Low-level repeated exposure to diazinon and chlorpyrifos decrease anxiety-like behaviour in adult male rats as assessed by marble burying behaviour

Abstract

Occupational exposure to organophosphate (OPs) pesticides is reported to increase in the risk of developing anxiety and depression. Preclinical studies using OP levels, which inhibit acetylcholinesterase activity, support the clinical observations, but little is known of the effects of exposure below this threshold. We examined the effects of low level OP exposure on behaviours and neurochemistry associated with affective disorders. Adult rats were administered either diazinon (1 mg/kg i.p.) which is present in sheep dip and flea collars, chlorpyrifos (1 mg/kg i.p.) which is present in crop sprays, or vehicle for 5 days. OP exposure did not affect acetylcholinesterase activity (blood, cerebellum, caudate putamen, hippocampus, prefrontal cortex), anhedonia-like behaviour (sucrose preference), working memory (novel object recognition), locomotor activity or anxiety-like behaviour in the open field arena. In contrast OP exposure attenuated marble burying behaviour, an ethological measure of anxiety. The diazinon-induced reduction in marble burying persisted after exposure cessation. In comparison to vehicle, dopamine levels were lowered by chlorpyrifos, but not diazinon. 5-HT levels and turnover were unaffected by OP exposure. However, 5-HT transporter expression was reduced by diazinon suggesting subtle changes in 5-HT transmission. These data indicate exposure to occupational and domestic OPs, below the threshold to inhibit acetylcholinesterase, can subtly alter behaviour and neurochemistry.

Gene expression analysis reveals chronic low level exposure to the pesticide diazinon affects psychological disorders gene sets in the adult rat

“…We have previously reported that marble burying behaviour is a sensitive behavioural measure of low level OP exposure (Savy et al, 2015), and the current study supports this. Marble burying behaviour is frequently described as an ethological measure of anxiety in rodents and has been used to screen anxiolytic drugs in rodents (Broekkamp et al, 1986;Njung'e and Handley, 1991).…”

“…In addition, we assessed AChE and butrylcholinesterase (BChE) activity in blood and brain to determine if OP exposure was below the threshold to inhibit ChE activity, and also marble-burying behaviour during the chronic exposure period. Marble burying behaviour is an ethological measure of anxiety in rodents, and we have found that it is a sensitive behavioural measure of low level OP exposure (Savy et al, 2015).…”

“…Furthermore, the vast majority of genes altered by diazinon (n = 70) and chlorpyrifos (n = 50) were different, with chlorpyrifos significantly affecting genes encoding neurotrophins and neuropeptides such as brain-derived neurotrophic factor (Lee et al, 2016). As neurotrophins and neuropeptides are involved in neural development and psychological disorders it could be argued that that there may be a shared mechanism of action, but given the differences in gene expression and that low level exposure to diazinon and chlorpyrifos can have disparate neurochemical effects (Savy et al, 2015), diazinon may have neurological effects below the threshold for cholinesterase inhibition that chlorpyrifos does not.…”

“…Briefly, rats were placed in individual test cages containing a 5 cm layer of sawdust and 9 glass marbles arranged evenly at one end of the cage for 10 mins. The number of marbles buried, the latency to first dig, latency to bury the first marble, time spent in the marble half of the cage and frequency of rears were recorded (Savy et al, 2015).…”

Determinants of organophosphate pesticide exposure in pregnant women: A population-based cohort study in the Netherlands

“…Animal studies have demonstrated that OP pesticide exposure levels even below the threshold for acetylcholinesterase inhibition can alter psychological disorder related gene expression (Savy et al, 2018), induce changes in behavior and neurochemistry (Savy et al, 2015), and result in cognitive impairments (dos Santos et al, 2016; Terry, 2012). Moreover, low level OP pesticide exposure can change neuronal cell development (Slotkin et al, 2008), induce oxidative stress (Slotkin and Seidler, 2010; Zafiropoulos et al, 2014), and influence the thyroid hormone levels and the reproductive system (Androutsopoulos et al, 2013; De Angelis et al, 2009; Haviland et al, 2010).…”