Bisphenol A induces miR-708-5p through an ER stress-mediated mechanism altering neuronatin and neuropeptide Y expression in hypothalamic neuronal models.

Bisphenol A (BPA) is an endocrine disrupting chemical that promotes obesity. It acts on the hypothalamus by increasing expression of the orexigenic neuropeptides, Npy and Agrp. Exactly how BPA dysregulates energy homeostasis is not completely clear. Since microRNAs (miRNA) have emerged as crucial weight regulators, the question of whether BPA could alter hypothalamic miRNA profiles was examined. Treatment of the mHypoA-59 cell line with 100 µM BPA altered a specific subset of miRNAs, and the most upregulated was miR-708-5p. BPA was found to increase the levels of miR-708-5p, and its parent gene Odz4, through the ER stress-related protein Chop. Overexpression of an miR-708-5p mimic resulted in a reduction of neuronatin, a proteolipid whose loss of expression is associated with obesity, and an increase in orexigenic Npy expression, thus potentially increasing feeding through converging regulatory pathways. Therefore, hypothalamic exposure to BPA can increase miR-708-5p that controls neuropeptides directly linked to obesity.

Evaluation of green tea extract and epigallocatechin gallate effects on bisphenol A-induced vascular toxicity in isolated rat aorta and cytotoxicity in human umbilical vein endothelial cells.

This study was designed to assess bisphenol A (BPA)-induced vascular toxicity, the effectiveness of green tea extract and epigallocatechin gallate (EGCG) against BPA toxicity, and possible underlying mechanisms. In isolated rat aorta, contractile and relaxant responses as well as malondialdehyde levels were evaluated. Cell viability and effects on the protein levels of apoptotic (bax, bcl2, and caspase-3), autophagic (LC3), and cell adhesion molecules were calculated using the MTT method and western blotting in human umbilical vein endothelial cells (HUVECs). BPA increased aorta MDA levels (p < .0001) and decreased vascular responses to KCl [20 and 40 mM (p < .0001), 80 mM (p < .001)], phenylephrine [10-8 , 10-6 , and 10-5 M (p < .001), 10-7 and 10-4 M (p < .0001)], and acetylcholine [10-6 M (p < .01), 10-5 and 10-4 M (p < .0001)]. In HUVECs, BPA enhanced the levels of LC3A/B, bax/bcl2 ratio, cleaved caspase-3, and vascular cell adhesion molecule-1. Green tea extract, EGCG, and vitamin E co-treatment with BPA diminished the toxic effects of BPA. These findings provide evidence that green tea extract and EGCG possess beneficial effects in preventing BPA-induced vascular toxicity through increasing the antioxidant activities and the regulation of signaling pathways.

Effects of Nigella sativa oil and thymoquinone against bisphenol A-induced metabolic disorder in rats.

The underlying mechanisms of bisphenol A (BPA)-induced metabolic disorder and the protective impact of Nigella sativa oil (NSO) and thymoquinone (TQ) against BPA-induced metabolic disorder were investigated. Rats were treated as follows: Control, BPA (10 mg/kg), TQ (2 mg/kg), NSO (84 µL/kg), BPA + TQ (0.5, 1, 2 mg/kg), and BPA + NSO (21, 42, 84 µL/kg). BPA was administered by gavage, while, TQ and NSO were injected intraperitoneally (daily, 54 days). The weight, blood pressure, serum parameters [glucose, lipid profile, hepatic enzymes, insulin, interlukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), leptin, adiponectin], malondialdehyde (MDA), glutathione (GSH) and insulin signaling pathways [insulin receptor substrate (p-IRS,IRS); kinase (p-Akt,Akt); glycogen synthase kinase (p-GS3K,GS3K)] were measured. BPA increased the blood pressure, MDA, lipid profile, hepatic enzymes, insulin, IL-6, TNF-α, and leptin, and decreased the GSH and phosphorylated forms of IRS, Akt, GS3K but did not alter weight, glucose, IRS, AKT, and GS3K in the liver. Administration of NSO or TQ with BPA reduced the blood pressure, liver level of MDA, lipid profile, hepatic enzymes, insulin, IL-6, TNF-α, leptin, and increased the liver level of GSH and p-IRS, p-AKT, p-GS3K. TQ and NSO are thought to be effective in controlling metabolic disorders induced by BPA.

The Effect of Korean Red Ginseng on Bisphenol A-Induced Fatty Acid Composition and Lipid Metabolism-Related Gene Expression Changes.

Bisphenol A (BPA), which is known to be an endocrine-disrupting chemical (EDC), is associated not only with estrogen activity and reproductive toxicity but also with a variety of metabolic disorders. BPA affects glucose tolerance, cholesterol biosynthesis, and fatty acid synthesis. Ginseng is a traditional medicinal plant that has been widely used in East Asia for more than 2000 years, and a number of health effects have been reported. Korean Red Ginseng (KRG) has also been shown to have effects on lipid metabolism and body weight reduction in vivo in obese mice. In this study, we administered BPA and KRG to ovariectomized (OVX) ICR mice. BPA (800 mg/kg/day) and KRG (1.2 g/kg/day) were orally administered to OVX mice for 3 days. KRG inhibited the increase in total fatty acid level by BPA as determined by lipid profiling in the liver of OVX mice. In addition, transcriptome analysis showed that KRG inhibited BPA-induced changes in lipid metabolic process-related genes. Our findings suggest that KRG can regulate BPA-induced changes in lipid metabolism.

The effect of hormonal levels and oxidative stress on bisphenol A and soy isoflavone reproductive toxicity in murine offspring.

Previous studies have suggested that human exposure to bisphenol A (BPA) and soy isoflavones (SIFs) can occur during pregnancy. The combination of these chemicals is hypothesized to have a toxic impact on the fetus. While BPA is an industrial chemical used widely in the manufacture of polycarbonate plastics and epoxy resins, SIFs are naturally occurring estrogen­like phytoestrogens. To determine the impact of the combination of BPA and SIFs on fetal development, the body weight, organ weight, anogenital distance and histopathological changes in the testes of F1 offspring were assessed in mice. Hormonal effects were determined by measuring serum levels of estrogen receptor (ESR), follicle­stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T). Additionally, mitochondrial DNA copy numbers, and the serum levels of malondialdehyde and superoxide dismutase, were determined to evaluate alterations in oxidative stress and potential toxicity. Exposure to BPA increased the body weight of the pups and reduced the ratio of anogenital distance to body weight, as well as testes weight. Moreover, BPA exposure also induced testicular lesions. The seminiferous tubules of testis were denatured in varying degrees and the lumen wall structure was disordered. The levels of ESR in all offspring and the T levels in male offspring significantly increased, compared with controls. Co­exposure to BPA and SIFs exacerbated these changes in body weight, testicular lesions and hormonal levels, relative to BPA exposure alone. Additionally, oxidative damage was only induced by high­dose BPA. Collectively, these findings suggested that BPA and SIFs could have synergistic effect on the reproductive system, which could be mediated by the regulation of ESR expression and testosterone release.

Bisphenols and Male Reproductive Health: From Toxicological Models to Therapeutic Hypotheses.

Bisphenols, and in particular bisphenol A (BPA), have been widely used for the production of plastic manufacts in the last 50 years. Currently, BPA is present in a variety of daily use polycarbonate plastics and epoxy resins, and dietary ingestion is considered the main route of human exposure. Accordingly, BPA is the chemical pollutant with the widest exposure in humans, involving nearly 90% of general population, according to recent studies. Concerns about BPA effects on human health date back to 1930s, when severe impact on male sexual development was suggested. Now, the acknowledged biological effects of BPA are various. In regard to human fertility, BPA has been shown to disrupt hormone signaling even at low concentrations. Results from human epidemiological studies have reported BPA interference with follicle stimulating hormone, inhibin B, estradiol, testosterone levels, and sexual function in male subjects. Moreover, recent studies have reported an association between BPA levels and reduced sperm concentration, motility, normal morphology, sperm DNA damage, and altered epigenetic pattern, resulting in trans-generational legacy of BPA effects. In this review, the recognized effects of BPA on male reproductive health are described, from the most recent issues on experimental models to epidemiological data. In addition, the very recent interest about the use of nutraceutical remedies to counteract BPA effects are discussed.

Bisphenol a Exposure in Utero Disrupts Hypothalamic Gene Expression Particularly Genes Suspected in Autism Spectrum Disorders and Neuron and Hormone Signaling.

Bisphenol A (BPA) is an endocrine-disrupting compound detected in the urine of more than 92% of humans, easily crosses the placental barrier, and has been shown to influence gene expression during fetal brain development. The purpose of this study was to investigate the effect of in utero BPA exposure on gene expression in the anterior hypothalamus, the basal nucleus of the stria terminalis (BNST), and hippocampus in C57BL/6 mice. Mice were exposed in utero to human-relevant doses of BPA, and then RNA sequencing was performed on male PND 28 tissue from whole hypothalamus (n = 3/group) that included the medial preoptic area (mPOA) and BNST to determine whether any genes were differentially expressed between BPA-exposed and control mice. A subset of genes was selected for further study using RT-qPCR on adult tissue from hippocampus to determine whether any differentially expressed genes (DEGs) persisted into adulthood. Two different RNA-Seq workflows indicated a total of 259 genes that were differentially expressed between BPA-exposed and control mice. Gene ontology analysis indicated that those DEGs were overrepresented in categories relating to mating, cell-cell signaling, behavior, neurodevelopment, neurogenesis, synapse formation, cognition, learning behaviors, hormone activity, and signaling receptor activity, among others. Ingenuity Pathway Analysis was used to interrogate novel gene networks and upstream regulators, indicating the top five upstream regulators as huntingtin, beta-estradiol, alpha-synuclein, Creb1, and estrogen receptor (ER)-alpha. In addition, 15 DE genes were identified that are suspected in autism spectrum disorders.

Protective effect of coenzyme Q10 against bisphenol-A-induced toxicity in the rat testes.

The present study was conducted to investigate the antioxidant, histomorphometric, histochemical, immunohistochemical, biochemical, and cytological effects of coenzyme Q10 (CoQ10) against bisphenol-A (BPA)-induced testicular toxicity in rats. A total of 40 adult male Wistar rats were divided into five equal groups. The control group remained untreated. The vehicle control group was administered corn oil (2 ml/kg/day), the BPA group was given BPA (100 mg/kg/day), the CoQ10 group was supplemented with CoQ10 (10 mg/kg/day), and the rats in the CoQ10-BPA group received CoQ10 (10 mg/kg/day) followed by BPA (100 mg/kg/day) 1 h later. The treatments were administered by oral gavage for 14 days. Results showed that the seminiferous tubule diameters (STDs) and seminiferous epithelium heights (SEHs) at stages VII-VIII and XII-XIV, number of undifferentiated embryonic cell transcription factor-1 (UTF-1) positive cells per tubule, UTF-1 positive tubules (%), plasma glutathione (GSH), and serum superoxide dismutase activities, testicular GSH activity and sperm viability (%) decreased whereas the number of terminal dUTP nick end labeling (TUNEL) positive cells per tubule, TUNEL positive tubules (%), testicular and serum malondialdehyde (MDA) levels, and the rate of mid-piece sperm abnormality increased in the BPA administered group. However, while the STDs at stages VII-VIII and XII-XIV, SEHs at stages VII-VIII, plasma GSH, and serum SOD activities increased, serum MDA level decreased in the CoQ10-BPA group. In conclusion, these results suggest a protective effect of CoQ10 against BPA-induced testicular toxicity in rats.

Effect of antioxidants on BPA-induced stress on sperm function in a mouse model.

In the past few years, bisphenol A, (BPA) an endocrine-disrupting chemical, has received increasing attention because of its detrimental health effects. There is ample evidence to support that BPA interferes with the reproductive health of humans and animals. In spermatozoa, BPA-induced adverse effects are mostly caused by increased oxidative stress. Using an in vitro experimental model, we examined whether antioxidants (glutathione, vitamin C, and vitamin E) have defensive effects against BPA-induced stress in spermatozoa. The results showed that antioxidants inhibit the overproduction of reactive oxygen species (basically cellular peroxides) and increase intracellular ATP levels, thereby preventing motility loss and abnormal acrosome reaction in BPA-exposed spermatozoa. In particular, glutathione and vitamin E reduced the protein kinase A-dependent tyrosine phosphorylation in spermatozoa and, thus, prevented the precocious acrosome reaction from occurring. Furthermore, we found that the compromised fertilisation and early embryo development mediated by BPA-exposed spermatozoa can be improved following their supplementation with glutathione and vitamin E. Based on these findings, we suggest that antioxidants reduce oxidative stress in BPA-exposed spermatozoa, thus preventing detrimental effects on their function and fertility.

Scientific Validation of Ethnomedicinal Use of Ipomoea batatas L. Lam. as Aphrodisiac and Gonadoprotective Agent against Bisphenol A Induced Testicular Toxicity in Male Sprague Dawley Rats.

Sweet potato (Ipomoea batatas L. Lam.), known as "Shakarqandi" in Pakistan, is an imperative root vegetable with large size, traditionally used as aphrodisiac, antiprostatic, anti-inflammatory, antidiabetic, cardiotonic, and anticancer agent. Present study was conducted to gauge aphrodisiac potential of Ipomoea batatas ethyl acetate (IPT-EA, IPA-EA) and methanol (IPT-M, IPA-M) extracts from tuber and aerial part, respectively, via behavioral and biochemical tests and their possible protective role in BPA-induced gonadotoxicity at the dose 300 mg/kg in male Sprague Dawley rats. Phytochemical analysis was done qualitatively and quantitatively through total phenolic and flavonoid content (TPC and TFC) and high performance liquid chromatographic (HPLC-DAD) fingerprinting while antioxidant profiling used multimode in vitro assays. To calculate sexual excitement mount latency, intromission latency, mount frequency, intromission frequency, ejaculatory latency, and postejaculatory interval were examined while for biochemical ratification semen characteristics, levels of testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol were measured. Gonadoprotective ability was assessed through comet assay and histomorphological examination of testes. Qualitative analysis ensured the presence of phenols, flavonoids, tannins, anthocyanin, saponins, coumarins, terpenoids, and betacyanin. Quantitatively maximal TPC (304.32±7.20 µg GAE/mg dry extract) and TFC (214.77±4.09 µg QE/mg DE) were estimated in IPA-EA extract. IPT-EA yielded maximum rutin (7.3±0.12) and myricetin (2.7±0.14 µg/mg DE) while IPA-EA and IPA-M yielded maximum caffeic acid (4.05±0.22 and 1.92±0.17 µg/mg DE, respectively) in HPLC-DAD analysis. Extracts enhanced sexual excitement, improved semen quality, levels of testosterone, FSH, LH, and estradiol, and successfully attenuated toxic effects of BPA. Levels of endogenous antioxidant enzymes (CAT, SOD, POD, and GSH) were restored and NO abundance was minimized. Significant stimulation in sexual behavior, amelioration of toxicity symptoms, elevated spermatic production, raised viability, vitalized levels of gonadal hormones, maintained endogenous enzymes, genoprotection, and reformed testicular histology endorsed I. batatas as a better aphrodisiac alternative and gonadoprotective agent.

Neuroprotective effects of Withania somnifera in BPA induced-cognitive dysfunction and oxidative stress in mice.

BACKGROUND: Bisphenol A (BPA), a major endocrine disruptor and a xenobiotic compound is used abundantly in the production of polycarbonate plastics and epoxy resins. Human exposure to this compound is primarily via its leaching from the protective internal epoxy resin coatings of containers into the food and beverages. In addition, the plastics used in dental prostheses and sealants also contain considerable amount of BPA and have a high risk of human exposure. Since it is a well-known endocrine disruptor and closely mimics the molecular structure of human estrogen thereby impairing learning and memory. Withania somnifera (Ws), commonly known as Ashwagandha is known for its varied therapeutic uses in Ayurvedic system of medicine. The present study was undertaken to demonstrate the impairment induced by BPA on the spatial learning, working memory and its alleviation by Ws in Swiss albino mice. The study was conducted on thirty Swiss albino mice, randomly distributed among three groups: control, BPA and BPA + Ws. The behavioral recovery after treatment with Ws was investigated using the Y-maize and Morris water maize test. Whereas, for the estimation of recovery of NMDA receptor which is related to learning and memory in hippocampus region by western blot and immunohistochemistry. Furthermore, the oxidative stress and antioxidant level was assessed by biochemical tests like MDA, SOD and catalase. RESULTS: The study revealed that administration of Ws alleviated the behavioral deficits induced by BPA. Alongside, Ws treatment reinstated the number of NMDA receptors in hippocampus region and showed anti-oxidative property while ameliorating the endogenous anti-oxidant level in the brain. CONCLUSION: These findings suggest that Ws significantly ameliorates the level of BPA intoxicated oxidative stress thereby potentially treating cognitive dysfunction which acts as the primary symptom in a number of neurodegenerative diseases.

[The role of hypothalamus polycomb gene methylation in bisphenol A exposure during pregnancy and premature puberty in female offspring].

Objective: To explore the role of hypothalamus Polycomb Group (PcG) gene (Eed, Ezh) methylation in the relationship between bisphenol A (BPA) exposure during pregnancy and premature puberty in female offspring. Methods: A total of 40 pregnant CD-1 mice were randomly and averagely assigned into four groups: control group (corn oil) and low, middle and high BPA-exposed groups (the poisonous doses were 8 mg/kg, 40 mg/kg, and 200 mg/kg, respectively) by random number table method. Each group was administered by gavage from gestational day (GD) 1 to 18. The vaginal opening of female offspring was observed from postnatal day (PND) 21 to 33. All female offsprings were sacrificed, and hypothalamus was remained on the PND 34. The methylation levels of Eed and Ezh in the hypothalamus were measured. The early puberty of CD-1 mice was evaluated by the rate of vaginal opening in advance, initial time of vaginal opening, the first estrus occurrence and vaginal opening days in advance. The path model was used to explore the role of Eed and Ezh gene methylation in the early puberty of female offspring with maternal BPA exposed including the number of days of vaginal opening in advance as a dependent variable and BPA exposure as an independent variable. Results: The rate of vaginal opening on the 28 day in each maternal BPA-exposure group [low, middle and high BPA-exposed groups were 40.00% (29/72), 47.62% (25/53) and 37.84% (20/53), respectively] was higher than that rate in the control group [14.06%(9/64)]. Similarly, the P(50)(P(25), P(75)) values of initial time of vaginal opening in low, middle and high BPA-exposed group were 28 (26, 30), 28 (26, 29), 28 (26, 30) days, respectively and the P(50)(P(25), P(75)) values of the first estrus occurrence in low, middle and high BPA-exposed group were 31 (27, 32), 30 (27, 31), 31 (28, 33) days, respectively, which were earlier than those in the control group [initial time of vaginal opening was 30(28, 31) days, and the first estrus occurrence was 32(30, 33) days] (all P values<0.05). Compared with the control group (the methylation levels of Eed1, Eed2, Ezh2 were 1.47%, 1.26%, 2.56%, respectively), the methylation levels of Eed1 (1.61%-1.82%), Eed2 (1.36%-1.43%) and Ezh2 (2.87%-3.05%) in female offspring were significantly higher in BPA-exposed groups (all P values<0.05). The results of path model analysis showed that BPA had no direct influence on puberty in advance, but had an indirect effect on puberty in advance (indirect effect path coefficient was 0.045 and 0.142, respectively) by mediating methylation of Eed2, and Ezh2. Conclusion: Early puberty in female offspring induced by maternal exposure to BPA during pregnancy through the increased methylation levels of hypothalamus PcG gene (Eed, Ezh) in female offspring.

Maternal bisphenol A exposure disrupts spermatogenesis in adult rat offspring.

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that is widely used in the manufacturing of plastics and inner linings of food cans. Previously, it was reported that BPA disturbed the sexual dimorphic nucleus of the hypothalamus and delaying the onset of puberty attributed to an estrogenic action. In addition, BPA during the perinatal period increased LH serum concentrations in male offspring of dams at doses below the reproductive NOAEL (No Observable Adverse Effect Level) based upon World Health Organization guidelines. Based upon these findings, the objective of this study was to (1) determine the effects of perinatal treatment with low doses of BPA on regulation of spermatogenesis in adult offspring and (2) elucidate molecular mechanisms involved in the pathogenesis of gonadal dysfunction. The expression of genes related to spermatogenesis was disrupted with adverse consequences on sperm production, reserves, and function. Both BPA treated groups exhibited reduction in sperm production and epithelial height of seminiferous tubules, accompanied by diminished integrity of the acrosome and plasma membrane, decreased mitochondrial activity and increased incidence of morphological abnormalities. The sperm transit time was also slower. However, only in the group receiving the higher BPA dose was transcript expression of genes affected (reduced Ar and increased Esr1). It is of interest that serum testosterone levels were elevated in the same group where Ar was decreased. Data suggest that exposure to low BPA doses during hypothalamic sexual differentiation period produces permanent deleterious effects on spermatogenesis in adulthood.

Regulation of Gpr173 expression, a putative phoenixin receptor, by saturated fatty acid palmitate and endocrine-disrupting chemical bisphenol A through a p38-mediated mechanism in immortalized hypothalamic neurons.

GPR173 is a highly conserved G protein coupled receptor associated with the hypothalamic-pituitary-gonadal reproductive axis. It is expressed in the brain and ovaries, however considerable knowledge about its function remains unknown. One putative ligand for this receptor is phoenixin (PNX), a newly identified reproductive peptide involved in hypothalamic coordination of the estrous cycle. In order to characterize GPR173, it is vital to determine how Gpr173 is regulated in the hypothalamus. Since the hypothalamus senses compounds from the blood, such as nutrients and chemicals, we examined the effect of palmitate, a saturated fatty acid, and bisphenol A (BPA), an endocrine disrupting chemical, on Gpr173 gene expression. Immortalized hypothalamic neurons were treated with palmitate or BPA for 2-24 h and Gpr173 mRNA levels were assessed with RT-qPCR. Palmitate and BPA both reduced Gpr173 mRNA levels, in part through the mitogen-activated protein kinase (MAPK), p38. Pre-treatment with palmitate for 24 h blocked the PNX-induction of phosphorylated cAMP response element-binding protein (CREB) levels. In conclusion, nutrition levels and environmental chemicals may influence reproductive function through modulation of Gpr173 expression, which may prove to be a future therapeutic target in reproductive health.

Influence of Sodium Glucose Cotransporter 2 Inhibition on Physiological Adaptation to Endurance Exercise Training.

CONTEXT: The combination of two beneficial antidiabetes interventions, regular exercise and pharmaceuticals, is intuitively appealing. However, metformin, the most commonly prescribed diabetes medication, attenuates the favorable physiological adaptations to exercise; in turn, exercise may impede the action of metformin. OBJECTIVE: We sought to determine the influence of an alternative diabetes treatment, sodium glucose cotransporter 2 (SGLT2) inhibition, on the response to endurance exercise training. DESIGN, PARTICIPANTS, AND INTERVENTION: In a randomized, double-blind, repeated measures parallel design, 30 sedentary overweight and obese men and women were assigned to 12 weeks of supervised endurance exercise training, with daily ingestion of either a placebo or SGLT2 inhibitor (dapagliflozin: ≤10 mg/day). OUTCOME MEASUREMENTS AND RESULTS: Endurance exercise training favorably modified body mass, body composition (dual-energy x-ray absorptiometry), peak oxygen uptake (graded exercise with indirect calorimetry), responses to standardized submaximal exercise (indirect calorimetry, heart rate, and blood lactate), and skeletal muscle (vastus lateralis) citrate synthase activity (main effects of exercise training, all P < 0.05); SGLT2 inhibition did not influence any of these physiological adaptations (exercise training × treatment interaction, all P > 0.05). However, after endurance exercise training, fasting blood glucose was greater with SGLT2 inhibition, and increased insulin sensitivity (oral glucose tolerance test/Matsuda index) was abrogated with SGLT2 inhibition (exercise training × treatment interaction, P < 0.01). CONCLUSION: The efficacy of combining two beneficial antidiabetes interventions, regular endurance exercise and SGLT2 inhibition, was not supported. SGLT2 inhibition blunted endurance exercise training-induced improvements in insulin sensitivity, independent of effects on aerobic fitness or body composition.

Interactions between Microcystis aeruginosa and coexisting bisphenol A at different phosphorus levels.

Microcystis aeruginosa is known as the main contributor to cyanobacterial bloom, which is prevalent globally and degrades freshwater systems worldwide. The argument that the introduction of anthropogenic contaminants in fresh water stimulates cyanobacterial growth and microcystin production has attracted widespread attention. Bisphenol A (BPA), one of the most abundant endocrine-disrupting compounds, is often detected in various water bodies due to its notably high annual levels of production and use. Research on the combined effects of endocrine-disrupting compounds and environmental factors on cyanobacteria remains limited. To investigate the mechanism of interactions between contaminants and cyanobacteria at the cellular and proteomic levels, the growth rate, chlorophyll-a content, photosynthetic activities, microcystin-LR (MC-LR) production and release, reactive oxygen species (ROS) content, superoxide dismutase (SOD) activities, malondialdehyde (MDA) content, and proteome expression of M. aeruginosa under 1 µM BPA stress at a standard phosphorus level were investigated. The results showed that stress responses to BPA included increases in the growth rate, chlorophyll-a content, and Fv/Fm and rETRmax values under the low phosphorus condition. Responses involving ROS, SOD, and MDA indicated that phosphorus sufficiency and BPA caused oxidative stress in M. aeruginosa. Moreover, phosphorus sufficiency and BPA stimulated the production and release of MCs. Compared to levels in the non-BPA-treated group, exposure of M. aeruginosa to BPA caused 72 up-regulated proteins, which were primarily associated with photosynthesis, ribosome, fatty acid biosynthesis, glycolysis/glyconeogenesis, and carbon fixation in photosynthetic organisms. The 105 down-regulated proteins were related to quorum sensing, base excision repair, ABC transporters, longevity regulating and cell cycle-caulobacter, suggesting that the cytotoxicity of cyanobacterial cells induced by BPA was significantly increased. These findings provide insights into the molecular mechanism of the effects of BPA and phosphorus on M. aeruginosa, suggesting that coexisting pollutants may cause greater harm to and health risks in the environment.

A Review on the Effects of Bisphenol A and Its Derivatives on Skeletal Health.

Bisphenol A (BPA) is an endocrine disruptor which can bind to the oestrogen receptor. It also possesses oestrogenic, antiandrogenic, inflammatory and oxidative properties. Since bone responds to changes in sex hormones, inflammatory and oxidative status, BPA exposure could influence bone health in humans. This review aimed to summarize the current evidence on the relationship between BPA and bone health derived from cellular, animal and human studies. Exposure to BPA (0.5-12.5 µM) decreased the proliferation of osteoblast and osteoclast precursor cells and induce their apoptosis. Bisphenol AF (10 nM) enhanced transforming growth factor beta signalling but bisphenol S (10 nM) inhibited Wnt signalling involved in osteoblast differentiation in vitro. In animals, BPA and its derivatives demonstrated distinct effects in different models. In prenatal/postnatal exposure, BPA increased femoral bone mineral content in male rats (at 25 ug/kg/day) but decreased femoral mechanical strength in female mice (at 10 µg/kg/day). In oestrogen deficiency models, BPA improved bone mineral density and microstructures in aromatase knockout mice (at very high dose, 0.1% or 1.0% w/w diet) but decreased trabecular density in ovariectomized rats (at 37 or 370 ug/kg/day). In contrast, bisphenol A diglycidyl ether (30 mg/kg/day i.p.) improved bone health in normal male and female rodents and decreased trabecular separation in ovariectomized rodents. Two cross-sectional studies have been performed to examine the relationship between BPA level and bone mineral density in humans but they yielded negligible association. As a conclusion, BPA and its derivatives could influence bone health and a possible gender effect was observed in animal studies. However, its effects in humans await verification from more comprehensive longitudinal studies in the future.

Oleuropein and hydroxytyrosol rich extracts from olive leaves attenuate liver injury and lipid metabolism disturbance in bisphenol A-treated rats.

In the present study, we investigated the protective effects of oleuropein- and hydroxytyrosol-rich extracts obtained from olive leaves against bisphenol A (BPA)-induced hyperlipidemia and liver injury in male rats. For this purpose, four groups of male rats (8 per group) were used: control group (Control), rats treated with BPA, rats treated with both BPA and oleuropein (OLE-BPA), and rats treated with both BPA and hydroxytyrosol (HYT-BPA). After 60 days of treatment, the results obtained using the DXA technique showed that treatment with BPA (10 mg per kg b.w.) increased the body weight and adipose tissue mass in male rats. Moreover, plasma levels of triglycerides, total cholesterol, LDL-cholesterol, AST, ALT, LDH, and TNF-α increased. The immunohistochemical analysis revealed a significant increase in the expression of COX-2 and p53 and a decrease in the expression of Bcl-2 related to liver inflammation. Oral administration of oleuropein and hydroxytyrosol-rich extracts obtained from olive leaves at 16 mg kg-1 reduced both the body weight and adipose tissue mass. These extracts were able to ameliorate liver damage and improve the elevated levels of TG and liver enzymes of BPA-treated rats possibly through enhancing CAT and SOD activities. Western blot results revealed that administration of the abovementioned extracts decreased the protein expression of NF-κB and TNF-α through the p38 signaling pathway. Overall, the findings suggest that the olive leaf extracts possess hypolipidemic and hepatoprotective effects against BPA-induced metabolic disorders through enhancing the antioxidative defense system and regulating the important signaling pathway activities.

Possible Obesogenic Effects of Bisphenols Accumulation in the Human Brain.

Evidence of bisphenols' obesogenic effects on humans is mixed and inconsistent. We aimed to explore the presence of bisphenol A (BPA), bisphenol F (BPF) and chlorinated BPA (ClBPA), collectively called the bisphenols, in different brain regions and their association with obesity using post-mortem hypothalamic and white matter brain material from twelve pairs of obese (body mass index (BMI) >30 kg/m2) and normal-weight individuals (BMI <25 kg/m2). Mean ratios of hypothalamus:white matter for BPA, BPF and ClBPA were 1.5, 0.92, 0.95, respectively, suggesting no preferential accumulation of the bisphenols in the grey matter (hypothalamic) or white matter-enriched brain areas. We observed differences in hypothalamic concentrations among the bisphenols, with highest median level detected for ClBPA (median: 2.4 ng/g), followed by BPF (2.2 ng/g) and BPA (1.2 ng/g); similar ranking was observed for the white matter samples (median for: ClBPA-2.5 ng/g, BPF-2.3 ng/g, and BPA-1.0 ng/g). Furthermore, all bisphenol concentrations, except for white-matter BPF were associated with obesity (p < 0.05). This is the first study reporting the presence of bisphenols in two distinct regions of the human brain. Bisphenols accumulation in the white matter-enriched brain tissue could signify that they are able to cross the blood-brain barrier.