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Endocrine disrupting chemicals and role for premature and early menopause

    Overview of Endocrine-Disrupting Chemicals (EDCs)

    Endocrine-disrupting chemicals (EDCs) are substances that can interfere with the normal functioning of the endocrine system in humans and wildlife. These chemicals have the ability to mimic, block, or alter hormone signals, leading to a variety of health issues. EDCs encompass a wide range of compounds, including but not limited to, phthalates, bisphenol A (BPA), polychlorinated biphenyls (PCBs), pesticides, and various industrial solvents.

    Exposure Pathways and Metabolism of EDCs

    Humans are exposed to EDCs through various pathways, including ingestion of contaminated food and water, inhalation of air pollutants, and dermal contact with products containing these chemicals. Once in the body, EDCs are metabolized primarily by the liver, but also by the kidneys, intestines, and skin. Metabolites may be excreted through urine and bile; however, some EDCs resist metabolism and accumulate in body tissues, potentially causing long-term health effects.

    Impact of EDCs on Female Reproductive Health

    EDCs have been linked to a range of adverse outcomes on female reproductive health, such as premature ovarian aging, disrupted follicle development, and early onset of menopause. These disruptions can lead to conditions like infertility, polycystic ovary syndrome (PCOS), and endometriosis, as well as increased risks for cardiovascular diseases, osteoporosis, and other chronic health issues associated with early menopause.

    Link Between Oxidative Stress and Reproductive Aging

    Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, is a key factor in reproductive aging. EDCs can contribute to oxidative stress by binding to nuclear receptors and altering the redox state within cells. This oxidative imbalance can impair folliculogenesis, ovulation, and overall oocyte quality, accelerating the onset of menopause.

    Objective of the Article

    The primary objective of this article is to explore the potential role of EDCs in premature and early menopause, particularly in relation to altered oxidative stress metabolism. By examining the mechanisms through which EDCs induce oxidative stress and disrupt female reproductive health, this article aims to shed light on the complex interactions between environmental chemicals, hormonal balance, and the aging process of the ovaries.

    Mechanisms of Oxidative Stress Induced by EDCs

    Oxidative Stress and Antioxidant Defense Systems

    Oxidative stress is characterized by an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify these reactive intermediates or repair the resulting damage. Antioxidant defense systems, which include enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), play a crucial role in neutralizing ROS and protecting the body from oxidative damage. These systems are essential for maintaining cellular homeostasis and preventing oxidative stress-related pathologies.

    EDCs and Disruption of Oxidative Balance

    Endocrine-disrupting chemicals (EDCs) can disrupt the delicate balance between ROS production and antioxidant defenses, leading to oxidative stress. EDCs such as phthalates, bisphenol A (BPA), pesticides, and toxic metals have been shown to interfere with the activity of antioxidant enzymes, reduce the levels of antioxidant molecules, and enhance the production of ROS. This disruption can have profound effects on cellular function and integrity, particularly in sensitive systems like the female reproductive system.

    Specific EDCs and Their Metabolic Byproducts

    Several EDCs have been identified to induce oxidative stress through their metabolic byproducts. For example, the metabolism of phthalates in the body can lead to the formation of oxidative metabolites that have the potential to cause cellular damage. Similarly, BPA and its analogs can generate ROS during their metabolic processes, contributing to oxidative stress. Pesticides such as organophosphates and organochlorines, as well as toxic metals like cadmium, can also disrupt oxidative balance by affecting antioxidant enzyme activities and increasing ROS levels.

    Impact on Oocyte Quality and Follicle Function

    The impact of EDC-induced oxidative stress on female reproductive health is significant. Oxidative stress can compromise oocyte quality by damaging the DNA, lipids, and proteins essential for oocyte maturation and viability. Furthermore, oxidative stress can impair follicle function by disrupting the growth and development of ovarian follicles, leading to follicular atresia or dysfunction. The cumulative effect of these disruptions can contribute to reproductive disorders such as premature ovarian insufficiency (POI) and early menopause, with associated risks for cardiovascular diseases, osteoporosis, and other health issues.

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    EDCs and Their Effects on Premature Ovarian Aging

    Phthalates and Ovarian Cell Function

    Phthalates, a group of synthetic chemicals found in a myriad of industrial products, have been implicated in the disruption of ovarian cell function. Studies have shown that phthalates like Di(2-ethylhexyl) phthalate (DEHP) and its metabolites can induce oxidative stress parameters such as 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) in oocytes, leading to impaired follicle growth and endometrial cell function. The inhibition of antioxidant enzymes like catalase (CAT) and glutathione peroxidase (GPx) by DEHP is particularly concerning as these enzymes play a crucial role in maintaining cellular redox balance, which is essential for oocyte quality and follicle function.

    Bisphenol A and Follicular Dynamics

    Bisphenol A (BPA), a common plasticizer, has been shown to exert endocrine-disrupting effects on the female reproductive system, including reduced fertility and premature ovarian failure. BPA exposure has been linked to oxidative damage in rat ovarian cells and impaired antioxidant status in bovine oocytes, suggesting a disruption of the delicate balance between oxidative stress and antioxidant defense mechanisms. This disruption can lead to altered follicular dynamics, inhibiting follicle growth and reducing follicle counts.

    Pesticides and Ovarian Toxicity

    Pesticides, widely used in agriculture, have been associated with ovarian toxicity. Organophosphates and organochlorides, in particular, have been shown to cause decreased estrous cycle, apoptosis in granulosa cells, and inhibition of follicular growth. The underlying mechanism involves a decrease in the activities of key antioxidant enzymes such as GPx, SOD, CAT, and GST, highlighting the role of oxidative stress in pesticide-induced ovarian damage.

    Toxic Metals and Ovarian Damage

    Toxic metals like Cadmium (Cd), found in industrial and agricultural products, have been identified as endocrine disruptors. Cd exposure leads to a decrease in antioxidant enzyme activities and an increase in oxidative stress markers like MDA and H2O2, resulting in reduced oocyte number and altered corpus luteum and oocyte tissue. The persistent exposure to EDCs, including toxic metals, is associated with early menopause in women, further emphasizing the link between EDCs, oxidative stress, and ovarian aging.

    In conclusion, EDCs such as phthalates, BPA, pesticides, and toxic metals contribute to premature ovarian aging by disrupting the oxidative stress metabolism. These chemicals impair antioxidant defense systems, leading to oxidative damage that affects oocyte quality, follicle function, and overall ovarian health. The association between EDC exposure and early menopause underscores the need for further research and interventions to mitigate the effects of these environmental contaminants on female reproductive health.

    Premature Ovarian Insufficiency (POI) and Menopause

    Definition and Prevalence of POI

    Premature Ovarian Insufficiency (POI), also known as premature ovarian failure, is a condition characterized by the loss of normal ovarian function before the age of 40. It affects approximately 1% of women and is marked by a significant reduction in the number of functioning ovarian follicles. Women with POI experience irregular or absent menstrual periods, decreased estrogen levels, and often have difficulty conceiving. The prevalence of POI varies globally, but it is a significant concern for women’s reproductive health and can have profound psychological and physiological impacts.

    Hormonal Changes and Oxidative Stress in Menopause

    Menopause is a natural biological process that marks the end of a woman’s reproductive years, typically occurring between the ages of 45-55. It is associated with hormonal changes, including decreased estrogen and increased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. These hormonal shifts can lead to oxidative stress, an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify these harmful compounds. Oxidative stress is implicated in the aging process and may contribute to the onset of menopause and related health issues.

    Environmental and Genetic Factors in POI

    The etiology of POI is multifactorial, with both environmental and genetic factors playing roles. Environmental factors include exposure to toxins, such as chemotherapy and radiation, as well as lifestyle factors like smoking. Genetic factors can involve chromosomal abnormalities, such as Turner syndrome, and gene mutations. The interplay between these factors can lead to the disruption of ovarian function and the early onset of menopause.

    EDCs as a Risk Factor for POI

    Endocrine Disrupting Chemicals (EDCs) are a class of compounds that can interfere with hormone action and are increasingly recognized as a risk factor for POI. EDCs, such as phthalates, bisphenol A (BPA), pesticides, and toxic metals, can accumulate in the body and exert toxic effects on the ovaries, leading to impaired follicle development and reduced ovarian reserve. Persistent exposure to EDCs has been associated with earlier menopause in women, suggesting a link between environmental toxins and the premature decline in ovarian function.

    Overall, POI and menopause are complex conditions influenced by a combination of genetic, environmental, and hormonal factors. The role of EDCs in disrupting ovarian function and accelerating reproductive aging is an area of growing concern, highlighting the need for further research and public health interventions to mitigate exposure to these harmful chemicals.

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    Antioxidant Therapies and Ovarian Function

    Oxidative Stress and Ovarian Dysfunction

    Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, has been implicated in the pathophysiology of ovarian dysfunction. The ovary is particularly susceptible to oxidative damage due to its high metabolic activity and the proliferation and differentiation processes that occur within follicles. Excessive ROS can lead to lipid peroxidation, DNA damage, and protein oxidation, ultimately compromising oocyte quality and follicle viability. This oxidative environment is exacerbated by the presence of endocrine-disrupting chemicals (EDCs), which can disrupt the delicate redox balance within ovarian tissues, contributing to premature ovarian insufficiency (POI) and early menopause.

    Potential of Antioxidant Treatments

    Antioxidant treatments have emerged as a potential therapeutic strategy to mitigate the detrimental effects of oxidative stress on ovarian function. By scavenging free radicals and enhancing the endogenous antioxidant defense systems, these treatments aim to restore redox homeostasis within the ovary. Antioxidants such as vitamins C and E, melatonin, and various polyphenols have been shown to improve follicular development, reduce apoptosis, and support steroidogenesis, thereby preserving ovarian reserve and extending reproductive lifespan.

    Examples of Antioxidant Interventions

    • Melatonin: Known for its potent antioxidant properties, melatonin has been shown to protect ovarian cells from oxidative damage, improve oocyte maturation, and enhance embryo quality.
    • Resveratrol: This polyphenolic compound found in grapes and berries has demonstrated efficacy in protecting ovarian cells from oxidative stress and improving mitochondrial function.
    • N-acetyl cysteine (NAC): As a precursor to glutathione, NAC supplementation can boost intracellular antioxidant levels, offering protection against ROS-induced damage in ovarian tissues.
    • Coenzyme Q10: CoQ10 is essential for mitochondrial ATP production and has been associated with improved ovarian response and oocyte quality in women undergoing assisted reproductive technologies.

    While these interventions show promise, further research is needed to fully elucidate their mechanisms of action, optimal dosing, and long-term effects on reproductive health.

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    Summary of EDCs Impact on Ovarian Aging

    Endocrine-disrupting chemicals (EDCs) have been implicated in a range of adverse health outcomes, particularly in the context of female reproductive health. EDCs, such as phthalates, bisphenols, pesticides, and toxic metals, have been shown to interfere with the endocrine system and contribute to oxidative stress, which can accelerate ovarian aging. The impact of EDCs on ovarian aging is multifaceted, affecting folliculogenesis, oocyte quality, and hormone regulation. These disruptions can lead to premature ovarian insufficiency (POI) and early menopause, increasing the risk of associated comorbidities such as cardiovascular disease, osteoporosis, and cognitive decline.

    The Role of Antioxidants in Mitigating EDCs Effects

    Antioxidants play a crucial role in counteracting the oxidative stress induced by EDCs. The body’s natural antioxidant defense system, which includes enzymes like superoxide dismutase (SOD) and glutathione peroxidase (GPx), works to neutralize reactive oxygen species (ROS) and protect cellular integrity. Exogenous antioxidants, obtained through diet or supplementation, can bolster this defense and have been shown to improve ovarian function and delay the onset of menopause. Nutrients such as vitamin C, vitamin E, and selenium, as well as compounds like resveratrol and melatonin, have demonstrated potential in mitigating the effects of EDCs on ovarian aging.

    Future Perspectives and Research Directions

    Future research should focus on elucidating the precise mechanisms by which EDCs contribute to ovarian aging and early menopause. Longitudinal studies are needed to establish causal relationships and to determine the critical windows of vulnerability. Additionally, there is a need for the development of safe and effective antioxidant therapies that can be used as preventive measures or treatments for those exposed to EDCs. Public health initiatives aimed at reducing exposure to EDCs, through stricter regulations and increased awareness, are also essential. Finally, further exploration into the genetic factors that may predispose individuals to the effects of EDCs will enhance our understanding and aid in the development of personalized interventions.

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    Ethical Considerations and Author Contributions

    Acknowledgments and Funding

    The authors would like to express their gratitude to the institutions and individuals who have supported the research and preparation of this article. Special thanks are extended to the research participants, without whom this study would not have been possible. The authors also acknowledge the contributions of colleagues who provided valuable insights and feedback during the manuscript development process.

    This work was supported by the Koc University Research Center for Translational Medicine (KUTTAM), funded by the Presidency of Turkey, the Presidency of Strategy and Budget. The funding body played no role in the design of the study, collection, analysis, and interpretation of data, or in writing the manuscript.

    Conflict of Interest Statement

    The authors declare that there are no conflicts of interest regarding the publication of this paper. The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

    Author Disclaimer

    The content of this article represents the views of the authors alone and does not necessarily reflect the official positions of the affiliated institutions, the funding agency, or the publisher. The authors are solely responsible for the factual accuracy of the information provided herein.

    Author Contributions

    DA and NU were responsible for conceptualizing the study and drafting the manuscript. All authors contributed significantly to the work reported, whether in the conception, study design, execution, data acquisition, analysis and interpretation, or in all these areas. They have drafted or written, or substantially revised or critically reviewed the article; have agreed on the journal to which the article will be submitted; have reviewed and agreed on all versions of the article before submission, during revision, and the final version accepted for publication; and agree to take responsibility and be accountable for the contents of the article.

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