PD is a chronic neurodegenerative disease characterized by the degeneration of dopaminergic neurons within the substantia nigra pars compacta. While the exact cause of neuronal loss remains elusive, several genetic and environmental factors are believed to contribute to its development (23). Among the environmental factors, pesticide exposure has emerged as a potential risk to PD progression. These chemicals are widely utilized to mitigate pests, combat crop diseases, and enhance agricultural yield (24). Exposure to pesticides and subsequent possible damage to human health may occur through various routes, such as inhalation (the act of breathing in air contaminated with pesticides), dermal contact (direct interaction with pesticide-treated surfaces), oral ingestion (consuming contaminated food, and water, or improper hygiene practices), occupational exposure, and environmental exposure (25). It is widely accepted that pesticide exposure is crucially related to chronic and acute disorders such as cardiovascular disease, type 2 diabetes, and neuro-related diseases (5, 26). OCPs, as illegal chemicals (despite the fact that the use of OCPs has been banned for many years, but they are still one of the most problematic poisons in many societies due to their high stability in the environment and possible abuses(, and OPPs )as pesticides that are widely used in various cases all over the world), are among the most common pesticides that cause various toxicities to humans and other organisms despite their high efficiency (27).
OCPs are lipophilic compounds with a long half-life and slow metabolism; hence, they can accumulate for a long time in adipose tissues and move between these tissues and body fluids such as plasma (28). Importantly, in living organisms, the production of dichlorodiphenyldichloroethylene (DDE) is facilitated by the enzyme cytochrome P450 through the reduction reactions on DDT (29). The results of the current study exhibited that individuals diagnosed with PD had elevated concentrations of OCPs, including 2,4-DDT, 4,4-DDT, 2,4-DDE, 4,4-DDE, α-HCH, β-HCH, and γ-HCH, in comparison to the control group. Moreover, there was a negative correlation between 4,4-DDT and the PDQ39 score that may suggest that further exposure to OCPs accelerates the progression of the disease. Previous studies revealed that levels of OCPs, such as αHCH, β-HCH, γ-HCH, δ-HCH, propanil, heptachlor, dieldrin, hexachlorobenzene, 4,4 DDT, and o,p’-dichloro-diphenyl-trichloroethane, were higher in PD patients than in the control group (24). Notably, the observed elevation in dieldrin concentrations may potentially be associated with alterations in dopaminergic response (30).
The evaluation of AChE and PON-1 enzyme activity unveiled a significant decrease in the activity of these enzymes in PD patients when compared to the control group. AChE serves as an enzymatic catalyst for the degradation of acetylcholine at nerve terminals. The presence of OPPs can irreversibly impede enzyme action, resulting in the accumulation of acetylcholine, interference with neural networks, and subsequent consequences (5). The decline in AChE activity indicated in the current study strongly implies an elevated exposure to OPPs within the aforementioned population. Similarly, Kumar et al. have made a noteworthy discovery regarding the reduced activity of this particular enzyme and the development of non-communicable diseases such as PD, obesity, and AD (31). PON-1 represents antioxidative properties and is a calcium-dependent enzyme that circulates in the bloodstream, predominantly bound to HDL. It exhibits various activities, including arylesterase, paraoxonase, and lactonase (5). The current findings revealed reduced activity of PON-1 in patients with PD, and this reduction was correlated to exposure to OPPs and 4,4 DDT, which in turn may indicate the mixed exposure of PD patients to OCPs and OPPs. Concordantly, it has been suggested that decreased activity of the aforementioned enzyme in patients with PD could serve as a valuable biomarker to assess the state of the disease and predict the prognosis (32). Moreover, a reduction in enzyme activity can lead to the accumulation of OPPs, exacerbating OS and ultimately elevating the susceptibility to neurodegenerative disorders like PD (32, 33).
A variety of enzymatic and non-enzymatic oxidative-related indicators were assessed in the current study in order to elucidate the oxidative status of patients with PD. The present findings revealed that NO levels increased considerably in patients with PD compared to the control group. Moreover, NO showed a positive correlation with 2,4 DDT. These findings are consistent with prior research indicating that serum NO levels and inflammatory response are elevated in PD patients (34, 35). It is also noteworthy that the results of Santos-Lobato's study revealed an increase in the NO ratio in CSF/plasma, which could indicate that the brain generates even more NO than peripheral tissues (36).
In addition, this study showed that MDA and CP levels were significantly higher in the patient group than in the control group. Carbonylation is an irreversible process and one of the most common post-translational modifications of proteins, which can be induced by both non-oxidative and oxidative agents. The increment in protein carbonylation is a sign of OS and can interfere with the normal function of proteins (37). Consistent with previous research (38), the present study found that protein carbonylation is increased in PD, which may have occurred following exposure to pesticides (39). The escalation of OS could also lead to lipid peroxidation and an elevate in its end-products, such as MDA. It has been established that exposure to pesticides can augment MDA levels by triggering OS (40). The present study found that MDA levels were significantly higher in the patient group than in the control, suggesting that these patients may have been exposed to pesticides. Concerning this matter, previous studies have reported both increased (41) and unchanged (42) MDA levels in people with PD compared to controls.
Assessment of antioxidant enzyme activity demonstrated a notable decrease in SOD3 and CAT activity in the patient group compared to the control group; however, GPx3 activity did not differ significantly when the two groups were compared. SOD3 catalyzes superoxide radicals, thereby contributing to the reduction of OS and inflammation (14). It has been documented that exposure to pesticides can decrease the activity of this enzyme and subsequently lead to induce OS and inflammation (43). As the results of this study showed, there is an inverse correlation between SOD3 activity and the levels of 2,4 DDT and 4,4 DDE, which represents that the level of enzyme activity has decreased with increasing exposure to these pesticides. Consistently, it has been established that SOD activity is significantly decreased in PD patients (44). Interestingly, Zhang's study found that decreased SOD activity after a mild acute ischemic stroke can lead to cognitive impairment, which underscores the critical role of this enzyme in the functioning of the nervous system (45). CAT, in cooperation with GPx3, functions in mitigating hydrogen peroxide levels and detoxifying a variety of peroxides (14). Several studies have investigated the impact of pesticides on CAT activity and gene expression. Some of these studies have shown that exposure to certain pesticides can decrease CAT activity and even expression (46). Moreover, enhanced CAT activity can serve as a protective measure against the detrimental impact of ROS induced by paraquat on the body (47). Moreover, a reduction in CAT activity has been observed in diseases such as PD. However, there is a divergence of views on the mechanism by which CAT activity decreases in PD. For instance, Yakunin et al. suggested that the increased accumulation of α-synuclein in PD, through the suppression of peroxisome proliferator-activated receptor γ (PPARγ) transcription activity, is implicated in the diminished expression of CAT as well as the escalated level of OS (48). Clarifying this issue and obtaining a definitive result requires more research in this field to correctly show the cause of the decrease in CAT activity. Regarding GPx3, a variety of findings have emerged, suggesting that this enzyme's function may either increase (42) or decrease (49) in individuals with PD as compared to a control group. Although pesticide exposure could potentially lower enzyme function (14), it's important to note that the gene expression of these enzymes might have heightened as a protective mechanism to offset reduced activity (50).
TAC denotes the serum's ability to neutralize oxidants and free radicals, which are influenced by a range of factors such as thiols, vitamin C, vitamin E, uric acid, and bilirubin (51). Pesticide exposure can reduce TAC by triggering OS and decreasing antioxidant enzyme activity (14). Conversely, a study conducted in 2018 showed that prolonged exposure of farmers to a combination of pesticides might augment TAC as a compensatory or adaptive mechanism (52). The findings of this investigation demonstrated that despite the escalation of pesticide exposure and the decline of certain antioxidant enzymes, the level of TAC in patients with PD increased significantly compared to the control group. This may suggest that the administration of medications such as L-dopa and supplements such as vitamin C, E, etc., which are commonly prescribed to PD patients, contributes to the increase in TAC levels (53, 54). Nevertheless, it is imperative to note that a comprehensive understanding of this issue necessitates further research, as some studies have reported reduced TAC levels in PD (32, 55).