Developmental exposure to bisphenol A (BPA), an endocrine-disrupting contaminant, impairs cognitive function in both animals and humans. However, whether BPA affects the development of primary sensory systems, which are the first to mature in the cortex, remains largely unclear. Using the rat as a model, we aimed to record the physiological and structural changes in the primary auditory cortex (A1) following lactational BPA exposure and their possible effects on behavioral outcomes. We found that BPA-exposed rats showed significant behavioral impairments when performing a sound temporal rate discrimination test. A significant alteration in spectral and temporal processing was also recorded in their A1, manifested as degraded frequency selectivity and diminished stimulus rate-following by neurons. These post-exposure effects were accompanied by changes in the density and maturity of dendritic spines in A1. Our findings demonstrated developmental impacts of BPA on auditory cortical processing and auditory-related discrimination, particularly in the temporal domain. Thus, the health implications for humans associated with early exposure to endocrine disruptors such as BPA merit more careful examination.
Humans ; Rats ; Animals ; Benzhydryl Compounds/toxicity* ; Phenols/toxicity* ; Auditory Perception/physiology* ; Neurons/physiology*

OBJECTIVETo investigate the relationship of time-concentration of bisphenol A (BPA) in male Sprague-Dawley (SD) rats after single oral BPA administration.

METHODSA total of 66 specific pathogen free (SPF) SD male rats were divided into 10 experimental groups and control group (n = 6). The experimental group rats were treated with BPA of 300 mg/kg by oral gavage and blood samples were taken from one group at 0.5, 1, 2, 4, 6, 12, 24, 36, 60, 84 h time point after oral administration, respectively. The serum BPA concentration was determined by fluorescence-high performance liquid chromatography (FL-HPLC) analysis.

RESULTSAfter oral administration of 300 mg/kg, the total serum BPA concentration of 17.13 microg/ml was the highest in rats at 1 h, then decreased, but it increased to 15.18 microg/ml again at 24 h, then gradually decreased to 0.51 microg/ml at 84 h. The level of serum free BPA was lower than that of total serum BPA after oral administration, the serum free BPA was 0.57 microg/ml at 0.5 h after oral administration. The serum free BPA level decreased to 0.06 microg/ml at 1 h, 0.03 microg/ml at 4 h, 0.01 microg/ml at 36 h after oral administration. The free BPA was only 4.15% (0.57/13.73) in total BPA in serum at 0.5 h after oral administration of 300 mg/kg BPA.

CONCLUSIONThese results suggested that conjugated BPA was the main metabolite of BPA in rat serum after single oral administration. Enterohepatic circulation of BPA glucuronide in rats may results in two peak levels of total BPA in serum.

Animals ; Benzhydryl Compounds ; Male ; Phenols ; blood ; pharmacokinetics ; toxicity ; Rats ; Rats, Sprague-Dawley ; Serum ; metabolism ; Time Factors

The reproductive toxicity of environmental endocrine disruptors has attracted substantial attention from researchers in recent years. Bisphenol A (BPA) is among the most prominent environmental estrogens worldwide, demonstrated to be related with the impairment of male reproductive function as well as other health problems, such as diabetes, obesity, cardiovascular diseases, and cancer. BPA acts primarily by mimicking antiandrogenic and estrogenic effects, disturbing the hypothalamic-pituitary-testicular axis and modulating gene expressions and enzyme activities in the hormone biosynthesis affecting steroids or its receptors. BPA is also involved in DNA methylation and the effects of epigenetics, resulting in dyszoospermia, oligoasthenoteratospermia/azoospermia and/or infertility in males. This review addresses the effects of BPA on male reproductive function, focusing on the mechanisms of its toxicity on spermatogenesis, semen quality, and the reproductive system.
Benzhydryl Compounds ; toxicity ; Endocrine Disruptors ; toxicity ; Endocrine System ; drug effects ; Environmental Pollutants ; toxicity ; Estrogens ; toxicity ; Humans ; Infertility, Male ; chemically induced ; Male ; Phenols ; toxicity ; Semen Analysis ; Spermatogenesis ; drug effects

BACKGROUND: Traditional toxicological studies focus on individual compounds. However, this single-compound approach neglects the fact that the mixture exposed to human may act additively or synergistically to induce greater toxicity than the single compounds exposure due to their similarities in the mode of action and targets. Mixture effects can occur even when all mixture components are present at levels that individually do not produce observable effects. So the individual chemical effect thresholds do not necessarily protect against combination effects, an understanding of the rules governing the interactive effects in mixtures is needed. The aim of the study was to test and analyze the individual and combined estrogenic effects of a mixture of three endocrine disrupting chemicals (EDCs), bisphenol A (BPA), nonylphenol (NP) and diethylstilbestrol (DES) in immature rats with mathematical models. METHOD: In the present study, the data of individual estrogenic effects of BPA, NP and DES were obtained in uterotrophic bioassay respectively, the reference points for BPA, NP and DES were derived from the dose-response ralationship by using the traditional no observed adverse effect (NOAEL) or lowest observed adverse effect level (LOAEL) methods, and the benchmark dose (BMD) method. Then LOAEL values and the benchmark dose lower confidence limit (BMDL) of single EDCs as the dose design basis for the study of the combined action pattern. Mixed prediction models, the 3 × 2 factorial design model and the concentration addition (CA) model, were employed to analyze the combined estrogenic effect of the three EDCs. RESULTS: From the dose-response relationship of estrogenic effects of BPA, NP and DES in the model of the prepuberty rats, the BMDL(NOAEL) of the estrogenic effects of BPA, NP and DES were 90(120) mg/kg body weight, 6 mg/kg body weight and 0.10(0.25) μg/kg body weight, and the LOAEL of the the estrogenic effects of three EDCs were 240 mg/kg body weight, 15 mg/kg body weight and 0.50 μg/kg body weight, respectively. At BMDL doses based on the CA concept and the factorial analysis, the mode of combined effects of the three EDCs were dose addition. Mixtures in LOAEL doses, NP and DES combined effects on rat uterine/body weight ratio indicates antagonistic based on the CA concept but additive based on the factorial analysis. Combined effects of other mixtures are all additive by using the two models. CONCLUSION Our results showed that CA model provide more accurate results than the factorial analysis, the mode of combined effects of the three EDCs were dose addition, except mixtures in LOAEL doses, NP and DES combined effects indicates antagonistic effects based on the CA model but additive based on the factorial analysis. In particular, BPA and NP produced combination effects that are larger than the effect of each mixture component applied separately at BMDL doses, which show that additivity is important in the assessment of chemicals with estrogenic effects. The use of BMDL as point of departure in risk assessment may lead to underestimation of risk, and a more balanced approach should be considered in risk assessment.
Animals ; Benzhydryl Compounds ; toxicity ; Diethylstilbestrol ; toxicity ; Dose-Response Relationship, Drug ; Drug Interactions ; Endocrine Disruptors ; toxicity ; Estrogens ; toxicity ; Models, Theoretical ; Phenols ; toxicity ; Rats ; Rats, Sprague-Dawley ; Risk Assessment

OBJECTIVETo explore the effect of environmental estrogens on the proliferation of breast cancer cell line MCF-7.

METHODSThe tested compounds were n-4-nonyphenol, Bisphenol A and dibutylphthalate. Human estradiol-dependent MCF-7 breast cancer cells were grown in DMEM medium containing 10% bovine serum. Five days before the addition of the test compounds, the cells were washed by phosphate-buffered saline, and the medium was substituted with a phenol red-free DMEM medium containing 5% dextral charcoal-stripped FBS. The respective test compound was added in fresh medium and the control cell received only the vehicle (ethanol). The proliferation of MCF-7 was analyzed by the MTT assay, (3)H-TdR incorporation assay and flow cytometry.

RESULTSCompared with the ethanol control, the proliferation and DNA synthesis of the test cells treated with n-4-nonyphenol (8 x 10(-7) mol/L, 96 h), Bisphenol A (8 x 10(-7) mol/L, 96 h) or dibutylphthalate (32 x 10(-6) mol/L, 96 h) treatment was markedly enhanced in a time-dependent and dose-dependent manner.

CONCLUSIONn-4-Nonyphenol, Bisphenol A and dibutylphthalate enhanced the proliferation of human breast cancer cell in vitro, which may demonstrate an estrogenic activity.

Benzhydryl Compounds ; Breast Neoplasms ; pathology ; Cell Division ; drug effects ; Cell Line, Tumor ; Dibutyl Phthalate ; toxicity ; Environmental Pollutants ; toxicity ; Estrogens, Non-Steroidal ; toxicity ; Female ; Humans ; Phenols ; toxicity

Bisphenol A (BPA) is a commonly used phenolic environmental estrogen. Long-term exposure of female mammalians to BPA can lead to endocrine disorders, followed by the morphological and functional changes in ovary, uterus, vagina, and oviducts. The interactions of BPA with various target molecules or tissues will cause different effects. To further elucidate the effects of BPA on female reproductive system, we review the changes in the structure and functions of female reproduction system after BPA exposure and their possible mechanisms.
Benzhydryl Compounds ; toxicity ; Endocrine Disruptors ; toxicity ; Estrogens, Non-Steroidal ; toxicity ; Female ; Humans ; Ovary ; drug effects ; Phenols ; toxicity ; Uterus ; drug effects ; Vagina ; drug effects

OBJECTIVETo explore the toxicity of joint exposure to diazinon, propoxur and bisphenol A on phagocytosis.

METHODSFlow cytometer was employed to detect the influence of diazinon and bisphenol A, propoxur and bisphenol A in mixture (mixed according to ratio of IC(50)) on mouse macrophage RAW264.7 cells' function to phagocyte fluorescent microspheres, adopting the percentage of phagocytic cells (PP) and the phagocytic index (PI) as measurement indicators. The final concentrations of mixture of diazinon and bisphenol A were (0.4 + 0.1), (3.6 + 0.7), (36.2 + 7.2), (43.4 + 8.7), (52.1 + 10.4), (62.5 + 12.5), (75.0 + 15.0) µg/ml; while those of mixture of propoxur and bisphenol A were (0.2 + 2.0 × 10(-2)), (2.4 + 0.2), (23.7 + 2.0), (35.6 + 3.0), (53.3 + 4.4), (80.0 + 6.7), (120.0 + 10.0) µg/ml. Then based on the dose-response relationship, a 2 × 2 factorial design was then carried out among different doses of mixture with statistical significance to statistically evaluate the interaction between diazinon and bisphenol A, propoxur and bisphenol A.

RESULTSAfter the joint exposure, compared to the control group (PP = (23.6 ± 2.2)%; PI = 0.36 ± 0.03), any dose of the mixture of diazinon and bisphenol A ((52.1 + 10.4), (62.5 + 12.5), (75.0 + 15.0) µg/ml) could significantly increase the levels of PP ((29.0 ± 1.4)%, t = 3.89, P < 0.05; (30.2 ± 2.3)%, t = 4.74, P < 0.05; (35.0 ± 3.4)%, t = 8.21, P < 0.05) and PI (0.43 ± 0.03, t = 3.86, P < 0.05; 0.41 ± 0.02, t = 2.95, P < 0.05; 0.46 ± 0.03, t = 5.34, P < 0.05); while that of propoxur and bisphenol A ((35.6 + 3.0), (53.3 + 4.4), (80.0 + 6.7), (120.0 + 10.0) µg/ml) reduced the levels of PP ((20.6 ± 1.1)%, t = -3.00, P < 0.05; (20.2 ± 1.0)%, t = -3.42, P < 0.05; (19.4 ± 1.3)%, t = -4.23, P < 0.05; (18.8 ± 2.1)%, t = -4.81, P < 0.05) and PI (0.31 ± 0.01, t = -4.75, P < 0.05; 0.31 ± 0.01, t = -4.58, P < 0.05; 0.30 ± 0.01, t = -4.92, P < 0.05; 0.27 ± 0.02, t = -7.80, P < 0.05) on the contrary. The 2 × 2 factorial design was carried out between the mixture of diazinon (60.0 µg/ml; PP = (28.5 ± 3.4)%; PI = 0.49 ± 0.07) and bisphenol A (12.0 µg/ml; PP = (35.7 ± 2.7)%; PI = 0.67 ± 0.07), and the mixture of propoxur (48.0 µg/ml ; PP = (28.1 ± 2.2)%; PI = 0.48 ± 0.04) and bisphenol A (4.0 µg/ml; PP = (34.4 ± 2.7)%; PI = 0.59 ± 0.07). The mixture of diazinon and bisphenol A (PP = (30.4 ± 1.4)%, F(interaction) = 6.22, P < 0.05; PI = 0.53 ± 0.03, F(interaction) = 7.35, P < 0.05) and the mixture of propoxur and bisphenol A (PP = (27.5 ± 4.1)%, F(interaction) = 4.56, P < 0.05; PI = 0.46 ± 0.08, F(interaction) = 11.13, P < 0.05) both showed a significant antagonistic interaction on phagocytosis of RAW264.7 cell.

CONCLUSIONIt is suggested that the interactions between diazinon & bisphenol A and propoxur & bisphenol A both played the antagonistic role on phagocytic function of macrophages in vitro.

Animals ; Benzhydryl Compounds ; Cell Line ; Diazinon ; toxicity ; Drug Synergism ; Environmental Exposure ; Macrophages ; cytology ; drug effects ; Mice ; Phagocytosis ; drug effects ; Phenols ; toxicity ; Propoxur ; toxicity

OBJECTIVE: Bisphenol A (BPA) is a monomer primarily used in the production of polycarbonate plastic and epoxy resins. Bisphenol F (BPF) is apparently the main BPA replacement that is used increasingly. BPF has been detected in canned food, thermal paper receipts, and soft drinks. In the present experiment, we did both in vitro and in vivo studies to evaluate the effect of low and high-dose BPF exposures on testosterone concentration, oxidative stress, and antioxidants activity in reproductive tissues of male rats. METHODS: Adult (80-90 days old) male Sprague Dawley rats (n = 36) obtained from the rodent colony of Animal Sciences Department of Quaid-i-Azam University. The direct effects of BPF on the antioxidant enzymes and testosterone secretion were measured in vitro and in vivo studies. In an in vivo experiment, adult male Sprague Dawley rats (n = 42) were exposed to different concentrations of bisphenol F (1, 5, 25, and 50 mg/kg/d) for 28 days. Various biochemical parameters were analyzed including the level of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), reactive oxygen species (ROS), and lipid peroxidation (LPO). Moreover, sperm motility, daily sperm production (DSP), comet assay, and histological analysis were performed. RESULTS: In vitro study showed that BPF exposure significantly (p < 0.05) induced oxidative stress biomarkers, i.e., ROS and LPO, while it did not change antioxidant enzyme and testicular testosterone concentration. Whereas, an in vivo study revealed that BPF induced dose-dependent effect and high-dose (100 mg/kg) exposure of BPF significantly reduced tissue protein (p < 0.05) content, CAT (p < 0.001), SOD (p < 0.05), and POD (p < 0.05) levels while significantly (p < 0.05) augmented ROS and lipid peroxidation. Furthermore, BPF reduces testosterone, LH, and FSH secretion in a dose-dependent manner. Significant (p < 0.001) reduction in plasma and intra-testicular testosterone, LH, and FSH was noticed at 100 mg/kg BFP dose. High-dose exposure reduces spermatogenesis. CONCLUSION BPF showed an antagonistic effect on male reproductive hormones and induce alterations in testicular morphology. Increased oxidative stress and decreased testicular antioxidant status might be the underlying mechanism of BFP-induced testicular toxicity.
Animals ; Antioxidants ; metabolism ; Benzhydryl Compounds ; toxicity ; Dose-Response Relationship, Drug ; Environmental Pollutants ; toxicity ; Male ; Oxidative Stress ; drug effects ; Phenols ; toxicity ; Rats ; Rats, Sprague-Dawley ; Testosterone ; metabolism

OBJECTIVETo explore the protective effect of modified danshou decoction (MDD) on teratogenicity of bisphenol A intoxicated pregnant rats.

METHODSForty-four successfully mated rats were randomly divided into 4 groups, 10 in the blank group and 10 in the model group, 12 in the MDD group and 12 in the positive control group. Bisphenol A (BPA) at the dose of 600 mg/kg was given to rats by gastrogavage in the latter three groups from the 1st day of mating to the 20th day, while the soybean oil was given to rats by gastrogavage in the blank group. No intervention was given to rats in the model group, but the normal saline, MDD condensed decoction, and shoutai pill (STP) condensed decoction was respectively given to rats in the rest three groups during the experimental period. All rats were sacrificed by the 20th pregnancy day.

RESULTSCompared with the model group, the body weight of pregnant rats and fetal rats, body length and tail length of the fetal rats significantly increased in the MDD group (P < 0.05). But the effect of MDD was superior to that of STP (P < 0.05). Moreover, the teratogenic rate was significantly lowered in the MDD group (P < 0.05).

CONCLUSIONMDD could promote the weight gaining of pregnant rats and fetal rats, improve the body length and tail length of fetal rats, and lower the teratogenic rate in fetal mice.

Animals ; Benzhydryl Compounds ; toxicity ; Drugs, Chinese Herbal ; pharmacology ; Female ; Phenols ; toxicity ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Reproduction ; drug effects ; Teratogens ; Weight Gain

Objective: To explore the relationship between male sexual function and daily exposure to bisphenol A (BPA) at a reproductive center in Taiyuan. Methods: Male patients who were seeking treatment of infertility due to problems caused by either of the spouse were selected from the Shanxi reproductive center between September 2014 and April 2015. Information on general characteristics, sexual function and fasting venous blood samples were collected. Total scores of sexual function were evaluated by Delphi expert scoring method. Levels of serum BPA were measured by high-performance liquid chromatography. Data was analyzed by Spearman rank correlation, rank sum test, multivariate logistic regression analysis and χ(2) trend test. Relationship between BPA and sexual function was presented as OR and corresponding 95%CI. Results: Among the 353 participants, 45.0% was defined as sexual dysfunction with low sexual desire (47.3%) as the major reason. BPA was detected in all the 353 patients, with a range of concentration as 0.38-21.93 ng/ml and an average as 5.79 ng/ml. Results from the Spearman rank correlation analysis revealed significant negative correlations between serum BPA and sexual function, sexual desire, erectile ability and ejaculation intensity, while serum BPA was positively correlated with premature ejaculation. According to the four percentile of BPA concentration (ng/ml), the subjects were divided into four groups. Compared with the low concentration group (0.38-3.79 ng/ml), the risk of sexual dysfunction significantly increased in the groups with higher BPA levels. Particularly, in the highest BPA group (8.68-21.93 ng/ml), more obvious effects were seen on sexual dysfunction (OR=1.55, 95%CI:1.00-3.23), reduced sexual desire (OR=4.75, 95%CI: 2.44-9.22), reduced erection ability (OR=2.40, 95%CI: 1.18-4.88), reduced ejaculation intensity (OR=2.53, 95%CI: 1.25-5.16) and premature ejaculation (OR=1.95, 95%CI: 1.02-3.72). Conclusion: Low sexual desire appeared as the main type of male sexual dysfunction, the exposure to higher levels of BPA in daily life might lead to male sexual dysfunction.
Benzhydryl Compounds/toxicity* ; Ejaculation/drug effects* ; Environmental Exposure/adverse effects* ; Erectile Dysfunction/chemically induced* ; Humans ; Male ; Occupational Exposure/adverse effects* ; Phenols/toxicity*