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

Abstract

Exposure to chlorpyrifos (CPF) during the late preweanling period in rats inhibits the endocannabinoid metabolizing enzymes fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL), resulting in accumulation of their respective substrates anandamide (AEA) and 2-arachidonylglycerol (2-AG). This occurs at 1.0 mg/kg, but at a lower dosage (0.5 mg/kg) only FAAH and AEA are affected with no measurable inhibition of either cholinesterase (ChE) or MAGL. The endocannabinoid system plays a vital role in nervous system development and may be an important developmental target for CPF. The endocannabinoid system plays an important role in the regulation of anxiety and, at higher dosages, developmental exposure to CPF alters anxiety-like behavior. However, it is not clear whether exposure to low dosages of CPF that do not inhibit ChE will cause any persistent effects on anxiety-like behavior. To determine if this occurs, 10-day old rat pups were exposed daily for 7 days to either corn oil or 0.5, 0.75, or 1.0 mg/kg CPF by oral gavage. At 12 h following the last CPF administration, 1.0 mg/kg resulted in significant inhibition of FAAH, MAGL, and ChE, whereas 0.5 and 0.75 mg/kg resulted in significant inhibition of only FAAH. AEA levels were significantly elevated in all three treatment groups as were palmitoylethanolamide and oleoylethanolamide, which are also substrates for FAAH. 2-AG levels were significantly elevated by 0.75 and 1.0 mg/kg but not 0.5 mg/kg. On day 25, the latency to emerge from a dark container into a highly illuminated novel open field was measured as an indicator of anxiety. All three CPF treatment groups spent significantly less time in the dark container prior to emerging as compared to the control group, suggesting a decreased level of anxiety. This demonstrates that repeated preweanling exposure to dosages of CPF that do not inhibit brain ChE can induce a decline in the level of anxiety that is detectable during the early postweanling period.

Developmental neurotoxicity of succeeding generations of insecticides

“…Importantly, there are sex-selective effects of decreased responsiveness to the muscarinic antagonist scopolamine on radial-arm maze reference memory performance in females (Levin and others 2001). Increased aggressive behavior was seen in CPF-exposed males, increased maternal responsiveness toward pups in CPF-exposed virgin females and reduced anxiety levels and motivation to build the nest and defend it from a male intruder in lactating females (Carr and others 2015; Ricceri and others 2003; Ricceri and others 2006; Venerosi and others 2008). Even though there are significant effects of exposure at late-postnatal stages, the comparison between distinct periods of brain development indicates that several of them tend to reduce in magnitude and fade during the course of postnatal development, which is consistent with evidence of higher susceptibility to OPs in younger animals.…”

Effects of low‐dose chlorpyrifos on neurobehavior and potential mechanisms: A review of studies in rodents, zebrafish, and Caenorhabditis elegans

“…6). Postnatal CPF treatment at 0.5 mg kg −1 day −1 decreased anxiety in juvenile rats and yielded effects on the endocannabinoid system at a dose lower than that inhibitory for brain AChE (Carr et al, ).…”

“…Two of three studies that measured brain AChE inhibition reported that gavage CPF administration from PND 10–16 (Carr et al, ) or CPF sc injection from PND 11–14 (Ricceri et al, ) showed significant brain AChE inhibition only at doses higher than those eliciting significant anxiety effects. Treatment of rat pups with CPF sc injections at 1.0 mg kg −1 day −1 from PND 1–4, which showed anxiety effects, also showed brain AChE inhibition; however, this was the lowest dose tested.…”

“…Brain AChE was not inhibited in Long‐Evans rats tested using the MWM (LOEL: 0.3 mg kg −1 day −1 ) after receiving CPF treatment on PND 7, 11, and 15 (Dam et al, ). Pups treated on PND 10–16 had decreased anxiety at 0.5 mg kg −1 day −1 while the LOEL for brain AChE inhibition (19%) was 1.0 mg kg −1 day −1 (Carr et al, ). There was a 20–23% inhibition of brain AChE in Swiss CD‐1 mice that showed both positive and negative social behavior effects after receiving treatment from PND 1–4 (Ricceri et al, ).…”

“…For example, decreased locomotor activity, neuromotor function (NMF), cognition, anxiety/depression, and social behaviors induced by CPF exposure to children during early development could be modeled in rodents. In rodents, CPF exposure during critical neurodevelopment stages has been associated with disruptions in the endocannabinoid (Buntyn et al, ; Carr et al, ; Carr, Alugubelly, & Mohammed, , chap. 5; Qiao, Seidler, & Slotkin, ; Qiao, Seidler, Tate, Cousins, & Slotkin, ; Zheng, Olivier, Won, & Pope, ), dopaminergic (Aldridge, Meyer, Seidler, & Slotkin, ), and serotonergic systems (Aldridge, Levin, Seidler, & Slotkin, ; Aldridge, Seidler, Meyer, Thillai, & Slotkin, ; Aldridge, Seidler, & Slotkin, ).…”