The possible role of the endocrine disrupting chemicals on the premature and early menopause associated with the altered oxidative stress metabolism

COPYRIGHT © 2023 Aydemir and Ulusu. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Opinion PUBLISHED 14 February 2023 DOI 10.3389/fendo.2023.1081704

. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. menopause associated with an increased risk of cardiovascular diseases, dementia, osteoporosis, mood disorders, sexual dysfunction, and mortality (8).
Since oxidative stress causes impaired folliculogenesis, meiosis, and ovulation, it can contribute to premature and early menopause. Furthermore, antioxidant administration improves the quality of maternally aged oocytes, blastocyst formation, and oocyte aging, preventing or delaying ovarian dysfunction (9). EDCs and their metabolized products contribute to oxidative stress by binding PPARs in the ovary and other tissues; also, adverse effects of the EDCs have been reported on the female reproductive system (10). Therefore, this paper discussed the possible role of EDCs-induced oxidative stress in premature and early menopause.
The role of EDCs-induced oxidative stress in the female reproductive system Oxidative stress is described by the imbalance between the antioxidant capacity and the production of reactive oxygen species (ROS) in the cell. Antioxidant defense in the cell is regulated via different antioxidant molecules and enzymes such as glutathione (GSH), glucose 6-phosphate dehydrogenase (G6PD), 6phosphogluconate dehydrogenase (6-PGD), glutathione reductase (GR), glutathione s-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT). G6PD and 6-PGD take part in the pentose phosphate pathway (PPP), producing nicotinamide adenine dinucleotide phosphate (NADPH), which GR uses to convert oxidized glutathione (GSSG) to reduced glutathione (GSH). GSH/GSSG ratio is the primary biomarker for the oxidative stress, since increased levels of the GSSG indicate impaired redox balance in the cell. On the other hand, GPx and CAT detoxify hydrogen peroxide (H 2 O 2 ), where SOD breaks down superoxide (O 2.-) into water (H 2 O 2 ) (11-13). Impaired oxidative stress status has been reported in the pathogenesis of various diseases such as cancer, diabetes, metabolic disorders, endocrine dysfunction, cardiovascular diseases, infertility, and neurological diseases, since ROS attack the DNA, lipid, proteins, and nucleic acids (14,15). On the other hand, oxidative stress affects follicular fluid, oocyte maturation, ovarian steroid biosynthesis, ovulation, formation of blastocysts, implantation, embryogenesis, miscarriage, early birth, ovarian germ cell, and pre-eclampsia, according to the literature (16).
Bisphenol A (BPA) is a plasticizer exerting endocrinedisrupting effects on the female reproductive system, such as reduced fertility, premature ovarian failure, inhibiting follicle growth, and decreased follicle counts (25). Moreover, 25 mg/kg/ day BPA induced oxidative damage in the rat ovarian cells (26). BPA, bisphenol S (BPS), and bisphenol F (BPF) impaired the antioxidant status of bovine oocytes by reducing GPx and SOD activities (27). Pesticides are widely used chemicals in agriculture applications causing toxicity in the soil and water, and other natural resources. Organophosphates and organochlorides cause the decreased estrous cycle, apoptosis in granulosa cells, clumping of oocytes, deletions in microvilli, inhibition of follicular growth, and damage in ovarian surface epithelium (OSE) via decreased GPx, SOD, CAT and GST activities in the rat and mice (28)(29)(30). Cadmium (Cd) is found in industrial products and agricultural activities, exerting endocrinedisrupting effects. Cd decreases antioxidant enzyme activities such as CAT and increases levels of MDA and H 2 O 2 in the rat ovary. Also, Cd-induced oxidative stress cause reduced oocyte number and altered corpus luteum and oocyte tissue (31). On the other hand, persistent exposure to EDCs is associated with early menopause in women (32). Since different types of EDCs impair antioxidant capacity and increase oxidative stress in the female reproductive system, premature or early menopause can result from EDCsinduced oxidative stress.

Discussion
Menopause is a natural gradual process that occurs in females between the ages of 45-55, resulting from the age-dependent decline in fertility. On the other hand, premature ovarian insufficiency (POI) or premature ovarian failure, also known as early and premature menopause, is characterized by ovarian failure before age 40, affecting 1% of women (33,34). Decreased estrogen, increased follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are characteristics of menopause. Compared to pre-menopausal women, increased oxidative stress and decreased antioxidant capacity have been reported in menopausal and postmenopausal women (35). For instance, reduced levels of SOD, CAT, GPx, GSH, vitamin C, and vitamin E have been reported in postmenopausal women compared to pre-menopausal females (36,37). On the other hand, decreased estrogen levels during menopause contribute to impaired redox balance in females since estrogen has antioxidant effects (38).
Increased levels of urinary phthalates are tightly associated with the POI and decreased estradiol levels (41). BPA, DEHP, MHP, dichlorodiphenyltrichloroethane (DDT), MTX, 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD), and bis-hydroxy methoxychlor (HPTE) exposure cause decreased estrogen and increased LH and testosterone contributing to the POI pathogenesis in the females (42). Three mechanisms, including follicle depletion, increased follicular recruitment, and impaired follicular maturation, are discussed as major contributors to EDCsinduced POI that all associated with the impaired oxidative stress metabolism (39). Enhanced oxidative stress or decreased antioxidant defense have adverse effects on both ovary and ovarian follicles. Dysfunction in the corpus luteum, altered follicular fluid, abnormal proliferation in the interstitial cells, apoptosis, decreased steroid synthesis in the granulosa cells, inhibition in the follicle growth and degeneration have been reported as oxidative stress-induced alteration in the ovary and ovarian follicles (43). On the other hand, antioxidant administration including melatonin, curcumin, resveratrol, quercetin, genistein, vitamin E, selenium, catalpol and hyperoside improved ovarian function and aging. For instance, SOD, CAT, GPx, GSH and thioredoxin reductase levels increased, whereas ROS, MDA, GSSG, 8-OHdG and H 2 O 2 levels decreased upon antioxidant treatment (44).

Conclusion
EDCs have been found in almost all types of industrial products such as cosmetics, toys, medical devices, food wrappings and household exerting adverse health effects by interfering with the hormone metabolism. Although EDCs are metabolized in the liver, kidney, skin and intestines, some parts of them remain without metabolization and accumulate in the body causing metabolic disorders, infertility, reproductive dysfunction, diabetes, cancer and neurological disorders. EDCs-induced oxidative stress leads to the ovarian aging, PCOS, apoptosis in follicles, reduced follicle reserve, impaired follicle formation, growth, and activity which are directly correlated with POI pathogenesis. POI affects %1 women under age of 40 associated with increased risk of mortality, cardiovascular diseases, metabolic disorders and diabetes. EDCs exposure have been associated with POI induced by different mechanisms including follicle depletion, increased follicular recruitment, and impaired follicular maturation correlated with impaired oxidative stress metabolism. On the other hand, antioxidant treatment improved oxidative stress-induced alteration in the ovary and ovarian follicles. In conclusion, EDCs-induced oxidative stress may result in the early and premature menopause which can be improved or eased via antioxidant treatment.

Author contributions
DA and NU are responsible for the conceptualization and writing the manuscript. All authors contributed to the article and approved the submitted version.