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Developmentally-regulated sodium channel subunits are differentially sensitive to alpha-cyano containing pyrethroids
Connie A Meacham1, Peter D Brodfuehrer, Jennifer A Watkins
1Neurotoxicology Division, NHEERL, ORD, U.S. Environmental Protection Agency, RTP, NC 27711, USA.
Insights
Juvenile rats show higher sensitivity to deltamethrin neurotoxicity due to age-related differences in voltage-gated sodium channel (Nav) isoforms. Specifically, embryonic Na(v)1.3/beta(3) channels are more susceptible to pyrethroids than adult Na(v)1.2/beta(1) channels.
Area of Science:
- Neuroscience
- Toxicology
- Molecular Biology
Background:
- Juvenile rats exhibit increased sensitivity to deltamethrin neurotoxicity compared to adults.
- While toxicokinetic factors are known, age-dependent toxicodynamic differences in pyrethroid toxicity remain unexplored.
- Voltage-gated sodium channels (Nav), the primary targets of pyrethroids, consist of alpha and beta subunits with developmentally regulated isoforms.
Purpose of the Study:
- To investigate potential toxicodynamic differences in voltage-gated sodium channels (Nav) that may explain age-dependent deltamethrin toxicity.
- To compare the effects of deltamethrin on different combinations of rat Nav alpha (Na(v)1.2, Na(v)1.3) and beta (beta(1), beta(3)) subunits.
Main Methods:
- Xenopus laevis oocytes were injected with various combinations of rat Nav alpha and beta subunits.
- Deltamethrin's effects on sodium currents were measured across different subunit combinations and concentrations.
- Structure-activity relationships were assessed using other pyrethroids (permethrin, tetramethrin, cypermethrin, beta-cyfluthrin, esfenvalerate, fenpropathrin).
Main Results:
- Deltamethrin induced concentration-dependent tail currents and modified channels in all tested isoform combinations.
- Channels containing the Na(v)1.3 subunit were more affected by deltamethrin than those with Na(v)1.2.
- The presence of a beta subunit, particularly beta(3), significantly enhanced deltamethrin's effects, especially on Na(v)1.3/beta(3) channels compared to Na(v)1.2/beta(1).
- Other pyrethroids, including cypermethrin and esfenvalerate, showed greater effects on Na(v)1.3/beta(3) than Na(v)1.2/beta(1) channels.
Conclusions:
- Age-dependent toxicodynamic differences in Nav subunit composition contribute to varying deltamethrin sensitivity.
- The Na(v)1.3/beta(3) subunit combination, prevalent in embryonic development, exhibits higher sensitivity to deltamethrin and related pyrethroids compared to the adult-predominant Na(v)1.2/beta(1) combination.
- These findings highlight the role of specific Nav isoforms in mediating pyrethroid neurotoxicity across different developmental stages.
Abstract:
Juvenile rats have been reported to be more sensitive to the acute neurotoxic effects of the pyrethroid deltamethrin than adults. While toxicokinetic differences between juveniles and adults are documented, toxicodynamic differences have not been examined. Voltage-gated sodium channels, the primary targets of pyrethroids, are comprised of alpha and beta subunits, each of which have multiple isoforms that are expressed in a developmentally-regulated manner. To begin to test whether toxicodynamic differences could contribute to age-dependent deltamethrin toxicity, deltamethrin effects were examined on sodium currents in Xenopus laevis oocytes injected with different combinations of rat alpha (Na(v)1.2 or Na(v)1.3) and beta (beta(1) or beta(3)) subunits. Deltamethrin induced tail currents in all isoform combinations and increased the percent of modified channels in a concentration-dependent manner. Effects of deltamethrin were dependent on subunit combination; Na(v)1.3-containing channels were modified to a greater extent than were Na(v)1.2-containing channels. In the presence of a beta subunit, deltamethrin effects were significantly greater, an effect most pronounced for Na(v)1.3 channels; Na(v)1.3/beta(3) channels were more sensitive to deltamethrin than Na(v)1.2/beta(1) channels. Na(v)1.3/beta(3) channels are expressed embryonically, while the Na(v)1.2 and beta(1) subunits predominate in adults, supporting the hypothesis for age-dependent toxicodynamic differences. Structure-activity relationships for sensitivity of these subunit combinations were examined for other pyrethroids. Permethrin and tetramethrin did not modify currents mediated by either subunit combination. Cypermethrin, beta-cyfluthrin, esfenvalerate and fenpropathrin all modified sodium channel function; effects were significantly greater on Na(v)1.3/beta(3) than on Na(v)1.2/beta(1) channels. These data demonstrate a greater sensitivity of Na(v)1.3 vs Na(v)1.2 channels to deltamethrin and other cyano-containing pyrethroids, particularly in the presence of a beta subunit.
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