Synthetic pyrethroids, an important class of neurotoxic insecticides used worldwide in agriculture and public health, cause toxic effects in animals by modifying the normal function of voltage-sensitive sodium channels. Sodium channels in mammalian tissues exist as multiple isoforms that exhibit differential tissue distribution and developmental regulation and are encoded by members of a multigene family. Previous studies of pyrethroid action have not considered the differential sensitivity of sodium channel isoforms as a determining factor in the toxicity of these compounds. The proposed research will test the hypothesis that differences in the pyrethroid sensitivity of mammalian sodium channel isoforms are important determinants of the nature and severity of pyrethroid intoxication. Specific experimental aims are: (1) to define the actions of pyrethroid insecticides on cloned rat sodium channel isoforms expressed in frog (Xenopus laevis) oocytes or transfected mammalian cells;(2) to compare the actions of pyrethroids on orthologous rat and human sodium channel isoforms expressed in Xenopus oocytes or trnasfected mammalian cells;and (3) to map the the structural determinants of pyrethroid action by the construction, functional expression and pharmacological characterization of specifically mutated sodium channels. Cloned sodium channel isoforms will be expressed in Xenopus oocytes or transiently transfected mammalian cells (e.g., HEK-293) and the actions of pyrethroid insecticides on expressed channels will be assessed using electrophysiological recordings of macroscopic sodium currents under two-electrode voltage-clamp or whole cell patch-clamp conditions. Structural determinants of pyrethroid sensitivity will be identified by site-directed mutagenesis, expression, and pharmacological comparison of native a mutated sodium channel isoforms. Results of these studies will define the role of different sodium channel isoforms in pyrethroid toxicity, establish whether rat sodium channels are valid toxicological models for the sensitivity of human sodium channels to pyrethroids, and identify sodium channel domains that determine pyrethroid sensitivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013686-05
Application #
8016700
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Kirshner, Annette G
Project Start
2007-04-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$251,459
Indirect Cost
Name
Cornell University
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Soderlund, David M; Tan, Jianguo; He, Bingjun (2016) Functional reconstitution of rat Nav1.6 sodium channels in vitro for studies of pyrethroid action. Neurotoxicology :
He, Bingjun; Soderlund, David M (2016) Effects of the β1 auxiliary subunit on modification of Rat Na(v)1.6 sodium channels expressed in HEK293 cells by the pyrethroid insecticides tefluthrin and deltamethrin. Toxicol Appl Pharmacol 291:58-69
He, Bingjun; Soderlund, David M (2014) Functional expression of Rat Nav1.6 voltage-gated sodium channels in HEK293 cells: modulation by the auxiliary β1 subunit. PLoS One 9:e85188
McCavera, Samantha J; Soderlund, David M (2012) Differential state-dependent modification of inactivation-deficient Nav1.6 sodium channels by the pyrethroid insecticides S-bioallethrin, tefluthrin and deltamethrin. Neurotoxicology 33:384-90
Soderlund, David M (2012) Molecular mechanisms of pyrethroid insecticide neurotoxicity: recent advances. Arch Toxicol 86:165-81
Tan, Jianguo; Soderlund, David M (2011) Independent and joint modulation of rat Nav1.6 voltage-gated sodium channels by coexpression with the auxiliary β1 and β2 subunits. Biochem Biophys Res Commun 407:788-92
Tan, Jianguo; Choi, Jin Sung; Soderlund, David M (2011) Coexpression with Auxiliary ýý Subunits Modulates the Action of Tefluthrin on Rat Na(v)1.6 and Na(v)1.3 Sodium Channels. Pestic Biochem Physiol 101:256-264
He, Bingjun; Soderlund, David M (2011) Differential state-dependent modification of rat Na(v)1.6 sodium channels expressed in human embryonic kidney (HEK293) cells by the pyrethroid insecticides tefluthrin and deltamethrin. Toxicol Appl Pharmacol 257:377-87
Tan, Jianguo; Soderlund, David M (2011) Actions of Tefluthrin on Rat Na(v)1.7 Voltage-Gated Sodium Channels Expressed in Xenopus Oocytes. Pestic Biochem Physiol 101:21-26
Tan, Jianguo; Soderlund, David M (2010) Divergent actions of the pyrethroid insecticides S-bioallethrin, tefluthrin, and deltamethrin on rat Na(v)1.6 sodium channels. Toxicol Appl Pharmacol 247:229-37

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