and validate biomarkers for predicting these toxicological responses. The development of an integrated framework through the identification of toxicological pathways and data analysis tools is an integral part of the overall attempt to understand the adverse effects of chemicals and other stressors on human health and the environment. Particular focus will be placed on the development, assessment and application of methods for assessing the adverse effects of environmental chemicals. This will include the development and evaluation of Integrated Testing Strategies to describe all the toxicological interactions that occur within a living system under stress and use our knowledge of toxicogenomic responses in one species to predict the modes-of-action of similar agents in other species.

Mission and goals
Systems toxicology group attempts to integrate the traditional methods of experimental toxicology with high throughput systems and with data analysis and modelling tools to allow for a more sensitive and earlier identification of adverse effects for use in risk assessments, as well as in the development of novel biomarkers of exposure and effect.

Competencies

  • Environmental and Molecular Epidemiology.
  • Molecular mechanisms and predictive markers of neurotoxicity.
  • Molecular mechanisms of pulmonary injury & immunotoxicity.
  • Assessment of phototoxicity of chemicals.
  • Role of miRNAs in tumor development and control.
  • Biomarkers for health risk assessment.

Glimpses of current research

Determine/characterize cellular pathogenic mechanism of action of metals and pesticides on developing brain:

Epidemiological survey reveals that exposure to environmental metals and pesticides is a critical concern for the developing central nervous system (CNS). With this in mind, the toxic effect of metals and metal aggregates, and pesticides on developing CNS needs to be investigated. Genomics and proteomics based approaches are being used to identify the aberrations of CNS development when exposed to the metals and pesticides. Both animal and cell culture studies are being performed for the purpose.

Mechanism of sporadic and pesticides induced Parkinson's disease and development of molecular fingerprints:

Microarray and proteomics approaches are being utilized to understand the molecular mechanism of sporadic and pesticides induced PD, to develop signature fingerprints/biomarkers for an early diagnosis and to establish the mechanism of caffeine/nicotine mediated neuroprotection.

Developmental neurotoxicity of pesticides:

Exposure to environmental chemicals such as pesticides during early fetal development can cause brain injury at doses much lower than that affecting adult brain function and can even lead to irreversible changes in the brain. Studies are being therefore pursued to investigate the molecular mechanism of vulnerability of brain to low levels exposure to cypermethrin (CP), a type II synthetic pyrethroid, lindane, an organochlorine pesticide and monocrotophos (MCP), an organophosphate insecticide, during critical period of brain development in rat and develop and validate in vitro model for developmental neurotoxicity.

Role of microRNA in neuronal cell differentiation and their regulation in pesticide induced neurotoxicity:

Recent studies have indicated that miRNAs are involved in specific neuronal functions and are rapidly emerging as key regulators of neuronal development and function. However, the regulation of miRNAs expression during neuritogenesis and identification of their target proteins remains to be understood. In vitro approaches are better suited to investigate the role of these small RNAs in neuritogenesis. Further, the effect of potential developmental neurotoxins like cypermethrin on expression of neuritogenesis regulating miRNAs at different stages of differentiation in an in vitro model (NGF differentiated PC12 cells) is being pursued to identify the role of miRNAs in developmental neurotoxicity.

Heavy metal toxicity and therapeutic intervention strategies:

Oxidative stress is one of the underlying mechanisms of cell death caused by heavy metals (cadmium and tributyltn chloride) in the immune and testicular cells of rodents. Investigations on various cellular markers of oxidative stress and apoptosis both in vitro and in vivo reveal the critical role played by ROS in modulating apoptosis. The involvement of MAP kinases upstream of mitochondrial dysfunction dissects the signaling cascade of events leading to heavy metal induced toxicity.

Phototoxicity Assessment of polycyclic aromatic hydrocarbons (PAHs):
likely to induce phototoxic responses including skin cancer. Polycyclic aromatic hydrocarbons (PAHs) readily absorb sunlight in UV and visible range and are sensitive to photochemical effects. The phototoxic potential of benz(a)anthracene, pyrene, benzanthrone and anthracene is being evaluated by irradiating under environment intensities of UV-A(2.2mW/cm2) and UV-B(0.9mW/cm2). The photoxicity is assessed by studying the solubility, absorption spectra, photodegradation, generation of reactive oxygen species (ROS) like (1O2) and (O- 2), degradation of 2, deoxyguanosine and cell viability.

Identifying the role of different signal molecules in the onset and development of asthma:
The mechanism of airway injury is being investigated following repeated exposure to allergen. The data has revealed overexpression of SOCS3 gene and under-expression of stat3 gene that may be associated with airway dysfunction following repeated exposure to antigens. Presently, the mechanism as to how SOCS3 is under-expressed in normal condition and overexpressed in cell lines and lung tissues after prolonged exposure is being dissected out by looking at the methylation status of the CpG island of the promoter region of the SOCS3 gene.

Predictive toxicity portal for industrial and environmental chemicals:
Current research focus is to develop a decision support system for health risk assessment by integrating diagnostic tools based on artificial neural network, support vector machine and fuzzy logics for common diseases. Construction of a predictive toxicity portal for industrial and environmental chemicals and their mixtures/ novel materials/ metals is also in process.

Facilities:

  • Tissue Culture Facility
  • Neurobehavioral Facility
  • Medium Throughput Facility for receptor binding
  • Microarray Facility
  • Protein Sequencer

Scientists involved:
Prof Alok Dhawan Dr. V.K. Khanna Dr. A.B. Pant
Dr. R.K. Chaturvedi Dr. B.N. Paul Dr. R.S. Ray
Dr. (Mrs.) Chetna Singh Dr. (Mrs.) S. Bandyopadhya Dr. Devendra Parmar
Dr. S.K. Gupta (on leave) Dr. C. Kesavachandran Dr. Sanjay Yadav
Dr. M.P. Singh
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