br Acknowledgment br Introduction Pesticides are largely use
Introduction Pesticides are largely used in agriculture to enhance food production and, to a lesser extent, to control unwanted pests and disease vectors in public health. However, these compounds are often associated with toxicity in non-target species including humans. Occupational pesticide handlers, as a result of mixing or applying these compounds, are at an elevated risk for adverse health effects due to the potential for high exposure events or chronic low-level exposure through skin contact, inhalation or accidental ingestion . The use of biomarkers is gaining growing interest as an integrated measure of exposure and/or adverse health effects because of difficulties in identification of exposure sources and the need of more integrated data for risk assessment. Hence, biomonitoring data are valuable to make associations with the risk of adverse outcomes. Occupational monitoring programs for cholinesterase depression generally rely on measuring the activity of either of two common blood cholinesterases: erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE), which serve as proxy measurements for nervous system AChE. Furthermore, decreases in enzyme activity between two different time-points of a crop season (pre- and post-exposure or high versus low pesticide use) can be used as a quantitative estimation of exposure. This procedure allows to overcome the substantial variability in baseline cholinesterase levels in the general population, with BuChE activity having greater reproducibility and lower variability than AChE activity . However, AChE can be successfully applied in human biomonitoring as it is easy to measure and sensitive, shows a dose-dependent response to pesticide exposure and is linked to health adverse effects . Over the last years, a number of chemicals other than OPs and carbamate insecticides have been increasingly reported to decrease AChE activity, including pesticides from different chemical families (e.g., pyrethroids, triazines and paraquat), heavy metals, polycyclic aromatic hydrocarbons, detergents and different AZ505 ditrifluoroacetate of nanoparticles (reviewed in Ref. . Thus, mixed exposures to different compounds may produce a significant reduction in AChE activity, eventually leading to additive anticholinesterase effects. This indicates the need to reconsider the usefulness of AChE in biomonitoring and risk assessment as this biomarker could provide an integrative measurement of the overall risk posed by the whole burden of chemicals present in the environment . BuChE provides protection from adverse effects of OPs and methylcarbamates insecticides, as well as other chemicals, binding them stoichiometrically (molecule-for-molecule), thereby sparing circulating levels of AChE. In turn, paraoxonase-1 (PON1) affords protection against OPs by catalytically inactivating the bioactive oxon metabolites of OPs. The marked inter-individual variation in expression of these enzymes can largely influence pesticide toxicity by increasing or decreasing the sensitivity to these compounds . The BCHE gene shows multiple nucleotide variations with the wild type “U” (usual) allele being the most common one, followed by the K, A, and F mutations . PON1 is a calcium-dependent enzyme associated with serum HDL particles exhibiting esterase, lactonase and peroxidase activity. These activities might explain the antioxidant and anti-inflammatory potential of the enzyme, which plays a relevant role in the maintenance of a low oxidative state in the blood , . Reduced serum arylesterase and paraoxonase activities (two substrate-specific assays for measuring PON1 function) have been linked to increased systemic oxidative stress and related clinical conditions . The wide interindividual variation in PON1 serum levels is influenced by genetic factors (such as polymorphisms in the PON1 gene, which account for more than 60% of the interindividual variation in enzyme concentration and activity), nutritional factors (intake of antioxidants), environmental agents (like exposure to oxidant agents) and lifestyle . PON1 is also modulated by some pathophysiological events such as inflammation and oxidative stress . Hernández et al.  reported that chronic pesticide exposure might result in long-lasting oxidative stress and that polymorphic genes encoding PON1 and BChE are relevant genetic determinants of pesticide toxicity that significantly interact with exposure to modify antioxidant enzyme activities.