Developmental pyrethroid exposure causes a neurodevelopmental disorder phenotype in mice

Abstract

Neurodevelopmental disorders (NDDs) are a widespread and growing public health challenge, affecting as many as 17% of children in the United States. Recent epidemiological studies have implicated ambient exposure to pyrethroid pesticides during pregnancy in the risk for NDDs in the unborn child. Using a litter-based, independent discovery–replication cohort design, we exposed mouse dams orally during pregnancy and lactation to the Environmental Protection Agency's reference pyrethroid, deltamethrin, at 3 mg/kg, a concentration well below the benchmark dose used for regulatory guidance. The resulting offspring were tested using behavioral and molecular methods targeting behavioral phenotypes relevant to autism and NDD, as well as changes to the striatal dopamine system. Low-dose developmental exposure to the pyrethroid deltamethrin (DPE) decreased pup vocalizations, increased repetitive behaviors, and impaired both fear conditioning and operant conditioning. Compared with control mice, DPE mice had greater total striatal dopamine, dopamine metabolites, and stimulated dopamine release, but no difference in vesicular dopamine capacity or protein markers of dopamine vesicles. Dopamine transporter protein levels were increased in DPE mice, but not temporal dopamine reuptake. Striatal medium spiny neurons showed changes in electrophysiological properties consistent with a compensatory decrease in neuronal excitability. Combined with previous findings, these results implicate DPE as a direct cause of an NDD-relevant behavioral phenotype and striatal dopamine dysfunction in mice and implicate the cytosolic compartment as the location of excess striatal dopamine.

Developmental pyrethroid exposure disrupts molecular pathways for MAP kinase and circadian rhythms in mouse brain

“…To follow up on these correlational findings in humans, mouse models of pyrethroid exposure have been developed 11,[17][18][19][20][21][22][23][24] . These models have established that exposure in mice to the pyrethroid deltamethrin during pregnancy and lactation at doses well below the EPA benchmark dose of 14.5 mg/kg is sufficient to cause broad male-biased changes in the brain and behavior of the resulting offspring.…”

Developmental pyrethroid exposure in mouse leads to disrupted brain metabolism in adulthood

“…Disruption of circadian rhythms and sleep are among the most common comorbidities in developmental disorders 78,79 . Finally, retinoic acid is highly expressed in the dopamine system and is a key regulator of dopamine synthesis and signaling 80,81 , both of which are disrupted in DPE mice 20,36 . Thus, our non-biased metabolomics study adds to the literature highlighting retinol and tryptophan metabolism as worthy targets for future investigations into the long-term effects of developmental pyrethroid exposure.…”

“…The use of a single dose of deltamethrin is also a key limitation. The 3 mg/kg dose was chosen because it is below the EPA-determined benchmark dose of 14.5 mg/kg for humans and is sufficient to cause a wide range of behavioral, transcriptional, and proteomic changes in mice 20,29,32,36 . Nonetheless, a careful look at dose-dependent effects of DPE is a critical next step.…”

“…Deltamethrin exposure in mice during pregnancy and lactation at doses well below the Environmental Protection Agency (EPA) benchmark dose of 14.5 mg/kg is sufficient to cause a broad range of changes in the brain and behavior of the offspring. Behaviorally, deltamethrin exposure during development results in male-biased hyperactivity, repetitive behaviors, reduced vocalizations, impulsivity, and learning deficits 20,25 . In the brain, developmental deltamethrin exposure leads to broad changes in striatal dopamine signaling, altered levels of voltage-gated sodium channels, elevated endoplasmic reticulum stress, altered brain-derived neurotrophic factor (BDNF) levels, and changes in molecular pathways for circadian rhythms and synaptic plasticity [26][27][28][29][30][31][32] .…”

“…In this study, we exposed pregnant mouse dams to a low level of deltamethrin (3 mg/kg every 3 days) throughout pregnancy and lactation. This dose was chosen based on prior studies showing behavioral and neurological effects in offspring at this developmental dose 20,32,36 and because it is substantially lower than the EPA-determined benchmark dose 19 . Because developmental pyrethroid exposure (DPE) is a whole-body manipulation, we chose the whole brain as our level of investigation, and we performed untargeted high-resolution metabolomics on whole-brain tissue collected from the resulting adult male offspring.…”