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Background This meta-analytic study explored the relationship between the risk of type 2 diabetes mellitus (T2DM) and bisphenol A concentrations. Methods The Embase and Medline (PubMed) databases were searched, using relevant keywords, for studies published between 1980 and 2018. A total of 16 studies, twelve cross-sectional, two case-control and one prospective, were included in the meta-analysis. The odds ratio (OR) and its 95% confidence interval (CI) were determined across the sixteen studies. The OR and its 95% CI of diabetes associated with bisphenol A were estimated using both fixed-effects and random-effects models. Results A total of 41,320 subjects were included. Fourteen of the sixteen studies included in the analysis provided measurements of urine bisphenol A levels and two study provided serum bisphenol A levels. Bisphenol A concentrations in human bio-specimens showed positive associations with T2DM risk (OR 1.28, 95% CI 1.14, 1.44). A sensitivity analysis indicated that urine bisphenol A concentrations were positively associated with T2DM risk (OR 1.20, 95% CI 1.09, 1.31). Conclusions This meta-analysis indicated that Bisphenol A exposure is positively associated with T2DM risk in humans.

Because of structural similarities with BPA (Fig. 1), these alternatives also show endocrine disruption effects like BPA, and many studies on adverse health effects of these alternatives are being reported. In a systematic review regarding comparison of the hormonal activity of BPA substitutes, the hormonal activities of BPS and BPF were in the same order of magnitude and of similar action as BPA (estrogenic, anti-estrogenic, androgenic, and anti-androgenic) in vitro and in vivo [9]. ER[alpha], human estrogen receptors [alpha]; ER[beta], human estrogen receptors [beta]; AR, androgen receptor; GR, glucocorticoid receptor; PXR, pregnane X receptor; CAR, constitutive androstane receptor; REC20, the concentrations of the compound equal to 20% of the maximal response of the positive control intensity; RIC20, the concentrations of the test compounds showing 20% inhibition of the activities induced by the endogenous hormones or vehicle control. 1.

Background: Bisphenol A (BPA) is an endocrine disruptor that in animal studies can bind to the thyroid hormone receptor and affect thyroid function. Relevant epidemiologic studies are limited and results are inconsistent. We explored the relationship between urinary BPA and thyroid function in a Chinese population. Methods: The study population included 3394 subjects age 40 years or older who were enrolled in a population-based study from Songnan Community, Baoshan District, Shanghai, China, from June through August 2009. We analyzed the association between urinary BPA and thyroid function using multivariate linear regression. Participants were further divided according to thyroid function status, and logistic regression was applied to determine the relationship between urinary BPA and thyroid function. Results: Each one-quartile increase in BPA was related to an increase of 0.068 pmol/l (95% confidence interval = 0.065— 0.071) in free triiodothyronine and a 0.084 μIU/ml decline (—0.099 to —0.069) in thyroid-stimulating hormone (TSH) in men. For women, there was a 0.10 pmol/l (0.09 to 0.11) increase in free triiodothyronine and a 0.13 μIU/ml decline (—0.14 to —0.11) in TSH. High urinary BPA level was associated with increased thyroid function (adjusted odds ratio = 1.71 [1.26 to 2.32]). Conclusions: Our results support previous reports of associations between BPA exposure and altered thyroid hormones in animal models and epidemiologic studies. Because our study is cross-sectional, no causal relationships can be established.

To investigate the effect of phenolic environmental estrogens on uterine leiomyoma from the perspective of clinical epidemiology. Urine and blood samples were collected from Han women with uterine leiomyoma and women without uterine leiomyoma, living in Nanjing, China, between September 2011 and February 2013. A total of 156 urine samples and 214 blood samples were collected from the uterine leiomyoma group and 106 urine samples and 126 blood plasma samples from the control group. Bisphenol A (BPA), nonylphenol (NP) and octylphenol (OP) concentrations were determined by solid-phase extraction (SPE) coupled with liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Phenolic environmental estrogens in the uterine leiomyoma and control groups were compared based on: gravida>3 and gravida ≤ 3. In participants with gravida>3, urine OP concentration was significantly (P<0.05) higher in the uterine leiomyoma group than in the control group. In participants with gravida ≤ 3, urine NP concentration was significantly (P<0.05) higher in the uterine leiomyoma group compared to controls. Despite obstetric history, urine BPA mean exposure concentration was significantly (P<0.05) different between uterine leiomyoma group and control group. The urine BPA concentration was not significantly (P>0.05) different between gravida>3 and gravida ≤ 3 patients. There was no significant (P>0.05) difference in plasma concentrations of BPA, OP and NP between the leiomyoma group and control group. Mean exposure concentration and range of distribution of BPA, OP and NP plasma concentration differed between the uterine leiomyoma and control group. Exposure level of phenolic environmental estrogens in human was related with leiomyoma tumorigenesis.

Beneficial Effects of Soy Phytoestrogen Intake in Postmenopausal Women With Type 2 Diabetes Vijay Jayagopal , MRCP 1 , Paula Albertazzi , MRCOG 1 , Eric S. Kilpatrick , MRCPath 2 , Elaine M. Howarth , MSC 3 , Paul E. Jennings , FRCP 1 4 , David A. Hepburn , FRCP 1 and Stephen L. Atkin , FRCP 1 1 Department of Medicine, University of Hull, Hull, U.K. 2 Department of Clinical Biochemistry and Immunology, Hull Royal Infirmary, Hull, U.K. 3 Department of Applied Statistics, University of Hull, Hull, U.K. 4 Department of Medicine, York District General Hospital, York, U.K. Abstract OBJECTIVE —Phytoestrogen consumption has been shown to reduce risk factors for cardiovascular disease. Type 2 diabetes confers an adverse cardiovascular risk profile particularly in women after menopause. The aim of this study was to determine whether a dietary supplement with soy protein and isoflavones affected insulin resistance, glycemic control, and cardiovascular risk markers in postmenopausal women with type 2 diabetes. RESEARCH DESIGN AND METHODS —A total of 32 postmenopausal women with diet-controlled type 2 diabetes completed a randomized, double blind, cross-over trial of dietary supplementation with phytoestrogens (soy protein 30 g/day, isoflavones 132 mg/day) versus placebo (cellulose 30 g/day) for 12 weeks, separated by a 2-week washout period. RESULTS —Compliance with the dietary supplementation was >90% for both treatment phases. When compared with the mean percentage change from baseline seen after 12 weeks of placebo, phytoestrogen supplementation demonstrated significantly lower mean values for fasting insulin (mean ± SD 8.09 ± 21.9%, P = 0.006), insulin resistance (6.47 ± 27.7%, P = 0.003), HbA 1c (0.64 ± 3.19%, P = 0.048), total cholesterol (4.07 ± 8.13%, P = 0.004), LDL cholesterol (7.09 ± 12.7%, P = 0.001), cholesterol/HDL cholesterol ratio (3.89 ± 11.7%, P = 0.015), and free thyroxine (2.50 ± 8.47%, P = 0.004). No significant change occurred in HDL cholesterol, triglycerides, weight, blood pressure, creatinine, dehydroepiandrosterone sulfate, androstenedione, and the hypothalamic-pituitary-ovarian axis hormones. CONCLUSIONS —These results show that dietary supplementation with soy phytoestrogens favorably alters insulin resistance, glycemic control, and serum lipoproteins in postmenopausal women with type 2 diabetes, thereby improving their cardiovascular risk profile. CVD, cardiovasular disease HOMA-IR, insulin resistance measured by Homeostasis Model Assessment OGTT, oral glucose tolerance test Footnotes Address correspondence and reprint requests to Dr. Vijay Jayagopal, Michael White Centre for Diabetes and Endocrinology, Brocklehurst Building, Hull Royal Infirmary, 220-236, Anlaby Road, Hull, HU3 2RW, U.K. E-mail: v.jayagopal{at}hull.ac.uk . Received for publication 18 March 2002 and accepted in revised form 1 July 2002. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. DIABETES CARE

Broadly defined, phytoestrogens include isoflavones, coumestans, and lignans. A number of these compounds have been identified in fruits, vegetables, and whole grains commonly consumed by humans. Soybeans, clover and alfalfa sprouts, and oilseeds (such as flaxseed) are the most significant dietary sources of isoflavones, coumestans, and lignans, respectively. Studies in humans, animals, and cell culture systems suggest that dietary phytoestrogens play an important role in prevention of menopausal symptoms, osteoporosis, cancer, and heart disease. Proposed mechanisms include estrogenic and antiestrogenic effects, induction of cancer cell differentiation, inhibition of tyrosine kinase and DNA topoisomerase activities, suppression of angiogenesis, and antioxidant effects. Although there currently are no dietary recommendations for individual phytoestrogens, there may be great benefit in increased consumption of plant foods

Investigations into human exposure to bisphenol A (BPA) have, for the most part, assessed intake based on food consumption estimates combined with measurements or estimates of BPA in foods. In this study, nationally representative data on urinary levels of BPA in the United States (US) from the 2003–2004 National Health and Nutrition Examination Survey (NHANES) were used to estimate daily intake of BPA, assuming steady-state excretion. Distributions of intakes for the US population were determined for (i) all NHANES participants with urinary BPA data; (ii) participants by the following age groups: 6–11 years, 12–19 years, 20–39 years, 40–59 years, and 60+ years; and (iii) participants by gender. On the basis of the NHANES urinary BPA data and the assumptions described in this paper, daily BPA intakes for male participants are statistically significantly higher than for female participants, and there are statistically significant differences in daily BPA intakes according to age groups, with the oldest group having the lowest estimated intakes. Median intake was approximately three orders of magnitude below health-based guidance values of 50  μ g/kg-day.

Women commonly use soy products, herbs, and other complementary and alternative medicine (CAM) therapies for menopausal symptoms. Randomized, controlled trials have evaluated the efficacy and short-term safety of these therapies. To review randomized, controlled trials of CAM therapies for menopausal symptoms in order to better inform practice and guide future research. Searches of MEDLINE for articles published from January 1966 through March 2002, of the Alternative and Complementary Database (AMED) of the British Library for articles published from January 1985 through December 2000, and of the authors' own extensive files. Search terms were hot flash/flush, menopause, and climacteric, combined with phytoestrogens, alternative medicine, herbal medicine, traditional medicine, Traditional Chinese Medicine (TCM ), Ayurveda, naturopathy, chiropractic, osteopathy, massage, yoga, relaxation therapy, homeopathy, aromatherapy, and therapeutic touch. 29 randomized, controlled clinical trials of CAM therapies for hot flashes and other menopausal symptoms were identified; of these, 12 dealt with soy or soy extracts, 10 with herbs, and 7 with other CAM therapies. Each author extracted information from half of the studies on the number of patients, study design, outcome measures, and results; the other author then checked these results. Soy seems to have modest benefit for hot flashes, but studies are not conclusive. Isoflavone preparations seem to be less effective than soy foods. Black cohosh may be effective for menopausal symptoms, especially hot flashes, but the lack of adequate long-term safety data (mainly on estrogenic stimulation of the breast or endometrium) precludes recommending long-term use. Single clinical trials have found that dong quai, evening primrose oil, a Chinese herb mixture, vitamin E, and acupuncture do not affect hot flashes; two trials have shown that red clover has no benefit for treating hot flashes. Black cohosh and foods that contain phytoestrogens show promise for the treatment of menopausal symptoms. Clinical trials do not support the use of other herbs or CAM therapies. Long-term safety data on individual isoflavones or isoflavone concentrates are not available.

The phytochemical resveratrol, which is found in grapes and wine, has been reported to have a variety of anti-inflammatory, anti-platelet, and anti-carcinogenic effects. Based on its structural similarity to diethylstilbestrol, a synthetic estrogen, we examined whether resveratrol might be a phytoestrogen. At concentrations (approximately 3-10 micromolar) comparable to those required for its other biological effects, resveratrol inhibited the binding of labeled estradiol to the estrogen receptor and it activated transcription of estrogen-responsive reporter genes transfected into human breast cancer cells. This transcriptional activation was estrogen receptor-dependent, required an estrogen response element in the reporter gene, and was inhibited by specific estrogen antagonists. In some cell types (e.g., MCF-7 cells), resveratrol functioned as a superagonist (i.e., produced a greater maximal transcriptional response than estradiol) whereas in others it produced activation equal to or less than that of estradiol. Resveratrol also increased the expression of native estrogen-regulated genes, and it stimulated the proliferation of estrogen-dependent T47D breast cancer cells. We conclude that resveratrol is a phytoestrogen and that it exhibits variable degrees of estrogen receptor agonism in different test systems. The estrogenic actions of resveratrol broaden the spectrum of its biological actions and may be relevant to the reported cardiovascular benefits of drinking wine

Whether environmental exposure to bisphenol A (BPA) may induce reproductive disorders is still controversial but certain studies have reported that BPA may cause meiotic abnormalities in C. elegans and female mice. However, little is known about the effect of BPA on meiosis in adult males. To determine whether BPA exposure at an environmentally relevant dose could induce meiotic abnormalities in adult male rats, we exposed 9-week-old male Wistar rats to BPA by gavage at 20 μg/kg body weight (bw)/day for 60 consecutive days. We found that BPA significantly increased the proportion of stage VII seminiferous epithelium and decreased the proportion of stage VIII. Consequently, spermiation was inhibited and spermatogenesis was disrupted. Further investigation revealed that BPA exposure delayed meiosis initiation in the early meiotic stage and induced the accumulation of chromosomal abnormalities and meiotic DNA double-strand breaks (DSBs) in the late meiotic stage. The latter event subsequently activated the phosphatidylinositol 3-kinase-related protein kinase (ATM). Our results suggest that long-term exposure to BPA may lead to continuous meiotic abnormalities and ultimately put mammalian reproductive health at risk.