The present study reported the impact of heavy metal on oxidative stress, which constitutes a paramount cause in etiology of PCOS. There was no significant differences in the sociodemographic characteristics between the studied groups yet with some significant variation in the variables like irregular menses and problem of acne. Elevated levels of heavy metals with diminished antioxidant status among PCOS women constitutes the main hallmark findings of the current study. Serum levels of GSH and SOD decreased significantly between the two groups (P < 0.001). There was a strong negative correlation between GSH and As (P < 0.01), GSH and Pb (P < 0.05) and GSH and Hg (P < 0.01). SOD was negatively correlated with As & Pb at P < 0.05.Furthermore, significant positive correlation was determined between Pb & Cd, Cd & Hg at P < 0.001.
Heavy metal exposure seems to have devastating effect on the humans. They are considered as systemic toxicants/human carcinogens owing to multiple organ damage they cause6. Regardless of a extensive research on PCOS, its etiology is still unknown. Oxidative stress could be one of the paramount cause underlying pathophysiology of PCOS. In view of the existence of correlation between oxidative stress and PCOS, present study hypothesizes the role of heavy metal toxicity in generation of oxidative stress that plays a major role in etiology underlying PCOS.
In the current report, sociodemographic data, oxidative stress biomarkers, and heavy metals (As, Cd, Pb & Hg)were evaluated between the two study groups. Most of the participants were young and married. Sociodemographic characteristics were less likely to confound the obtained results. Irregular menses (56%) and acne (60%) were some of the variable which differ significantly among the studied groups suggesting that the Saudi women has phenotype similar to South Asian and Omani women owing to proximity in the geographical location and cultural conditions. PCOS women exhibited higher BMI, however the difference between the groups was non-significant. Parallely, in a report in National Health and Nutrition Examination Survey (NHANE), reported no significant correlation between BMI and heavy metals 22.
Dyslipidemia could be viewed as a possible complication of PCOS, with abnormalities in lipid and lipoprotein metabolism 23.PCOS women had higher TG compared to controls, yet with no significant changes in the levels of TC, HDL-C, and LDL-C. Contradictorily, with regard to altered TG levels, no significant difference in levels of TG was observed between the two groups a Nigerian study 24.Nevertheless, diminished SOD levels observed in the current report is in homology to the findings reported in Nigerian study. This variation could be attributed to the geographical location and origin. Further the lack of significant association between lipid parameters and heavy metals is reflective of role of lipid profile as independent variable in etiology of PCOS. In addition, LH hormone was negatively correlated with decreased SOD indicating that levels of fertility hormones are under the influence of oxidative stress in human body as is evident in the current report.
As stated previously, heavy metallic elements can act as Endocrine disruptor chemicals (EDCs) by generating OS 25,26. OS is best defined as disturbances in the normal oxidation reaction of cells with the production of free radicals or reactive oxygen species (ROS) and peroxides that can cause toxic effects/ cell damage. Interestingly, cells harbor molecules that prevent the generation of OS by detoxifying ROS. These molecules which are termed as antioxidants includes highly complex antioxidant enzymatic and non-enzymatic systems. GSH; a non-enzymatic antioxidant and SOD; an enzymatic antioxidant constitutes as prominent antioxidant markerspredicting the status of OS in cellsindirectly. The main hallmark features of the current investigation were the lowered GSG and SOD in PCOS group when compared to control group (p < 0.001).GSH functions as an important antioxidant performing vital cellular functions27.GSH catalyzes detoxification of oxidizing compounds via its thiol groups28. Various chronic conditionsincluding cancer, gastrointestinal and cardiovascular diseases are reported to have lowered antioxidant status 29.Lowered levels of GSH among PCOS women asevidenced in the current report, are in accordance with previous findings30,31. Interestingly, similar trend in antioxidant status was observed with repect to SOD. SOD levels decreased significantly in PCOS women compared to control. SOD is an enzymatic antioxidant which acts catalyzing detoxification of superoxide anions (O2‑), as a major oxygen radical to H2O2 and finally to water32. SOD exists in different forms with either Cu/Zn, Fe and Mn as cofactor 33. Decreased SOD activity and GSH in PCOS women could be due to surplus production of free radicals produced by metal intoxication. On contrary, Yilmaz et al.,2016 reported no significant change between the test and control groups 34. Parallel to current observation, Hilali et al.,2013 reported diminished antioxidant status among PCOS vs control group 35. Furthermore, decreased levels of SOD observed in PCOS women in the current study is in homology to previous findings36,37but not with certain other works 38 that demonstrated significantly higher SOD activity in PCOS patients. The inconsistency in data of SOD might have been due to a compensatory response by the body’s defense mechanisms to higher circulating levels of oxidants.
There are numerous sources by which the human are exposed to these heavy metals like occupational exposure ,environmental pollution, and or through food consumption. Although the mechanisms pertaining to the adverse reproductive effects caused by toxic metals have notbeen fully defined, toxicological studies have provided some insights. Yet, evidence of certain heavy metalscontributing to adverse effects on fertility remains incomplete, and knowledge remains fairly limited. Heavy metals including Cd, Pb, and As are ubiquitous in the environment following many years of industrial use, with most adults having measurable levels of these nonessential elements in their blood. Review from previous reports on the levels of trace elements in PCOS women are conflicting. In a study by Zheng et al.,2015, no significant change was reported in the level of these heavy metals in Chinese women39. On contrary, Kirmizi et al.,2020 demonstrated increased levels of Cd, Hg and Pb between the two groups30. Intriguingly, heavy metals investigated (As, Cd ,Pb and Hg) in the present study exhibited significant increase in the levels of these elements among PCOS women (P < 0.001) which are in accordance with previous finding 30.Nevertheless, with respect to As, levels exhibited significant difference in contrast to the finding of Kirmizi et al.,2020.30
Cd is non-essential element with no physiological or biochemical significance. Leafy vegetables, grains, crustaceans, mushrooms, shellfish, mussels, liver and kidney are few food sources contains adequate amount of Cd and responsible for Cd intoxication 40. Cd intoxication causes deleterious effects on cellular functioning by indirectly synthesizing ROS. Presumably Cd induced OS, includes alteration in the thiol protein, metabolic and endocrine inhibition, alterations of metalloenzymes, DNA and other vital molecules 41.The reproductive and teratogenic effects of Cd have seen studied in animal models too. Numerous researches have investigated cadmium relationship with female reproductive disorders. In a Turkish based study on PCOS females, Kurdoglu etal .,2012 reported no significant difference in levels of Cd and reported lowered Pb levels among these females42.On contrary, the current study observed an increase in serum Cd among PCOS. Nevertheless, increased Cd did not exhibited any significant association with antioxidant markers as observed in previous finding 30.As is found detrimental to human body effecting various organ and organ systems 43. In addition to Cd and As, another important environmental toxicant/ pollutant that is widespread is Hg. It is identified to cause adverse health effects by inducing rigorous alterations in human body 44. Various routes of exposure to Hg could be through occupational operations, environmental pollution, dental care, preventive medical practices, and industrial and agricultural operations. Notably, dental amalgams and fish are recognized as chronic sources of Hg 45. Effect of chronic and relatively low Hg exposure on are known to inhibit enzymatic activity thereby inducing OS and can be sometimes genotoxic to the cells46.Hg occupational and experimental exposures have shown that Hg induces several reproductive and metabolic abnormalities, such as reproductive cyclicity disturbances, irregular ovarian follicular development, ovulation inhibition, infertility, spontaneous miscarriage, increase visceral adiposity, risk of diabetes mellitus, and metabolic syndrome in rodent and human models44,47.Besides As and Cd, Pb and Hg are also known to exert deleterious effects on human health by cellular dysfunction generatingOS. The increased levels of Hg among PCOS are in line with previous finding 30.
Further, Pearson correlation performed revealed a significant negative association between antioxidant markers and concentrations of heavy metals investigated (Table 4). Figure 2 &3 depicts the multiple regression analysis between heavy metals and antioxidant markers. Negative correlation between Pb and antioxidant markers (SOD and GSH ) is reflective of the decreased antioxidant status among PCOS females due to oxidation of glutathione causing reduction of serum GSH levels30. Nonetheless, elevated levels of serum Hg in PCOS females correlated negatively with GSH levels indicating the oxidative property of Hg in generation of OS. Further exploring the inter-element relationship between the heavy metals, the present study demonstrated a significant positive correlation among the heavy metals (As, Cd, Pb and Hg)indicating the pathophysiology developed in PCOS are probably due to enhanced levels of these heavy metals that works in consortium leading to OS.