Protective role of vildagliptin against bisphenol-A induced liver injury: targeting oxidative stress, apoptosis, and endoplasmic reticulum stress

The exposure to bisphenol A (BPA) is inevitable owing to its common use in the production of polycarbonate plastics. Studies to reduce side effects are gaining importance since BPA causes severe toxicities in important tissues such as testes, lungs, brain, liver and kidney. The current study was planned to study ameliorative effect of 18β-glycyrrhetinic acid (18β-GA) on BPA induced neurotoxicity. Fourty Wistar albino rats were divided into five equal groups as follows: I-Control group, II-18β-GA group (100mg/kg), III- BPA group (250mg/kg), IV-250mg/kg BPA + 50mg/kg 18β-GA group, V-250mg/kg BPA + 100mg/kg 18β-GA group. BPA intoxication was associated with increased MDA level while reduced GSH concentration, activities of glutathione peroxidase, superoxide dismutase, and catalase. BPA supplementation caused apoptosis in the brain by up-regulating caspase-3 and Bax levels and down-regulating Bcl-2. BPA also caused endoplasmic reticulum (ER) stress by increasing mRNA transcript levels of PERK, IRE1, ATF-6 and GRP78. Additionally, it was observed that BPA administration activated JAK1/STAT1 signaling pathway and levels of TNF-α, NF-κB, p38 MAPK and JNK in the brain. However, co-treatment with 18β-GA at a dose of 50 and 100mg/kg considerably ameliorated oxidative stress, inflammation, apoptosis, ER stress and JAK1/STAT1 signaling pathway in brain tissue. Overall, the data of this study indicate that brain damage associated with BPA toxicity could be ameliorated by 18β-GA administration.

Bisphenol A (BPA) is a commonly used material in daily life, and it is argued to cause oxidative stress in liver and ovarian tissue. α-Lipoic acid (ALA) and α-tocopherol (ATF), two of the most effective antioxidants, may play a role in preventing the toxic effect. Therefore, the purpose of this study was to examine the beneficial effects of ALA, ATF, and that of ALA + ATF combination on oxidative damage induced by BPA. Female Wistar rats were divided into five groups (control, BPA, BPA + ALA, BPA + ATF, and BPA + ALA + ATF). BPA (25 mg/kg/day), ALA (100 mg/kg/day), and ATF (20 mg/kg/day) were administered for 30 days. The levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), liver malondialdehyde (L-MDA) and glutathione peroxidase (L-GPx), and ovarian malondialdehyde (Ov-MDA) and nitric oxide (Ov-NO) were significantly higher in the BPA-treated groups compared with the control group. The levels of AST and ALT decreased in the BPA + ALA, BPA + ATF, and BPA + ALA + ATF groups compared with the BPA group. Similarly, BPA + ALA or BPA + ATF led to decreases in L-MDA and Ov-MDA levels compared with the BPA group. However, the BPA + ALA + ATF group showed a significant decrease in L-MDA levels compared with the BPA + ALA group and the BPA + ATF group. The levels of L-GPx decreased in the BPA + ATF and the BPA + ALA + ATF groups compared with the BPA group. The administration of ATF and ALA + ATF significantly decreased the Ov-NO levels. This study demonstrates that BPA causes oxidative damage in liver and ovarian tissues. ALA, ATF, or their combination were found to be beneficial in preventing BPA-induced oxidative stress.

Investigation of long-term bisphenol A exposure on rainbow trout (Oncorhynchus mykiss): Hematological parameters, biochemical indicator, antioxidant activity, and histopathological examination.

This study investigated the effects of ethinyl estradiol (EE) and bisphenol‐A (BPA) on the maturation of fetuses, reproductive organ, brain development, and behavior. Twenty‐eight Jcl‐ICR pregnant mice were divided into 0.2 mg/kg of EE, 0.02 mg/kg of EE, BPA and control groups. Pregnant mice belonging to 0.2 mg/kg of EE and 0.02 mg/kg of EE group were daily injected subcutaneously either 0.2 mg/kg or 0.02 mg/kg of EE dissolved in olive oil from 11 to 19 days of gestation. The BPA group received an injection of 100 mg/kg of BPA dissolved in olive oil while the control group received an injection of olive oil alone subcutaneously on the same days of gestation. Neurological and behavioral development was examined by means of the sensorimotor reflexes until day 10 and openfield test on day 40 after birth. Myelination of the brain and maturation of testis were histologically examined. Obtained results were: 1) Pregnant mice in the 0.2 mg/kg EE group had no live births. 2) The mean litter size in the 0.02 mg/kg EE group was smaller than that in the BPA and control groups. The mean body weight at birth and that at the age of 60 days showed no significant differences among groups. 3) In the openfield test at the age of 40 days, the mean number of grooming and line‐crossing in the inner field in the 0.02 mg/kg EE group were significantly higher than those in the control group and the mean number of grooming, rearing and line‐crossing in the outer field in 0.02 mg/kg EE group were significantly higher than those in the BPA group. The mean numbers of defecation in both 0.02 mg/kg EE group and BPA group were less than those in the control group. 4) The mean diameter of seminiferous tubules and number of spermatocytes layers in the 0.02 mg/kg EE group and BPA were significantly less than those in the control group. 5) The mean diameter of tractus mamillothalamics in the 0.02mg/kg EE group and BPA group showed no significant differences compared with that in the control group. These findings suggested that prenatal exposure to EE or BPA adversely affects litter size, openfield behavior and spermatogenesis.

It has been proposed that a global decline in sperm counts, semen quality, and several male reproductive disorders are associated with exposure to environmental chemicals. Thus, the present study examined the effects of two estrogenic chemicals, octylphenol (OP) and bisphenol A (BPA), on epididymal sperm counts and sperm motility, luteinizing hormone (LH)-releasing hormone (LHRH)-stimulated plasma LH and steroid hormones, insulin-like growth factor I (IGF-I), and accessory reproductive organs in pubertal male Wistar rats. Fifty-day-old rats in the OP group (n=11) and BPA group (n=11) received daily sc injections of the respective chemical at a dose of 3 mg/kg bw dissolved in 0.2 mL DMSO. Rats in the control group (DMSO group; n=10) received 0.2 mL DMSO alone. After 2 wk of treatment, a jugular blood sample was taken, and, on the next day, a second blood sample was taken 1 h after an sc injection of LHRH (250 ng). After 5 wk of treatment, rats were deeply anesthetized and heart blood was collected. Epididymal sperm motility and sperm head counts were determined. LHRH increased plasma LH to higher levels in all groups, but the increases were significant (p<0.01) in the BPA and OP groups. However, despite higher LH levels after LHRH injection, the incremental responses of testosterone and pro-gesterone in the OP and BPA groups were small compared to those in the DMSO group, which showed a small LH response. After 5 wk of treatment, plasma testosterone levels were significantly (p<0.01) reduced in the OP and BPA groups and this was accompanied by reduced (p<0.05) epididymal sperm counts. However, the chemical-treated groups had high basal progesterone levels. No significant effects of chemicals on sperm motility parameters were noted. The chemical-induced increases (p<0.05) of the weight of ventral prostate gland were coincided with elevated plasma IGF-I levels in the BPA (p<0.05) and OP (p<0.01) groups. The present results demonstrated that OP and BPA can reduce sperm counts resulting from lowered plasma testosterone in male rats just after puberty. The enlarged ventral prostate gland may possibly be associated with increased plasma IGF-I, raising the possibility of a link between these chemicals and prostate diseases because IGF-I has been implicated in the pathogenesis of human prostate cancers.

Objective: Endocrine disrupting chemicals (EDC) in plastics may disrupt proper endocrine system functioning. Zebrafish embryos are formed through external fertilization, and their rapid development, short life cycle, and transparency provide imaging advantages. In zebrafish embryos, neural crest development occurs similarly to other vertebrate embryos and crestin is found in the neural crest during embryogenesis. The aim of our study is to evaluate the effects of bisphenol A (BPA) and Di (2-ethylhexyl) phthalate (DEHP), which are the most widely used EDCs, on the expression of crestin, apoptosis, and inflammation-related parameters in zebrafish embryos. Materials and Methods: The embryos were exposed to either DEHP or BPA in well plates for 72 h post fertilization (hpf). Expressions of crestin were evaluated by in situ hybridization, while the expressions of bax, casp8, casp3a, ifng1, fas, and tp53 were evaluated by RT-PCR. Results: Expressions of bax and casp8 increased and casp3a, ifng1, and fas decreased in BPA and DEHP groups. tp53 expression increased in the BPA group but decreased in the DEHP group compared with the control group. In the DEHP group, casp3a, ifng1, fas, bax, casp8, and tp53 expressions decreased compared with the BPA group. No significant change was observed in the crestin expressions in the groups. When compared with the control group, an inverse relation between ifng1 expression and apoptosis, as evidenced by increased bax and casp8 expressions, was observed in the BPA and DEHP groups. Conclusion: Our study provided important data on the effects of EDCs on the relationship between inflammation and apoptosis.

Ginger volatile oil inhibits the growth of MDA-MB-231 in the bisphenol A environment by altering gut microbial diversity

The aim of this study was to investigate the positive effects of decursin and decursinol angelate (D/DA) on the reproductive system of male rats as well as to examine whether D/DA is able to ameliorate the effects of bisphenol A (BPA). Adult rats were divided into the following four groups: (1) control, (2) BPA, (3) D/DA, and (4) BPA+D/DA. Organ weight ratio of vital organs decreased in the kidney (9.5%) and increased in the prostate (24.07%) and epididymis (22.14%) in the BPA+D/DA group compared to the values in the BPA group. A significant decrease (P<0.05) in sperm count was found in the BPA+D/DA (18.91%) and BPA(54.05%) groups compared to the count in the control group. In only D/DA (20.14%) group, sperm count was significantly increased. D/DA ameliorated the histopathological changes induced by BPA in the testis, consistent with these data. D/DA was also identified as promoting the activities of antioxidant enzymes such as catalase (CAT) and glutathione peroxidase (GPx), the levels of which were significantly increased compared to the corresponding levels in the BPA group. Fas/FasL (FAS) and caspase-3 (CAP) levels were significantly decreased in rats. The results suggest that D/DA reduces apoptosis of Leydig and germ cells in the mouse testis through the Fas-signaling pathway.

Investigation of the protective effect of Lavandula stoechas against the damage caused by Bisphenol A in the liver tissue of rats

Bisphenol A (BPA) is a raw material that has been widely used in the manufacture of plastics and cooking tools. However, it has been proven to be reproductively toxic. In order to investigate the effects of exposure to BPA on the uterus and blood BPA concentration of mice during pregnancy, forty-eight 8-month-old specific pathogen-free (SPF) pregnant mice with similar body weight (18-22 g) were randomly divided into two groups with the same diet (Control group and BPA group). The control group had 24 mice, and all the mice were fed with water at the beginning of the pregnancy (day 0) until 18 days. The BPA group had 24 mice, and all the mice were fed with water + 50mg/kg BPA at the beginning of the pregnancy (day 0) until 18 days. All mice from the two groups were sacrificed on days 3, 6, 9, 12, 15, and 18. In the meantime, blood samples were collected to determine serum BPA levels, and the uterus samples were collected to measure the number of embryos and immune health conditions. The results show that the concentration of BPA in the serum of pregnant mice of the BPA group at each time point (day 3 to day 18) is significantly higher than the Control group (P&amp;lt; 0.05). The number of embryos of mice in the BPA group is significantly lower than the number in the Control group on day 18 (P&amp;lt; 0.05). For the immune health conditions, the results show that the ratio of CD4/CD8, an indicator of the balance and overall health, in the uterus of the Control group on days 9 and 12 is significantly higher than the BPA group (P&amp;lt; 0.05). The results indicate that exposure to BPA during pregnancy via water could cause the abortion and affect the health condition of the uterus of mice.

We used the immature rat uterotrophic assay to determine the estrogenicity of bisphenol A (BPA). We administered BPA (in sesame oil) to rats subcutaneously (sc; 0, 8, 40, and 160 mg/kg/day) or orally (0, 40, 160, and 800 mg/kg/day) for 3 days beginning on postnatal day (PND) 18; rats were sacrificed 24 hr after the last administration. Uterine wet, blotted, and relative weights increased in all groups given BPA sc. After oral administration, uterine relative weight increased in 160 and 800 mg/kg BPA groups, and wet and blotted weights increased in the 800 mg/kg BPA group. Plasma concentrations of BPA at 1 hr after the last administration were detected in all groups given BPA sc and in groups given 160 and 800 mg/kg BPA orally, with a dose-response effect. The study was then reproduced under the same conditions. After sc injections, uterine wet and blotted weights increased in the 40 and 160 mg/kg BPA groups, and relative weight increased in all groups given BPA sc. By contrast, uterine wet, blotted, and relative weights increased only in the 160 and 800 mg/kg oral BPA groups. Also, to examine time-course changes in uterine weight, we administered BPA (in sesame oil) sc from PND 18 to PND 20 for 3 days at doses of 0, 8, 40, and 160 mg/kg/day; uterine weights were then measured at 6, 12, 18, and 24 hr after the last administration. Uterine wet, blotted, and relative weights increased in all BPA groups at 6 and 24 hr and in 40 and 160 mg/kg BPA groups at 12 hr. By contrast, at 18 hr, uterine wet, blotted, and relative blotted weights increased in all BPA groups and relative wet weight increased in 40 and 160 mg/kg BPA groups. The percentage increases in uterine wet and relative weights of 40 and 160 mg/kg BPA groups at 6 hr were higher than those at 24 hr relative to the controls, but the coefficient of variation in these weights in the group given 8 mg/kg BPA at 24 hr was smaller than that at 6 hr. These findings demonstrate BPA-induced uterotrophy in the immature uterotrophic assay in rats administered 8 mg/kg/day sc and in rats given 160 mg/kg/day orally, and suggest that the autopsy at 24 hr after the last administration is suitable.

We used the immature rat uterotrophic assay to determine the estrogenicity of bisphenol A (BPA). We administered BPA (in sesame oil) to rats subcutaneously (sc; 0, 8, 40, and 160 mg/kg/day) or orally (0, 40, 160, and 800 mg/kg/day) for 3 days beginning on postnatal day (PND) 18; rats were sacrificed 24 hr after the last administration. Uterine wet, blotted, and relative weights increased in all groups given BPA sc. After oral administration, uterine relative weight increased in 160 and 800 mg/kg BPA groups, and wet and blotted weights increased in the 800 mg/kg BPA group. Plasma concentrations of BPA at 1 hr after the last administration were detected in all groups given BPA sc and in groups given 160 and 800 mg/kg BPA orally, with a dose-response effect. The study was then reproduced under the same conditions. After sc injections, uterine wet and blotted weights increased in the 40 and 160 mg/kg BPA groups, and relative weight increased in all groups given BPA sc. By contrast, uterine wet, blotted, and relative weights increased only in the 160 and 800 mg/kg oral BPA groups. Also, to examine time-course changes in uterine weight, we administered BPA (in sesame oil) sc from PND 18 to PND 20 for 3 days at doses of 0, 8, 40, and 160 mg/kg/day; uterine weights were then measured at 6, 12, 18, and 24 hr after the last administration. Uterine wet, blotted, and relative weights increased in all BPA groups at 6 and 24 hr and in 40 and 160 mg/kg BPA groups at 12 hr. By contrast, at 18 hr, uterine wet, blotted, and relative blotted weights increased in all BPA groups and relative wet weight increased in 40 and 160 mg/kg BPA groups. The percentage increases in uterine wet and relative weights of 40 and 160 mg/kg BPA groups at 6 hr were higher than those at 24 hr relative to the controls, but the coefficient of variation in these weights in the group given 8 mg/kg BPA at 24 hr was smaller than that at 6 hr. These findings demonstrate BPA-induced uterotrophy in the immature uterotrophic assay in rats administered 8 mg/kg/day sc and in rats given 160 mg/kg/day orally, and suggest that the autopsy at 24 hr after the last administration is suitable.

Hepatoprotective effects of oridonin against bisphenol A induced liver injury in rats via inhibiting the activity of xanthione oxidase

Exposure to bisphenol A during gestation and lactation causes loss of sex difference in corticotropin-releasing hormone-immunoreactive neurons in the bed nucleus of the stria terminalis of rats

The aim of the present study was to assess and compare the individual adverse effects of bisphenol A (BPA) and octylphenol (OP) on the reproductive system of prepubertal male rats. Rats were exposed to BPA and OP at doses of 125 and 250 mg/kg/day, by gavage, for 90 days. At the end of the study, the testes, epididymis, prostate gland, and seminal vesicle were removed and examined histopathologically. Also, 3-β-hydroxysteroid dehydrogenase expressions were analyzed and serum testosterone and luteinizing hormone (LH) levels were measured. Sperm head count of caput epididymis was performed using a hemocytometer. Seminiferous and epididymal round tubules were evaluated for tubule diameter, lumen diameter, and height of tubule epithelium. There were significant increases in relative testes weights in BPA125, OP125, and OP250 groups compared with the control. Atrophic tubules, pyknotic tubules, combined tubules, congestion, vacuolization of Sertoli cell, cell debris in the lumen, tubules without sperm, and degeneration of tubules were noted in the tissue specimens obtained from the treatment groups compared with the control group. Sperm head counts were decreased in all treatment groups except for the low-dose BPA group. Testosterone (T) levels decreased in the BPA and high-dose OP treatment groups. LH levels increased in BPA treatment groups and the low-dose OP treatment group and decreased in the high-dose OP group. Epithelial height of high-dose BPA and OP treatment groups increased compared with the control group. Furthermore tubular height of low-dose BPA and high-dose OP groups increased with respect to control levels. In the OP250 treatment group, thyroxine hormone level was increased compared to other groups. Also, in the OP125 treatment group, triiodothyronine hormone level was increased compared with other groups. The results of this study showed that BPA and OP affect the steroidogenic enzyme expression and T production in Leydig cells. In conclusion, BPA and OP have adverse effects on the male reproductive system of prepubertal rats.