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Increasing evidence has shown that gut microbes play an important role in the reproductive endocrine system and the development of polycystic ovary syndrome (PCOS). However, whether environmental factors are involved in these gut microbiota alterations has seldom been studied. In this study, we aimed to explore the crucial role of an imbalanced gut microbiota on abnormal ovarian follicle development induced by Cu. A 1:1 matched case-control study with 181 PCOS patients and 181 controls was conducted using a propensity score matching protocol. Information regarding dietary Cu intake was obtained from a face-to-face dietary intake interview. Alterations in the gut microbiota were detected by high-throughput 16 S rDNA sequencing. The results showed that dietary Cu intake was positively correlated with the risk of PCOS, and the risk threshold was approximately 1.992 mg/d. Compared with those with dietary Cu intakes lower than 1.992 mg/d, those who had a higher dietary Cu intake had a 1.813-fold increased risk of PCOS (OR=1.813, 95% CI: 1.150-2.857). PCOS patients had a lower relative abundance of Bacteroides than controls (P = 0.003), and Bacteroides played a partial mediating role between dietary Cu exposure and PCOS (P indirect effect =0.026, 95% CI: 0.002-0.072). In addition, an animal model of Cu exposure through the diet showed that Cu can induce gut microbiota disorder; increase serum levels of LPS, MDA, and IL-6; and alter host ovarian steroidogenesis to affect ovarian follicle development. Staphylococcus played a partial mediating role between Cu exposure and CYP17A1 (P g_Staphylococcus =0.083, 95% CI: 0.001-0.228). Overall, this study shows that long-term exposure to high dietary Cu levels can affect the composition of the gut microbiota, cause inflammation and oxidative stress, and then interfere with hormone signaling, ultimately affecting ovarian follicle development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Arsenic contamination is a worldwide public health problem, and the effect of arsenic on male reproduction has been extensively studied; however, data on the biotoxicity of arsenic in terms of female reproduction are more scarce. In this study, a human-cell-animal translational strategy was applied to explore the effect of arsenic exposure on ovarian steroidogenesis and its potential mechanism. We conducted a 1:1 propensity score matched case-control study involving 127 diminished ovarian reserve (DOR) cases and 127 healthy controls. The ovarian follicular fluid levels of 21 metal elements, including arsenic, were measured. The results showed that there were significant differences in follicular fluid metal profiles between DOR patients and controls and that arsenic, molybdenum, and strontium played important roles in DOR progression [OR (95 % CI): 2.203 (1.385, 3.503), 2.308 (1.490, 3.575) and 2.922 (1.864, 4.580), respectively]. In the primary ovarian granulosa cell culture model, we found that treatment with 8 μM arsenic for 24 and 48 h induced a decrease in human granulosa cell viability. The estradiol (E 2 ) level was significantly decreased after arsenic exposure (P < 0.05), which was dependent on significant alterations (P < 0.05) in key enzymes in steroidogenesis. In addition, a model for sodium arsenite exposure through water in rats from weaning to sexual maturity was established. We evaluated ovarian development by monitoring the estrous cycle, observing ovarian pathology, and calculating the follicular proportion. RT-qPCR, Western blotting, and bisulfite-sequencing PCR were used to investigate the effect of arsenic exposure on ovarian steroidogenesis and its possible mechanism. The results indicated that steroidogenic factor-1 (SF-1) was an important target of the steroidogenesis disorder induced by arsenic exposure. Arsenic significantly increased the DNA methylation level (P < 0.05) in the promoter region of SF-1 to reduce its expression, subsequently decreasing the levels of steroidogenic acute regulatory protein (StAR), P450 cholesterol side-chain cleavage enzyme (CYP11A1), and aromatase (CYP19A1) (P < 0.05), leading to premature depletion of ovarian follicles., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Obesity-related metabolic diseases have recently evoked worldwide attention. Studies have demonstrated that Enteromorpha polysaccharide (EP) exerts lipid-lowering effects, but the underlying mechanism remains unclear., Objectives: We investigated whether EP regulates lipid metabolism disorders in mice with high-fat diet (HFD)-induced obesity via an AMP-activated protein kinase (AMPK)-dependent pathway., Methods: Six-week-old male C57BL/6J mice (18 ± 2 g) were fed a normal diet (ND; 10% energy from fats) or an HFD (60% energy from fats) for 6 weeks to induce obesity and treated intragastrically with EP (200 mg/kg body weight) or distilled water (10 mL/kg body weight) for 8 weeks. Biochemical indicators, AMPK-dependent pathways, and lipid metabolism-related genes were evaluated to assess the effects of EP on HFD-induced lipid metabolism disorders. The essential role of AMPK in the EP-mediated regulation of lipid metabolism was confirmed using HFD-fed male Ampka2-knockout mice (aged 6 weeks; 17 ± 2 g) treated or not treated with the above-mentioned dose of EP. The data were analyzed by t-tests, 2-factor and 1-way ANOVAs., Results: Compared to the ND, the HFD resulted in a greater body weight (24.3%), perirenal fat index (2.2-fold), and serum total cholesterol (24.66%) and LDL cholesterol (1.25-fold) concentrations (P < 0.05) and dysregulated the AMPK-dependent pathway and the expression of most lipid metabolism-related genes (P < 0.05). Compared to the HFD, EP treatment resulted in a lower perirenal fat index (31.22%) and LDL cholesterol concentration (23.98%) and partly reversed the dysregulation of the AMPK-dependent pathway and the altered expression of lipid metabolism-related genes (P < 0.05). Ampka2 knockout abolished the above-mentioned effects of EP in obese mice and the EP-mediated effects on the expression of lipid metabolism-related genes (P > 0.05)., Conclusions: These findings suggest that EP can ameliorate lipid metabolism disorders in mice with HFD-induced obesity via an AMPK-dependent pathway., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Obesity-related metabolic diseases have recently evoked worldwide attention. Studies have demonstrated that Enteromorpha polysaccharide (EP) exerts lipid-lowering effects, but the underlying mechanism remains unclear., Objectives: We investigated whether EP regulates lipid metabolism disorders in mice with high-fat diet (HFD)-induced obesity via an AMP-activated protein kinase (AMPK)-dependent pathway., Methods: Six-week-old male C57BL/6J mice (18 ± 2 g) were fed a normal diet (ND; 10% energy from fats) or an HFD (60% energy from fats) for 6 weeks to induce obesity and treated intragastrically with EP (200 mg/kg body weight) or distilled water (10 mL/kg body weight) for 8 weeks. Biochemical indicators, AMPK-dependent pathways, and lipid metabolism-related genes were evaluated to assess the effects of EP on HFD-induced lipid metabolism disorders. The essential role of AMPK in the EP-mediated regulation of lipid metabolism was confirmed using HFD-fed male Ampka2-knockout mice (aged 6 weeks; 17 ± 2 g) treated or not treated with the above-mentioned dose of EP. The data were analyzed by t-tests, 2-factor and 1-way ANOVAs., Results: Compared to the ND, the HFD resulted in a greater body weight (24.3%), perirenal fat index (2.2-fold), and serum total cholesterol (24.66%) and LDL cholesterol (1.25-fold) concentrations (P < 0.05) and dysregulated the AMPK-dependent pathway and the expression of most lipid metabolism-related genes (P < 0.05). Compared to the HFD, EP treatment resulted in a lower perirenal fat index (31.22%) and LDL cholesterol concentration (23.98%) and partly reversed the dysregulation of the AMPK-dependent pathway and the altered expression of lipid metabolism-related genes (P < 0.05). Ampka2 knockout abolished the above-mentioned effects of EP in obese mice and the EP-mediated effects on the expression of lipid metabolism-related genes (P > 0.05)., Conclusions: These findings suggest that EP can ameliorate lipid metabolism disorders in mice with HFD-induced obesity via an AMPK-dependent pathway., (Copyright © 2022 American Society for Nutrition.)