A pesticide that disrupts the endocannabinoid system made developing rat pups less anxious | Research

The takeaway

Rat pups exposed to low doses of the pesticide chlorpyrifos during development showed elevated endocannabinoid levels and decreased anxiety-like behavior, even at doses too low to cause traditional neurotoxicity.

Read this if you want to understand how environmental chemicals can alter behavior through the endocannabinoid system.

Endocannabinoid disruption and altered anxiety at doses showing no traditional neurotoxicity

What the researchers found

Rat pups exposed to chlorpyrifos (CPF) daily from postnatal day 10 to 16 at doses of 0.5, 0.75, and 1.0 mg/kg showed inhibition of FAAH (the enzyme that breaks down anandamide) at all doses, leading to elevated anandamide levels. At 0.75 and 1.0 mg/kg, 2-AG was also elevated.

At the two lower doses (0.5 and 0.75 mg/kg), FAAH was inhibited without any measurable cholinesterase inhibition in the brain, meaning the endocannabinoid disruption occurred below the threshold for traditional neurotoxicity.

When tested at day 25 (about 9 days after the last exposure), all CPF-treated groups showed significantly decreased anxiety-like behavior, spending less time in a dark container before emerging into a brightly lit open field.

Why it matters

This study demonstrates that common pesticide exposure can alter anxiety behavior through the endocannabinoid system at doses considered "safe" by traditional neurotoxicity standards. It highlights that the endocannabinoid system may be a more sensitive target for environmental chemicals than the cholinergic system currently used to set safety limits.

The numbers in context

All doses (0.5, 0.75, 1.0 mg/kg): FAAH inhibited, anandamide elevated, anxiety decreased. 0.5-0.75 mg/kg: no brain cholinesterase inhibition. 2-AG elevated at 0.75 and 1.0 mg/kg. Palmitoylethanolamide and oleoylethanolamide (other FAAH substrates) also elevated at all doses.

How the study worked

Rat pups received daily oral doses of chlorpyrifos or corn oil vehicle from day 10 to 16. At 12 hours after the last dose, brain FAAH, MAGL, cholinesterase activity, and endocannabinoid levels were measured. On day 25, anxiety was assessed using an emergence test (latency to leave a dark container into a lit novel environment).

What this study cannot tell us

Animal study with direct oral dosing that may not reflect environmental human exposure. The anxiety test measured one dimension of behavior at one timepoint. "Decreased anxiety" is not necessarily beneficial; it could reflect altered risk assessment. The study did not follow animals into adulthood to assess persistence.

How to read the evidence

Controlled animal study with clear dose-response data. Demonstrates the principle but uses pesticide doses and delivery methods different from typical human exposure.

When this study was published

Published in 2017. Research on environmental endocannabinoid disruption continues to build the case for revising toxicity testing standards.

The bigger picture

The endocannabinoid system regulates anxiety, and disrupting it during development can produce lasting behavioral changes. If pesticides routinely used in agriculture alter this system at sub-toxic doses, current safety standards may not protect developing children from neurobehavioral effects mediated through cannabinoid pathways.

Questions still open

Is the decreased anxiety adaptive or maladaptive? Do these effects persist into adulthood? Could children exposed to pesticides show altered anxiety regulation? Should endocannabinoid system endpoints be included in pesticide safety testing?

Common questions

What does a pesticide have to do with anxiety?

The pesticide chlorpyrifos inhibits the enzymes that break down the body's natural cannabinoids (endocannabinoids), causing them to accumulate. Since endocannabinoids regulate anxiety, this accumulation altered anxiety-related behavior in developing rats.

Is less anxiety a good thing?

Not necessarily. While reduced anxiety sounds positive, appropriate anxiety is protective. It helps organisms avoid dangers. Altered anxiety during development could impair risk assessment and lead to inappropriate behavior in dangerous situations.

Read the original research

Decreased anxiety in juvenile rats following exposure to low levels of chlorpyrifos during development.

Neurotoxicology, 59, 183-190

View on PubMed ↗Publisher’s paper ↗

Citation

Carr, Russell L; Armstrong, Nathan H; Buchanan, Alenda T; Eells, Jeffrey B; Mohammed, Afzaal N; Ross, Matthew K; Nail, Carole A. (2017). Decreased anxiety in juvenile rats following exposure to low levels of chlorpyrifos during development.. Neurotoxicology, 59, 183-190. https://doi.org/10.1016/j.neuro.2015.11.016