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Published on: June 10, 2020
Folate prevents the autism-related phenotype caused by developmental pyrethroid exposure in prairie voles
Nilanjana Saferin1, Ibrahim Haseeb2, Adam M Taha3
1Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
Insights
Developmental pyrethroid pesticide exposure (DPE) causes neurodevelopmental deficits by altering folate metabolism. Maternal folate supplementation effectively reduced these effects in offspring, highlighting a potential preventative strategy for environmental risk factors.
Area of Science:
- Environmental toxicology
- Neuroscience
- Developmental biology
Background:
- Neurodevelopmental disorders (NDDs) affect 1 in 6 children, with causes often unclear.
- Developmental exposure to pyrethroid pesticides is an emerging environmental risk factor for NDDs.
- Previous research linked low-dose chronic pyrethroid exposure to altered folate metabolites in the brain.
Purpose of the Study:
- To investigate if developmental pyrethroid exposure (DPE) directly impacts folate metabolism.
- To determine if high-dose maternal folate supplementation can prevent or mitigate DPE-induced biobehavioral effects.
- To examine the effects of DPE and folate supplementation on specific folate pathway enzymes and proteins.
Main Methods:
- Pregnant prairie voles were exposed to deltamethrin (a pyrethroid pesticide) with or without methylfolate supplementation.
- Offspring behavior was assessed across five domains relevant to NDDs.
- Plasma folate levels and neural expression of folate-related proteins (SHMT1, FOLR1, MTHFR) were analyzed.
Main Results:
- DPE offspring exhibited significant behavioral deficits, increased plasma folate, and elevated neural SHMT1 expression.
- Maternal folate supplementation prevented most behavioral deficits, except for repetitive behaviors.
- Folate supplementation induced compensatory changes in neural FOLR1 and MTHFR expression.
Conclusions:
- Developmental pyrethroid exposure induces NDD-relevant behavioral deficits and alters folate metabolism.
- Maternal folate supplementation serves as an effective preventative intervention, reducing but not fully eliminating DPE's behavioral effects.
- Targeting folate metabolism offers a promising strategy for mitigating environmental risks associated with NDDs.
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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