Dose-dependent regional brain acetylcholinesterase and acylpeptide hydrolase inhibition without cell death after chlorpyrifos administration

Abstract

-Organophosphates (OPs) are important toxic compounds commonly used for a variety of purposes in agriculture, industry and household settings. It has been well established that the main mechanism of acute toxic action of OP is the inhibition of acetylcholinesterase (AChE). However, we observed long term deficit after acute subcutaneous exposure to Chlorpyrifos (CPF) even when AChE activity is restored. In fact, besides AChE inhibition, non-AChE targets have also been proposed as an alternative mechanism involved in the acute lethal action and side effects of short or long-term exposure. In this context, our main aim in this research was to establish a dose-response curve of Acylpeptide hydrolase (APH) and AChE regional brain activity after acute CPF administration that could explain these long term effects observed in the literature. Moreover, since available data suggest that long term effects of OPs exposure could involve neuronal cell death, our second aim was to evaluate, assessing by Fluoro-Jade B (FJB) staining, whether CPF produces induced cell death. Our results show that an acute exposure to 250 mg/kg CPF does not induce neuronal death as measured by FJB but produces highest AChE regional brain inhibition after administration. In addition, APH seems to be more sensitive than AChE to CPF exposure because after 31 days of exposure, complete recovery was seen only for APH activity at Frontal Cortex, Cerebellum and Brain Stem.

Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition

“…It is located in the synaptic region (Sandoval et al, 2012) and its inhibition by dichlorvos has been demonstrated to enhance long term potentiation in hippocampal slices (Olmos et al, 2009). While exposure to CPF results in higher levels of ChE inhibition than APH inhibition in the early periods following exposure, the inhibition of APH is much more persistent than is that of AChE (Quistad et al, 2005; Cardona et al, 2013; Lopez-Granero et al, 2013a). However, subsequent long term behavioral studies involving either a high dose acute exposure or a chronic feeding exposure to CPF did not find any association between APH activity and cognitive deficits observed (Lopez-Granero et al, 2013b; 2014).…”

Identification of metabolite biomarkers in serum of rats exposed to chlorpyrifos and cadmium

“…Interestingly, CPF and Cd have very different modes of action in the organisms. CPF inhibits the activity of acetylcholinesterase 25,26 . Cd causes the nephrotoxicity in the body 27,28 .…”

Metabolomic analysis for combined hepatotoxicity of chlorpyrifos and cadmium in rats

“…Thus, more attention needs to be given to the combined toxicity of CPF and Cd. CPF mainly inhibited the activity of acetylcholinesterase (Reiss et al, 2012;Cardona et al, 2013). Cd accumulated in the body and led to the nephrotoxicity (Johri et al, 2010).…”