Folate prevents the autism-related phenotype caused by developmental pyrethroid exposure in prairie voles

Saferin, N.; Haseeb, I.; Taha, A.; Beecroft, S.; Pillai, S.; Neifer, A. E.; Lakkuru, R.; Kistler, B. P.; Nawor, C. N.; Malik, I.; Hasan, D.; Carlson, J. A.; Zade, K. K.; Shah, R.; Gautam, S.; Vergis, J.; Neifer, K. L.; Johnson, Z. V.; Gustison, M. L.; Hall, F. S.; Burkett, J. P.

doi:10.1101/2024.11.25.625285

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bioRxiv · 10.1101/2024.11.25.625285

Folate prevents the autism-related phenotype caused by developmental pyrethroid exposure in prairie voles

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Abstract

Neurodevelopmental disorders (NDDs) have dramatically increased in prevalence to an alarming one in six children, and yet both causes and preventions remain elusive. Recent human epidemiology and animal studies have implicated developmental exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US, as an environmental risk factor for autism and neurodevelopmental disorders. Our previous research has shown that low-dose chronic developmental pyrethroid exposure (DPE) changes folate metabolites in the adult mouse brain. We hypothesize that DPE acts directly on molecular targets in the folate metabolism pathway, and that high-dose maternal folate supplementation can prevent or reduce the biobehavioral effects of DPE. We exposed pregnant prairie vole dams chronically to vehicle or low-dose deltamethrin (3 mg/kg/3 days) with or without high-dose folate supplementation (methylfolate, 5 mg/kg/3 days). The resulting DPE offspring showed broad deficits in five behavioral domains relevant to neurodevelopmental disorders (including the social domain); increased plasma folate concentrations; and increased neural expression of SHMT1, a folate cycle enzyme. Maternal folate supplementation prevented most of the behavioral phenotypes (except for repetitive behaviors) and caused potentially compensatory changes in neural expression of FOLR1 and MTHFR, two folate-related proteins. We conclude that DPE causes neurodevelopmental disorder-relevant behavioral deficits; DPE directly alters aspects of folate metabolism; and preventative interventions targeting folate metabolism are effective in reducing, but not eliminating, the behavioral effects of DPE.

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Saferin, N., Haseeb, I., Taha, A., Beecroft, S., Pillai, S., Neifer, A. E., Lakkuru, R., Kistler, B. P., Nawor, C. N., Malik, I., Hasan, D., Carlson, J. A., Zade, K. K., Shah, R., Gautam, S., Vergis, J., Neifer, K. L., Johnson, Z. V., Gustison, M. L., Hall, F. S., Burkett, J. P.. 2024-11-25. Folate prevents the autism-related phenotype caused by developmental pyrethroid exposure in prairie voles. https://doi.org/10.1101/2024.11.25.625285

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