Citation:

Kodavanti, P. Novel Methods at Molecular Level for Neurotoxicity Testing in 21st Century-Utility of Structure-Activity Relationship. 10th Annual Convention of Association of Biotechnology and Pharmacy and International Conference on, Tirupati, Andhra Pradesh, INDIA, December 21 - 23, 2016.

Impact/Purpose:

The objective is to develop in vitro models for neurotoxicity and developmental neurotoxicity testing using novel techniques at molecular level. This attempt will reduce large number of animal toxicity testing and cost-effective. These models will also be scientifically sound.

Description:

Current neurotoxicity and developmental neurotoxicity testing methods for hazard identification rely on in vivo neurobehavior, neurophysiological, and gross pathology of the nervous system. These measures may not be sensitive enough to detect small changes caused by realistic exposures to low concentrations of chemicals, are time consuming, expensive, and require large number of animals. In addition, there are more than 100,000 chemicals that need prioritization for further testing. It would be beneficial to develop cost-effective, rapid, reliable, and sensitive methods to detect neurotoxicity. Attempts to date have included medium throughput cell based assays of brain development such as proliferation, differentiation, apoptosis, and growth using the Cellomics ArrayScan as well as alternative species such as Medaka fish. However, we have focused on understanding the changes along the continuum from the molecular level to cellular response to organ response to whole animal response and developing protein signatures with proteomic and modeling technologies for use in neurotoxicity screening. Our initial approach involved two structurally related neurotoxic chemicals, polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). PCBs are banned chemicals, but were used before as heat transfer fluids in transformers. PBDEs are structurally similar to PCBs with a similar number of congeners with different position and number of halogens. Both these chemicals are well established developmental neurotoxicants in both humans and animal models. At the functional level, effects include deficits in learning and memory as well as psychomotor disturbances. At structural levels, the effects include decreased neuronal branching pattern and dendritic growth. Our neuroproteomic data using 2-DIGE have revealed that proteins related to energy metabolism (ATP synthase, sub unit β, creatine kinase B-type, and malate dehydrogenase), calcium signaling (endoplasmic reticulum ATPase, voltage-dependent anion-selective channel protein 1, myristoylated alanine-rich-C-kinase, and Ryanodine receptor type II), and growth of the nervous system (valosin-containing protein, collapsin response mediator protein 3, Dihydropyrimidinase-related protein) were altered by developmental exposure to these two chemicals. Although different proteins were differentially expressed by PCBs and PBDEs, the pathways affected were similar, suggesting common adverse-outcome pathways within this extended family of chemicals. Studies should be extended to other neurotoxic chemicals to identify common protein signatures and pathways (This abstract does not necessarily reflect USEPA policy and this is not an official visit).

Record Details: