CYC202 br Discussion This study characterized longitudinal c

Discussion This study characterized longitudinal changes of cholinesterase and PON1 enzyme activities in greenhouse workers over two periods of a crop season with different levels of pesticide exposure. Although study participants were not exposed to OP insecticides, because they worked under integrated pest management programs, AChE was significantly decreased in greenhouse workers as compared to controls. A plausible explanation for this finding is that pesticides indirectly generate oxidant molecules that attack cell membranes resulting in lipid peroxidation and further interference with membrane-dependent processes, including enzyme activities [12]. The AChE found on the surface of erythrocytes maintains the integrity of erythrocytes and can be inhibited as a result of a lipid-induced modification of the membrane [1]. AChE is known to be particularly sensitive to oxidative and/or nitrosative stress and is inactivated under oxidizing conditions [30], [45]. In particular, pyrethroids caused a decrease in erythrocyte and CYC202 AChE which was related to increased lipid peroxidation [11]. In experimental studies, significant decreases of AChE activity were observed for a number of triazole fungicides [48]. In a previous study, we also found that AChE activity was significantly reduced in workers exposed to both OPs and non-OPs pesticides [19]. These findings raise the possibility of using AChE activity as a surrogate marker of oxidative stress in the health surveillance of workers exposed to pesticides. An increase in BuChE activity was observed in greenhouse workers relative to controls regardless of the study period (Table 1, Table 3). However, BeChE activity from greenhouse workers was decreased in the period of high pesticide exposure relative to the one of low exposure, whereas activity from control subjects remained unchanged (Table 1). This behavior was substrate-dependent as it was not observed for BuChE. In a previous study, we also found a significant increase in BeChE in the period of higher pesticide exposure and this paradoxical effect was attributed to enhanced BeChE synthesis as a natural protective mechanism against sub-toxic pesticide exposures [19]. An alternative explanation is that both cholinesterases do not work independently from each other, but they are rather co-regulated or counter-regulated, which suggests that a homeostatic level of cholinesterase activity is required for an appropriate regulation of acetylcholine levels in both neural and non-neural tissues [5]. In this regard, AChE bound on erythrocytes plays an important role in termination of cholinergic anti-inflammatory pathway activation [33]. As BChE is supportive in the hydrolysis of acetylcholine by AChE, it can partly compensate for the action of AChE [39]. Hence, elevated BChE could lead to decreased acetylcholine levels, thereby resulting in a low-grade systemic inflammation. High plasma BuChE activity has been associated with obesity, insulin resistance and metabolic syndrome [21], which are now recognized as states of chronic, low-grade inflammation. Although this study did not assess these pathological entities, BuChE and BeChE were positively and significantly associated with BMI, and BMI measures are usually used to estimate overweight and obesity. In this study, PON1 activities were significantly increased in greenhouse workers relative to control subjects after adjusting for a number of covariates (Table 3). This observation is consistent with results from a previous study showing that greenhouse workers (either pesticide sprayers or non-sprayers) exhibited higher levels of POase and BeChE as compared to non-exposed subjects at the post-exposure period [16]. This finding was considered an adaptive biological response suggestive of PON1 up-regulation following long-term exposure to pesticides. However, pesticide exposure might contribute to enhanced oxidative stress [31] which in turn would result in reduced antioxidant PON1 enzymatic capacity. While PON1 protects against oxidative stress by covalent binding of oxidant molecules with its free sulfhydryl group from cysteine 284, this reaction results in a decreased catalytic activity. Thus, subjects with lower PON1 levels may be more prone to oxidative damage because the reduced PON1 activity will cause further accumulation of oxidative molecules. However, the lower catalytic activity may initiate a positive feedback mechanism to upregulate PON1 expression and synthesis.