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Earlier research has demonstrated that developmental exposure to bisphenol A (BPA) has persistent impacts on both adult brain growth and actions. It has been suggested that BPA might obstruct the methylation coding of the genes in the brain. In this study, the methylation changes in the hippocampus tissue of male rat pups were examined following prenatal BPA exposure. Pregnant Sprague-Dawley rats were treated with either vehicle (tocopherol-stripped corn oil) or BPA (4, 40, or 400 μg/kg·body weight/day) throughout the entire duration of gestation and lactation. At 3 weeks of age, the male rat offspring were euthanized, and the hippocampus were dissected out for analysis. The expression levels of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) and DNA demethylases (TET1, Gadd45a, Gadd45b, and Apobec1) were analyzed in the hippocampus by means of quantitative real-time polymerase chain reaction and Western blotting, respectively. The results showed that prenatal exposure to BPA upregulated the expression of enzymes associated with DNA methylation and demethylation processes in the hippocampus of male rat offspring. These findings suggest that prenatal exposure to a low dose of BPA could potentially disrupt the balance of methylation and demethylation in the hippocampus, thereby perturbing epigenetic modifications. This may represent a neurotoxicity mechanism of BPA. [ABSTRACT FROM AUTHOR]

Physis is a complex cartilaginous structure that is critical for longitudinal bone growth. As one of the endocrine-disrupting chemicals, bisphenol A (BPA) can interfere with the physis by deranging the complex networks of nutritional, cellular, paracrine, and endocrine factors, and this affects longitudinal bone growth, leading to different growth outcomes. However, the exact mechanisms underlying these phenomena remain unclear. Therefore, understanding the molecular pathways involved in the physis after neonatal exposure to low-dose BPA may permit the identification of research targets for therapeutics, which may aid in modulating the process of growth plate closure. In the present study, female Sprague–Dawley rats were exposed to 0.05 mg·kg−1·day−1 of BPA and corn oil vehicle from postnatal day 1 (PND1) to 15 via subcutaneous injection. Next-generation RNA sequencing was performed for the mRNA isolated from the physis. The levels of osteocalcin (OC), growth hormone (GH), and insulin-like growth factor 1 (IGF-1) were measured on PND30 (BPA0.05mg vs. Vehicle; n = 5 for each group). We observed statistically significant enrichment of gene sets in the BPA0.05mg tissues compared with the Vehicle tissues. Further analysis of the differentially expressed genes (DEGs) identified BPA0.05mg-specific networks of secreted proteins (LEP, NPY, AGT, ACE2, C4B, and C4BPA) as well as those of local matrix and protease proteins (FBN2, LAMC2, ADAMTS16, and ADAMTS19). Furthermore, the levels of OC and GH were affected by BPA exposure. Our results revealed the specific molecular characteristics of physis contaminated with BPA and may provide new clues for physis maturation and supervision of industrial products and occupational exposure. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that bisphenol A (BPA) induces liver pathological changes. Further, an association between BPA and circulating vitamin D (VitD) levels were documented. Aim: The role of VitD in BPA-induced liver pathological changes was explored in this study. Methods: Healthy 4.5-week-old male (n = 35) and female (n = 35) Swiss albino mice were used in this study. The animals were randomly divided into control and treated groups. The control groups were further divided into sham (no treatment) and vehicle (corn oil), whereas the treated groups were also divided into VitD (2195 U/kg), BPA (50 μg/kg), and BPA + VitD (50 μg/kg + 2195 U/kg) groups. For 6 weeks (twice a week), the animals were dosed intraperitoneally. One week later (at 10.5-weeks-old), the animals were sacrificed for biochemical and histological analyses. Results: BPA produced a considerable rise in the body and liver weights in both genders of mice when compared to control mice. BPA also caused significant increases in the liver damage markers alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT). It also induced liver histopathological changes, including higher apoptotic indices in both genders. On the other hand, treatment with VitD considerably reduced liver damage and slightly decreased the apoptotic index rate. The ALP, ALT, and GGT levels were also markedly reduced. VitD has been proven to have a protective effect on both genders. Conclusions: According to our findings, VitD protects mice from BPA-induced liver damage, possibly via suppressing liver damage markers. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is one of the most common worldwide chemicals involved in the industry of polycarbonate plastics, medical devices, and pharmaceuticals. Forty three-month-old albino rats were randomly classified into four groups. Group Ӏ received a daily corn oil dose (5 mL/kg/ body weight, BW) through a gastric tube for one month, Group ӀӀ received a daily dose of Curcumin (200 mg/kg body weight (B.W.) through a gastric tube for one month, Group ӀӀӀ received a daily dose of BPA (0.5 μg/kg B.W.) through a gastric tube for one month and Group ӀV received concomitant daily doses of Bisphenol A and Curcumin as the regimen described in groups ӀӀ and ӀӀӀ. The rats were sacrificed, and glandular portion of stomach was dissected and processed for light, immunohistochemical and ultrastructural study. BPA induced destructed gastric glands, dilated congested blood vessels, submucosal oedema, decreased PAS-positive reactivity, increased collagen fibres deposition, decrease in the positive BCL2 immunoexpression, increased positive PCNA immunoexpression, reduction in the gastric mucosal height and destructive changes in the enteroendocrine, chief and parietal cells. Curcumin coadministration provoked an obvious improvement in the gastric structure. BPA exposure has toxic effects on the glandular portion of the stomach in rats. Otherwise, Curcumin coadministration has exhibited protective impact on the architecture of the stomach. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a chemical component used in plastic products around the world. This study aims to examine the effects of these chemical compounds to which humans are frequently exposed in everyday life, on the heterogeneity and distribution of mast cells in the gastrointestinal system. For the study, 24 male Wistar albino rats were divided into 4 groups (control, sham, 25 mg/kg, and 50 mg/kg BPA treated). BPA was dissolved in corn oil and administration was done by oral gavage for thirty days. Gastrointestinal tissue samples taken from animals anesthetized with inhalation anesthesia were fixed using BLA (Basic Lead Acetate) and Carnoy fixation. Then, following routine tissue follow-up, they were blocked with Paraplast. Sections (6 µm) taken from the blocks were stained using Toluidine blue (TB) and Alcian blue-safranine O 8GX (AB-SO) combined dyes. Counting and statistical analysis of the mast cells in the TB-stained sections were performed. According to the results of the analysis, a higher number of mast cells was observed in the BLA fixation solution, while the increase in the number of mast cells was statistically significant in the groups treated with BPA (p<0.05). In the combined AB-SO 8GX staining results, AB (+), S (+), and Mix (+) mastocytes were found in almost all sections of the digestive tract. As a result of this staining process, again, no difference was found in the semi-quantitative evaluations performed including the groups treated with BPA. Although BPA does not affect the heterogeneity of mast cells, it does affect their distribution. Therefore, it is assumed that further studies will need to be carried out. [ABSTRACT FROM AUTHOR]

Due to highly exposure of BPA which is harmful substance, we investigate its role in induction of oxidative stress, its effect on pancreatic tissue and some physiological parameters in serum of rats, also make a compartive study of antioxidant role for both green and white tea alcoholic exctracts against this harmful substance. In our experiment 20 male albino rats had been used, their body weights were ranged between 180 and 200 grams. Four equal groups of rats were formed, (five animals each). The first group was treated with corn oil alone, while the second group received 500 mg/kg BPA liquified in corn oil, while the third group received BPA (500 mg/kg) and 300 mg/kg extract of green tea together, and the fourth group received BPA plus 300 mg/kg white tea alcoholic extract tea extract. Animal dosing was orally for 60 days. Level of serum MDA significantly inceased in rat group supplied with PBA while treatment with white and green tea alcoholic extract decreased MDA level. Serum superoxidedismutase (SOD) significantly decreased in PBA group while green tea significantly elevated antioxidant level, rats treated with white tea also showed elevation in serum SOD but it was non significant, indicating higher enhancment of green tea for anioxidant production than white tea. Histopathological examination revealded hemorrahge, apoptosis, necrosis and infiltration of inflammatory cells in pancreatic tissue of PBA of rats group, while treatment with green and white tea alcoholic extract nearly recovered histological architectur of pancreatic islets. Histochemical examination indicated depletion of mucopolysacchride by using a stain named alcian blue periodic-acid schiff stain (AB-PAS), protein also depleted when pancreatic tissue stained with bromophenol blue in rats supplied with PBA, while green tea showed better recovery for protein distribution than white tea. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA), a chemical involved in formation of plastic vessels, is one of the most widespread endocrine disrupting chemicals. The study was designed to investigate the effect of BPA on pancreas and thyroid gland of young and adult female Sprague Dawley rats. The rats were exposed to 330 mg/kg BPA orally every other day for 12 weeks; control rats were exposed orally to ethyl alcohol and corn oil. Samples were collected at 4, 8 and 12 weeks for hormonal, biochemical assays and histopathological examination. The insulin hormone in exposed young rats was decreased, but its level in adult ones was increased; the biochemical assay for blood sugar level showed a significant increase in young rats and decrease in adult ones. T3 hormone was increased in treated young and adult rats; T4 hormone was increased in treated adults, while calcium level was decreased in treated adult rats. The histopathological findings of pancreas revealed vacuolation in its endocrine parts in young rats, while in adult ones there was intralobular fatty infiltration -- a typical picture of diabetes. The thyroid gland in treated young female rats showed increased cellularity of parafollicular cells; moreover there was parafollicular haemorrhage, and in adult ones -- desquamation in lining epithelium of follicular cells. In conclusion, exposure of young and adult female rats to BPA resulted in changes in the pancreatic and thyroid gland cells manifested by morphological, hormonal and biochemical parameters. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is one of the most common worldwide chemicals involved in the industry of polycarbonate plastics, medical devices, and pharmaceuticals. Forty three-month-old albino rats were randomly classified into four groups. Group Ӏ received a daily corn oil dose (5 mL/kg/ body weight, BW) through a gastric tube for one month, Group ӀӀ received a daily dose of Curcumin (200 mg/kg body weight (B.W.) through a gastric tube for one month, Group ӀӀӀ received a daily dose of BPA (0.5 μg/kg B.W.) through a gastric tube for one month and Group ӀV received concomitant daily doses of Bisphenol A and Curcumin as the regimen described in groups ӀӀ and ӀӀӀ. The rats were sacrificed, and glandular portion of stomach was dissected and processed for light, immunohistochemical and ultrastructural study. BPA induced destructed gastric glands, dilated congested blood vessels, submucosal oedema, decreased PAS-positive reactivity, increased collagen fibres deposition, decrease in the positive BCL2 immunoexpression, increased positive PCNA immunoexpression, reduction in the gastric mucosal height and destructive changes in the enteroendocrine, chief and parietal cells. Curcumin coadministration provoked an obvious improvement in the gastric structure. BPA exposure has toxic effects on the glandular portion of the stomach in rats. Otherwise, Curcumin coadministration has exhibited protective impact on the architecture of the stomach. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates the role of endocrine disruptor bisphenol A (BPA) in many pathological conditions. Histone deacetylase (HDAC) inhibition has potential for the treatment of many diseases/abnormalities. Using a mouse BPA exposure model, this study investigated the hepatoprotective effects of the Food and Drug Administration–approved HDAC2 inhibitor valproic acid (VPA) against BPA-induced liver pathology. We randomly divided 30 adult male Swiss albino mice (8 weeks old; N = 6) into five groups: group 1, no treatment (sham control (SC)); group 2, only oral sterile corn oil (vehicle control (VC)); group 3, 4 mg/kg/day of oral BPA (single dose (BPA group)); group 4, 0.4% oral VPA (VPA group); and group 5, oral BPA + VPA (BPA + VPA group). At the age of 10 weeks, the mice were euthanized for biochemical and histological examinations. BPA promoted a significant decrease in the body weight (BW), an increase in the liver weight, and a significant increase in the levels of liver damage markers aspartate aminotransferase and alanine aminotransferase in the BPA group compared to SC, as well as pathological changes in liver tissue. We also found an increase in the rate of apoptosis among hepatocytes. In addition, BPA significantly increased the levels of oxidative stress indices, malondialdehyde, and protein carbonylation but decreased the levels of reduced glutathione (GSH) in the BPA group compared to SC. In contrast, treatment with the HDAC2 inhibitor VPA significantly attenuated liver pathology, oxidative stress, and apoptosis and also enhanced GSH levels in VPA group and BPA + VPA group. The HDAC2 inhibitor VPA protects mice against BPA-induced liver pathology, likely by inhibiting oxidative stress and enhancing the levels of antioxidant-reduced GSH. [ABSTRACT FROM AUTHOR]

Objective: To explore the protective effect and its mechanism of the protein and peptide extracts from the muscle of Chinese giant salamanders (SP) on the protection of bisphenol A (BPA)-induced sperm disorder in mice. Methods: Forty male C57BL/6 mice were divided into four groups, Control group, BPA group, BPA+CS group and BPA+SP group. BPA group was injected with 50 mg/kg/d of BPA, which dissolved in corn oil. Control group was injected with corn oil only. The BPA+CS group was given compound substances, which have been proved to be beneficial for spermatogenesis, and were used as controls. The BPA+SP group was given the above mentioned compounds plus SP dissolved in physiological saline. Mice received the compounds plus SP by gavage. The doses were 4 g/kg/d for both groups. The model was established continuously for 28 days, during which the body weight of mice was measured weekly. Testicular volume and testosterone-body ratio were measured after establishment of animal model. Epididymal sperms were collected to measure sperm number and sperm motility by using the computer aided analysis system (CASA). The amount of testosterone in the serum was determined by ELISA. HE staining and TUNEL staining were used to analyze testicular histopathology. Finally, immunofluorescence staining and Western blotting were used to analyze the expression of metastasis associated protein 2 (MTA2), and Oil Red O staining was used to observe the phagocytosis of Sertoli cells in vitro and in vivo. Results: Compared with the control group, the testicular volume (P<0.05), testicular weight (P<0.05), testosterone-body ratio (P<0.05), sperm number (P<0.05), sperm motility (P<0.05), and the amount of testosterone in the serum of mice (P<0.01) in BPA group were significantly decreased. Testicular morphology was damaged and the number of apoptotic spermatogenic cells in BPA group was increased compared with control group(P<0.01). At the same time, the expression of MTA2 and the phagocytosis of Sertoli cells in BPA group were decreased compared with control group (P<0.01). There was no difference between BPA + CS group and BPA group. Surprisingly, the above changes in BPA group were significant difference by using SP(P<0.05). Conclusion: SP has obvious protective effect on BPA-induced sperm disorder in mice, and the mechanism of action may be related to enhanced phagocytosis of Sertoli cells by improving the expression of MTA2. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is ubiquitous in the environment and its adverse effects on precocious puberty have been reported. But its mechanism is not clear. In the present study, the potential effects of BPA on endocrine functions of hypothalamus, especially in the arcuate (ARC) nucleus and anteroventral periventricular (AVPe) nucleus, were studied from postnatal day 15 (PND15) to PND35 in female Sprague-Dawley (SD) rats. Neonatal rats were exposed to 0.5 mg·kg−1·day−1 BPA or corn oil vehicle from PND1 to PND14 via intramuscular injection. From PND20 to PND 25, BPA caused enrichment of H3K4me2 and H3K4me3 at Kiss1 promoter, concurrent with elevated gene expressions of Kiss1 and GnRH1 in ARC and strikingly increased serum E2 levels in BPA group on PND25. Until PND30, BPA induced obviously overexpression of Kiss1 and GnRH1 in AVPe nucleus. Subsequently, the vagina opening and first ovulation had occurred earlier in rats with BPA exposure in respect to vehicle by PND35. In this study, it is suggested that the effects of BPA on precocious puberty may be due to its action to activate Kiss1 gene in ARC during the juvenile period (from PND20 to PND25) firstly, subsequently to evoke the AVPe neurons, resulting in precocious puberty in the end. • Puberty is initiated by activation of Kiss1 neurons in arcuate nucleus of hypothalamus. • Increased abundance of H3K4me2/3 is relevant to the pubertal activation of Kiss1. • Bisphenol A exposure promotes earlier H3K4me2/3 enrichment at Kiss1 promoter. • Bisphenol A induces precocious puberty by activating Kiss1 in arcuate nucleus in advance. [ABSTRACT FROM AUTHOR]

As the incidence of precocious puberty has risen in recent years and the age at puberty onset is younger, children may be at increased risk for health consequences associated with the early onset of puberty. Bisphenol A (BPA) is recognized as an endocrine disruptor chemical that is reported to induce precocious puberty. The effect of BPA exposure modes, times, and doses (especially low dose) were controversial. In the present study, we evaluated the potential effects of maternal exposure to low-dose BPA on the hypothalamus, particularly on the arcuate (ARC) nucleus and anteroventral periventricular (AVPV) nucleus during peri-puberty in offspring of BPA-treated rats. Pregnant rats were exposed to corn oil vehicle, 0.05 mg·kg−1·day−1 BPA, or 5 mg·kg−1·day−1 from gestation day 1 (GD1) to postnatal day 21 (PND21) by daily gavage. Body weight (BW), vaginal opening (VO), ovarian follicular luteinization, and relevant hormone concentrations were measured; hypothalamic Kiss1 and GnRH1 levels by western immunoblot analysis were also assessed as indices of puberty onset. During or after exposure, low-dose BPA restricted BW after birth (at PND1 and PND5), and subsequently accelerated puberty onset by promoting the expression of prepubertal Kiss1 and GnRH1 in the AVPV nucleus on PND30, leading to advanced VO, an elevation in LH and FSH concentrations (on PND30). We also noted increased BW on PND30 and PND35. Maternal oral exposure to low-dose BPA altered the BW curve during the neonatal and peripubertal periods, and subsequently accelerated puberty onset by promoting prepubertal Kiss1 expression in the AVPV nucleus. • Maternal exposure to low-dose BPA alters the bodyweight curve in female offspring. • Peripubertal hormone levels changed after exposure. • BPA accelerates the development of the ovaries and uteri. • Increased protein levels of Kiss1 and GnRH1 were observed in hypothalamus. [ABSTRACT FROM AUTHOR]

Bisphenols, synthetic organic compounds used in the production of plastics, are an extremely abundant class of Endocrine Disrupting Chemicals, i.e., exogenous chemicals or mixtures of chemicals that can interfere with any aspect of hormone action. Exposure to BPs can lead to a wide range of effects, and it is especially dangerous if it occurs during specific critical periods of life. Focusing on the perinatal exposure to BPA or its largely used substitute BPS, we investigated the effects on anxiety-related behaviors and the serotonergic system, which is highly involved in controlling these behaviors, in adult mice. We treated C57BL/6J dams orally with a dose of 4 μg/kg body weight/day (i.e., EFSA TDI) of BPA or BPS dissolved in corn oil or with vehicle alone, at the onset of mating and continued treatment until the offspring were weaned. Adult offspring of both sexes performed the elevated plus maze and the open field tests. Then, we analyzed the serotonergic system in dorsal (DR) and median (MnR) raphe nuclei by immunohistochemical techniques. Behavioral tests highlighted alterations in BPA- and BPS-treated mice, suggesting different effects of the bisphenols exposure on anxiety-related behavior in males (anxiolytic) and females (anxiogenic). The analysis of the serotonergic system highlighted a sex dimorphism in the DR only, with control females showing higher values of serotonin immunoreactivity (5-HT-ir) than control males. BPA-treated males displayed a significant increase of 5-HT-ir in all analyzed nuclei, whereas BPS-treated males showed an increase in ventral DR only. In females, both bisphenols-treated groups showed a significant increase of 5-HT-ir in dorsal DR compared to the controls, and BPA-treated females also showed a significant increase in MnR.These results provide evidence that exposure during the early phases of life to BPA or BPS alters anxiety and the raphe serotonergic neurons in a sex-dependent manner. [Display omitted] • Exposure to low-dose bisphenol A or S during the perinatal period represents a risk to the developing organism. • Anxiety-related behaviors are altered in bisphenol A or S-exposed mice. • Serotonergic system within dorsal and median raphe nuclei is altered in bisphenol A or S exposed mice. • Perinatal exposure to bisphenol A or S affected differentially the two sexes. • New and more stringent regulations on the use of BPA and its analogue BPS are needed. [ABSTRACT FROM AUTHOR]

Background: During early life, exposure to environmental toxicants, including endocrine disruptor bisphenol A (BPA), can be detrimental to the immune system. To our knowledge, a few researches have looked at the effects of developing BPA exposures on the spleen. Aim: The murine model was developed to investigate the underlying molecular mechanisms and mode of BPA actions on the spleen subsequent to prolonged early-life exposure to BPA. Methods: Immature (3-week-old) male and female Swiss Albino mice were intraperitoneally injected with 50 µg/kg BPA in corn oil or corn oil alone for 6 weeks. Mouse spleens were harvested and examined histologically at 10 weeks old (adulthood). Results: We observed neurobehavioral impairments and a significant increase in peripheral monocyte and lymphocyte counts in mice (males and females). Moreover, several spleen abnormalities in both male and female mice were observed in adulthood. BPA-treated mice's histopathological results revealed toxicity in the form of significantly active germinal centers of the white pulp and a few apoptotic cells. There was also a notable invasion of the red pulp by eosinophils and lymphocytes that were significantly higher than normal. Agarose gel electrophoresis provided further evidence of internucleosomal DNA fragmentation and apoptosis in the splenic tissues of BPA-treated mice compared to controls. In addition, there were increased levels of the lipid peroxidation malondialdehyde end-product, a marker of oxidative lipid damage, in the spleens of BPA-treated mice compared to controls. Conclusion: Our study provides evidence that oxidative stress injury induced by early-life exposures to BPA could contribute to a range of splenic tissue damages during adulthood. [ABSTRACT FROM AUTHOR]

Background: During early development, environmental compounds can induce adult onset diseases and disrupt the circulating vitamin D (VitD) levels. Aim: This study aimed to examine the protective role of VitD against the adverse effects of BPA on male and female mice. Methods: A total of 60 male and female Swiss Albino mice (3 weeks old) were randomly divided into 5 groups; each consisted of 12 mice (6 males and 6 females) and was treated as follows: Group I received no treatment (sham control); Group II, sterile corn oil only (vehicle control); Group III, BPA (400 μg/kg); Group IV, VitD (2,195 IU/kg); and Group V, BPA + VitD. At 10.5 weeks, the animals were sacrificed to conduct histological examinations. Results: BPA-exposed mice were found to have neurobehavioral abnormalities, heart, kidney, and lung diseases with increased apoptotic indices in both sexes. On the other hand, the treatment of BPA mice with VitD altered this scenario with modulated motor activity, enhanced body and organ weights, and preserved the heart, kidney, and lung architecture, alongside a decreased percent apoptotic index. Conclusion: Our findings illustrate that VitD protects mice against BPA-induced heart, kidney, and lung abnormalities. [ABSTRACT FROM AUTHOR]

Study Question: How does paternal exposure to bisphenol A (BPA) affect the fertility of male offspring in mice in future generations?Summary Answer: Paternal exposure to BPA adversely affects spermatogenesis, several important sperm functions and DNA methylation patterns in spermatozoa, which have both multigenerational (in F0 and F1) and partial transgenerational (mainly noticed in F2, but F3) impacts on the fertility of the offspring.What Is Known Already: BPA, a synthetic endocrine disruptor, is used extensively to manufacture polycarbonate plastics and epoxy resins. Growing evidence suggests that exposure to BPA during the developmental stages results in atypical reproductive phenotypes that could persist for generations to come.Study Design, Size, Duration: CD-1 male mice (F0) were treated with BPA (5 or 50 mg/kg body weight per day (bw/day)) or ethinylestradiol (EE) (0.4 μg/kg bw/day) for 6 weeks. Control mice were treated with vehicle (corn oil) only. The treated male mice were bred with untreated female mice to produce first filial generation (F1 offspring). The F2 and F3 offspring were produced similarly, without further exposure to BPA.Participants/materials, Setting, Methods: Histological changes in the testis along with functional, biochemical and epigenetic (DNA methylation) properties of spermatozoa were investigated. Subsequently, each parameter of the F0-F3 generations was compared between BPA-treated mice and control mice.Main Results and the Role Of Chance: Paternal BPA exposure disrupted spermatogenesis by decreasing the size and number of testicular seminiferous epithelial cells, which eventually led to a decline in the total sperm count of F0-F2 offspring (P < 0.05). We further showed that a high BPA dose decreased sperm motility in F0-F2 males by mediating the overproduction of reactive oxygen species (F0-F1) and decreasing intracellular ATP (F0-F2) in spermatozoa (P < 0.05). These changes in spermatozoa were associated with altered global DNA methylation patterns in the spermatozoa of F0-F3 males (P < 0.05). Furthermore, we noticed that BPA compromised sperm fertility in mice from the F0-F2 (in the both dose groups) and F3 generations (in the high-dose group only). The overall reproductive toxicity of BPA was equivalent to or higher (high dose) than that of the tested dose of EE.Large Scale Data: N/A.Limitations, Reasons For Caution: Further research is required to determine the variables (e.g. lowest BPA dose) that are capable of producing changes in sperm function and fertility in future generations.Wider Implications Of the Findings: These results may shed light on how occupational exposure to BPA can affect offspring fertility in humans.Study Funding/competing Interest(s): This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant No. NRF-2018R1A6A1A03025159). M.S.R. was supported by Korea Research Fellowship Program through the NRF funded by the Ministry of Science and ICT (Grant No. 2017H1D3A1A02013844). There are no competing interests. [ABSTRACT FROM AUTHOR]

Bisphenol-A (BPA) used in the production of plastic materials is a temperature-soluble agent. It also has a steroid hormone-like activity; therefore, it poses a danger to human health. In our study, we aimed to investigate the effects of BPA on lymph node and spleen in male rats exposed to this agent during prenatal stage. The pregnant female rats were divided into four groups: control, sham, low dose (300 µg/kg BPA), and high dose (900 µg/kg BPA). BPA was dissolved in 1 mL of corn oil and administered to the pregnant rats every day during pregnancy. On the 21st and 45th day after the birth, male rats' lymph node and spleen samples were taken and histopathological examination was performed. Samples were stained with hematoxylin and eosin to determine the general histological appearance, and with CD3 and CD20 immunohistochemically. The results of staining were evaluated by H-score, and statistical analysis was performed. In the samples, BPA applications were not found to cause significant tissue damage. But there was a significant decrease in the immunoreactivities of CD3 and CD20 after BPA applications in both 21st and 45th day samples. After high dose BPA administration, decreased CD3 immunoreactivity was statistically significant. It is thought that BPA does not cause histologically significant tissue damage, but it may impair organ function at cellular level. The investigation of molecules involved in organ function will be useful in revealing the mechanisms that will cause dysfunction. [ABSTRACT FROM AUTHOR]

Although bisphenol A (BPA) has been associated with impaired spermatogenesis, the mechanisms remain unclear. Tight junction occludin plays important roles in spermatogenesis. The objective of the present study was to explore the effects of BPA exposure in adolescent mice. Male mice were orally treated with low-dose (0.05 mg/kg/d), middle-dose (5.0 mg/kg/d), or high-dose (50 mg/kg/d) BPA in corn oil from postnatal day (PND) 35 to 65. Animals were killed on PND 65 and PND 125. On PND 65, the sperm count, sperm motility, and the expression of occludin showed a dose-related decline. On PND 125, the sperm count, sperm motility, and the expression of occludin were in recovery. However, there remained significant decreases in these parameters in the 50 mg/kg/d group on PND 125 compared with the control. The dose-related effects on the measured parameters and occludin expression suggest an early suppressive or damaging effect on the blood–testis barrier followed by recovery after dosing ceased. At a BPA dose of 50 mg/kg/d, recovery did not occur, suggesting that higher doses of BPA may cause irreversible damage to reproduction in male mice. [ABSTRACT FROM AUTHOR]

This study was performed to examine the transgenerational effects of bisphenol (BP) A analogs, BPE, and BPS on male reproductive functions using mice as a model. CD-1 mice (F0) were orally exposed to control treatment (corn oil), BPA, BPE, or BPS (0.5 or 50 µg/kg/day) from gestational day 7 (the presence of vaginal plug = 1) to birth. Mice from F1 and F2 offspring were used to generate F3 males. Prenatal exposure to BPA, BPE, and BPS decreased sperm counts and/or motility and disrupted the progression of germ cell development as morphometric analyses exhibited an abnormal distribution of the stages of spermatogenesis in F3 males. Dysregulated serum levels of estradiol-17β and testosterone, as well as expression of steroidogenic enzymes in F3 adult testis were also observed. In the neonatal testis, although apoptosis and DNA damage were not affected, mRNA levels of DNA methyltransferases, histone methyltransferases, and their associated factors were increased by BP exposure. Furthermore, BP exposure induced immunoreactive expression of DNMT3A in Sertoli cells, strengthened DNMT3B, and weakened H3K9me2 and H3K9me3 in germ cells of the neonatal testis, whereas DNMT1, H3K4me3, and H3K27ac were not affected. In adult testis, stage-specific DNMT3B was altered by BP exposure, although DNMT3A, H3K9me2, and H3K9me3 expression remained stable. These results suggest that prenatal exposure to BPA, BPE, and BPS induces transgenerational effects on male reproductive functions probably due to altered epigenetic modification following disruption of DNMTs and histone marks in the neonatal and/or adult testis. [ABSTRACT FROM AUTHOR]

This study was performed to examine the transgenerational effects of bisphenol (BP) A analogs, BPE, and BPS on female reproductive functions using mice as a model. CD-1 mice (F0) were orally exposed to control treatment (corn oil), BPA, BPE, or BPS (0.5 or 50 µg/kg/day) from gestational day 7 (the presence of vaginal plug = 1) to birth. Mice from F1 and F2 offspring were used to generate F3 females. Prenatal exposure to BPA, BPE, and BPS accelerated the onset of puberty and exhibited abnormal estrous cyclicity in F3 females, and those females exhibited mating difficulties starting at 6 months of age. Various fertility problems including reduced pregnancy rates, parturition, and nursing issues were also observed starting at 6 months, which worsened at 9 months. The levels of serum estradiol-17β were elevated by BPA or BPS exposure at the age of 6 months, whereas testosterone levels were not affected. The dysregulated expression of steroidogenic enzymes was observed in the ovary at 3 or 6 months of age by BPE or BPS exposure. However, BPA, BPE, and BPS exposure did not affect neonatal follicular development such as germ cell nest breakdown or follicle numbers in the ovary on postnatal day 4. These results suggest that prenatal exposure to BPA analogs, BPE and BPS, have transgenerational effects on female reproductive functions in mice. [ABSTRACT FROM AUTHOR]

This study was performed to examine whether prenatal exposure to bisphenol (BP) A analogues, BPE and BPS, negatively impacts female reproductive functions and follicular development using mice as a model. CD-1 mice were orally exposed to control treatment (corn oil), BPA, BPE, or BPS (0.5, 20, or 50 µg/kg/day) from gestational day 11 (the presence of vaginal plug = 1) to birth. Exposure to BPA, BPE, and BPS accelerated the onset of puberty and exhibited abnormal estrous cyclicity, especially with lower doses. Females exposed to BPA, BPE, and BPS exhibited mating difficulties starting at 6 months of age. By 9 months, mice exhibited various fertility problems including reduced pregnancy rate, parturition issues, and increased dead pups at birth. Furthermore, the levels of serum testosterone were elevated by BPE or BPS exposure at the age of 9 months, whereas estrogen levels were not affected. On the other hand, the dysregulated expression of steroidogenic enzymes was observed in the ovary at 3, 6, or 9 months of age by BPE or BPS exposure. When we examined neonatal ovary on postnatal day 4, BPA, BPE, and BPS exposure inhibited germ cell nest breakdown and reduced number of primary and secondary follicles. These results suggest that prenatal exposure to BPA analogues, BPE, and BPS, have effects on fertility in later reproductive life probably due to the disruption of early folliculogenesis. [ABSTRACT FROM AUTHOR]

This study was performed to examine whether bisphenol (BP) A analogues, BPE and BPS, negatively impacts reproductive functions using mice as a model. CD-1 mice were exposed to control treatment (corn oil), BPA, BPE and BPS (50 μg/kg or 10 mg/kg) from birth to postnatal day (PND) 60 by s.c. injection every three days. Sperm counts or motility was significantly reduced by BPA, BPE or BPS exposure on PND 60 or PND 90. Exposure of BPA, BPE and BPS disrupted the progression of germ cell development, as morphometric analyses exhibited an abnormal distribution of the stages of spermatogenesis. In females, postnatal BPA and BPE exposure accelerated the onset of puberty, and increased body weight after parturition. Furthermore, postnatal exposure of BPA, BPE and/or BPS increased steroid hormone levels in serum. These results suggest that BPA analogues (BPS and BPE) affects male and female reproductive functions. [ABSTRACT FROM AUTHOR]

Connections between the mixture containing bis(2- ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bisphenol A (BPA) and liver injury were explored through in silico investigation and 2 in vivo models. Comparative Toxicogenomics Database (CTD), ShinyGO, ToppCluster and Cytoscape were used for bioinformatic analysis. In vivo subacute study was performed on rats - five groups (n = 6): (1) Control: corn oil, (2) DEHP: 50 mg/kg b.w./day, (3) DBP: 50 mg/kg b.w./day, (4) BPA: 25 mg/kg b.w./day, (5) MIX: DEHP + DBP + BPA. Zebrafish embryos were exposed to the investigated substances in different doses, singularly and combined (binary and ternary mixtures). Liver injury was linked to 75 DEHP, DBP, and BPA genes, mostly connected to inflammation/oxidative stress. In rats, significant alterations in redox status/bioelements and pathohistology were most notable or exclusively present in MIX (probable additive effects). BPA decreased liver area (LA) index in dose-dependent manner. DEHP (< 2 µg/mL) and DBP (≤ 5 µg/mL) reduced LA values, while their higher doses increased LA index. The effect of DBP in binary mixtures led to a lethal outcome at the two highest concentrations, while the hepatotoxicity of DEHP/DBP/BPA mixture was dictated by BPA (confirmed by the benchmark dose analysis). [Display omitted] • Oxidative stress and inflammation – the most important mechanisms. • Changes in rat liver – most prominent/present only in the MIX group. • Redox status and bioelements changes – most prominent/present only in the MIX group. • Zebrafish: DBP in binary mixtures – lethal outcome at two highest concentrations. • Zebrafish: hepatotoxicity of DEHP/DBP/BPA mixture dictated by BPA. [ABSTRACT FROM AUTHOR]

Objective: To explore the effects of bisphenol A (bisphenol A, BPA) on the oocyte chromosome non-disjunction in iNos-/- mice. Methods: Female iNos-/- mice and iNos-/- mice, aged 20-22 days, were treated with BPA (100 or 200 µ g/kg body weight per day) by intragastric administration for 13 days. The isopyknic corn oil was used as control. Results: In the iNos-/- mice groups, the numbers of aneuploidy oocytes at metaphase M II were not increased by BPA treatment. Interestingly, the numbers of those oocytes with the error- prone chromosome segregation and the precocious chromatid separation in the iNos-/- mice groups were significantly increased by BPA treatment. Meanwhile, the expressions of polo-like kinase-1 (PLK1) and RAN GTPase (RAN) in oocytes of the iNos-/- mice were significantly down-regulated by BPA treatment. Conclusions: iNos-/- has a direct or indirect protection against the faithful chromosome segregation during meiosis, possibly by maintaining stable expression of PLK1 and RAN in mammalian oocytes. BPA exposure at low level may induce chromosomal aberrations in those oocytes of iNos-/- mice. [ABSTRACT FROM AUTHOR]

Abstract: Previous work has shown that exposure to bisphenol A (BPA) can affect anxiety behavior. However, no studies have examined whether administration of this endocrine disruptor during the perinatal period has the potential to induce alterations in cognitive behavior in both adult males and females as assessed in an appetitive task. The goal of the current study was to determine whether exposure to different doses of BPA during early development alters performance on the 17-arm radial maze in adulthood in Long–Evans rats. Oral administration of corn oil (vehicle), 4μg/kg, 40μg/kg, or 400μg/kg BPA to the dams occurred daily throughout pregnancy, and the pups received direct oral administration of BPA between postnatal days 1–9. Blood was collected from offspring at weaning age to determine levels of several hormones (thyroxine, thyroid stimulating hormone, follicle stimulating hormone, luteinizing hormone). One male and one female from each litter were evaluated on the 17-arm radial maze, a working/reference memory task, in adulthood. Results indicated that after exposure to BPA at both 4 and 400μg/kg/day, rats of both sexes had decreased levels of FSH at weaning. There were no significant effects of BPA on performance on the radial arm maze in males or females. In conclusion, exposure to BPA during early development had modest effects on circulating hormones but did not affect performance on a spatial learning and memory task. [Copyright &y& Elsevier]

The aim of this study was to explore the mechanisms of bis(2- ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bisphenol A (BPA) mixture-induced asthma development and test probiotic as a potential positive intervention. Comparative Toxicogenomics Database (CTD) and ToppGene Suite were used as the main tools for in silico analysis. In vivo 28-day experiment was conducted on rats - seven groups (n = 6): (1) Control: corn oil, (2) P: probiotic (8.78 * 108 CFU/kg/day); (3) DEHP: 50 mg/kg b.w./day, (4) DBP: 50 mg/kg b.w./day, (5) BPA: 25 mg/kg b.w./day; (6) MIX: DEHP + DBP + BPA; (7) MIX + P. Lungs, thymus and kidneys were extracted and prepared for redox status and essential metals analysis. By conducting additional in vitro experiment, probiotic phthalate and BPA binding ability was explored. There were 24 DEHP, DBP and BPA asthma-related genes, indicating the three most probable mechanisms - apoptosis, inflammation and oxidative stress. In vivo experiment confirmed that significant changes in redox status/essential metal parameters were either prominent, or only present in the MIX group, indicating possible additive effects. In vitro experiment confirmed the ability of the multy-strain probiotic to bind DEHP/DBP/BPA mixture, while probiotic administration ameliorated mixture-induced changes in rat tissue. [Display omitted] • MIX (DEHP + DBP + BPA): 24 mutual genes connected with asthma development. • Apoptosis, inflammation and oxidative stress – the most probable mechanisms. • Redox status and bioelements changes – most prominent/present only in the MIX group. • Multi-strain probiotic bound 29.25, 29.04 and 41.75% for DEHP, DBP and BPA. • Probiotic mitigated MIX-induced changes in rat lung, thymus and kidney tissue. [ABSTRACT FROM AUTHOR]

Abstract: This study examines the effects of neonatal exposure to the endocrine disruptor bisphenol A (BPA) on the hypothalamic circuitry controlling the female sexual behaviors of adult rats. From postnatal day 1 (PND1) to PND7, pups were injected with corn oil (control) or BPA (BPA20: 20mg/kg-d; BPA.05: 0.05mg/kg-d) and at PND85 the rats were bilaterally ovariectomized (OVX). At PND100, OVX-rats received estradiol alone or estradiol and progesterone to evaluate estrogen-dependent gene expression in the hypothalamus and sexual behavior. In BPA-exposed females, estrogen receptor alpha (ERα) expression was down-regulated in both the medial preoptic (MPN) and ventromedial nucleus (VMHvl), while repressor of estrogen receptor activity (REA) expression was up-regulated in the VMHvl. Interestingly, BPA-exposed females displayed significantly lower levels of proceptive behavior. Our results show that BPA permanently alters the hypothalamic estrogen-dependent mechanisms that govern sexual behavior in the adult female rat. [Copyright &y& Elsevier]

Growing evidence suggests that developmental exposure to bisphenol A (BPA)—a synthetic endocrine disruptor—causes atypical reproductive phenotypes that may persist for generations. However, the precise mechanism(s) by which BPA causes these adverse consequences is unclear. Here, pregnant female mice were orally exposed to 50 μg, 5 mg, and 50 mg BPA/kg body weight (bw)/day from 7 to 14 days of gestation. Corn oil treatments were used as control. The first filial generation (F1) and F2 males were used to generate F3 by mating them with unexposed females. High BPA doses impaired F1 and/or F1–F2 (multigenerational effect) male reproduction (i.e., disrupted testicular germ cell organization and spermatogenesis, altered sperm biochemical properties, and decreased sperm count, motility, and fertility) but not that of F3 males (transgenerational effect). Moreover, the observed multigenerational transmission of the abnormal reproductive traits was associated with alterations in the sperm DNA methylation patterns of specific male generations, with substantial proteomic changes in F1–F3 at the highest BPA dose. Given that the proteins related to male fertility and epigenetic modification are highly conserved among vertebrates, our findings may shed light on how exposure to environmental factors during pregnancy affects fertility in future generations in both humans and the other animals. [Display omitted] • BPA affects germ cell organization, spermatogenesis, sperm function, and fertility. • BPA significantly impaired sperm function/male fertility in F1 and/or F1–F2 males. • BPA effects linked to DNA methylation and proteome changes in male germ cells. • Levels of BPA exposure need to be redefined that are currently thought to be nontoxic. [ABSTRACT FROM AUTHOR]

Linkage between bis(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and bisphenol A (BPA) co-exposure and type 2 diabetes mellitus (T2DM), as well as ability of multi-strained probiotic to reduce DEHP, DBP and BPA mixture-induced oxidative damage in rat pancreas were investigated. The Comparative Toxicogenomics Database, Cytoscape software and ToppGene Suite were used for data-mining. Animals were sorted into seven groups (n = 6): (1) Control group: corn oil, (2) P: probiotic: Saccharomyces boulardii + Lactobacillus rhamnosus + Lactobacillus plantarum LP 6595 + Lactobacillus plantarum HEAL9; (3) DEHP: 50 mg/kg b.w./day, (4) DBP: 50 mg/kg b.w./day, (5) BPA: 25 mg/kg b.w./day, and (6) MIX: 50 mg/kg b.w./day DEHP + 50 mg/kg b.w/day DBP + 25 mg/kg b.w./day BPA; (7) MIX + P. Rats were sacrificed after 28 days of oral exposure. In silico investigation highlighted 44 DEHP, DBP and BPA mutual genes linked to the T2DM, while apoptosis and oxidative stress were highlighted as the main mechanisms of DEHP, DBP and BPA mixture-linked T2DM. In vivo experiment confirmed the presence of significant changes in redox status parameters (TOS, SOD and SH groups) only in the MIX group, indicating possible additive effects, while probiotic ameliorated mixture-induced redox status changes in rat pancreatic tissue. [Display omitted] • MIX (DEHP, DBP and BPA): 44 mutual genes linked to T2DM. • Apoptosis and oxidative stress – the most probable mechanisms of MIX-linked T2DM. • Significant redox status parameters changes (TOS, SOD and SH) only in the MIX group. • Polybiotic ameliorated MIX-induced redox status changes in rat pancreatic tissue. [ABSTRACT FROM AUTHOR]

Phthalates and bisphenol A, to which people are mainly exposed through food, interfere with the body's endocrine system, along with various other toxic effects. Literature data suggest that probiotic cultures might be able to decrease the adverse effects of toxic substances by various mechanisms. The aim of this study was to investigate if treatment with multi-strained probiotic could reduce the toxicity of phthalates and bisphenol A mixture in Wistar rats. Animals were divided into four experimental groups (n = 6): (1) Control (corn oil); (2) P (probiotic (8.78 * 108 CFU/kg/day): Saccharomyces boulardii + Lactobacillus rhamnosus + Lactobacillus planarum LP 6595+ Lactobacillus planarum HEAL9); (3) MIX (50 mg/kg b.w./day DEHP + 50 mg/kg b.w/day DBP + 25 mg/kg b.w./day BPA); (4) MIX + P. Animals were euthanized after 28 days of daily oral gavage treatment; blood and organs were collected for further analysis. Probiotic reduced systemic inflammation and had protective effects on liver, kidneys, spleen, lipid status and serum glucose level. It almost completely annulled the changes in biochemical, hematological and hormonal parameters and mitigated changes in relative liver size, food consumption and organ histology. These results suggest considering multi-strained probiotics as a dietary therapeutic strategy against toxicity of the investigated mixture. Image 1 • Probiotic reduced phthalates and bisphenol A mixture-induced organ toxicity. • The probiotic treatment attenuated mixture-induced systemic inflammation. • Probiotic annulled changes in biochemical, hematological and hormonal parameters. • Probiotic mitigated changes in liver weight, food consumption and organ histology. • Multi-strained probiotic – potential strategy against mixture toxicity. [ABSTRACT FROM AUTHOR]