A novel approach to assessing bisphenol-A hazards using an in vitro model system (original) (raw)
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Effect of antioxidants on BPA-induced stress on sperm function in a mouse model
Scientific Reports
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. Bisphenol A [BPA; 2,2-bis(4-hydroxyphenyl) propane] is a common endocrine disruptor that is widely used in plastic industries and is capable of altering the synthesis, metabolism, transport, and elimination processes of endogenous hormones and, thus, of mimicking/antagonizing hormonal activities in the body 1. Recent studies have suggested that BPA causes developmental, systemic, neurological, immune, and reproductive disorders 2,3. As a reproductive toxicant, it is linked with impaired steroidogenesis, defective embryo development, testicular/epididymal malfunction, abnormal accessory sex gland functions, and so on, and thus causes subfertility/ infertility 2,4,5. The easiest way to avoid BPA toxicity is to minimise its exposure. However, human exposure to this chemical is ubiquitous via oral, respiratory, and dermal routes 2,6,7 , and it is practically challenging to limit its use in everyday life. Therefore, the development of potential therapeutic strategies is one of the best options for minimizing BPA toxicity. BPA acts as a selective estrogen receptor (ER) modulator by binding with genomic (nuclear and cytoplasmic) and non-genomic (membrane bound) ERs in cells 2,7. In addition, BPA acts as an activator of estrogen-related receptor gamma 8 and growth factor receptors 9 , antagonises thyroid hormone receptor 10 , and possesses anti-androgenic properties 11. Mature spermatozoa contain the majority of these receptors (e.g. ERα, ERβ, growth factor, and androgen receptor) 12 ; therefore, spermatozoa are potentially a suitable model for examining the effects and molecular mechanism of BPA, as well as its subsequent effects on male fertility/reproduction. Recently, we showed that the exposure of mice spermatozoa to 100 µM BPA exhibits a rapid non-genomic estrogenic signaling by the activation of several kinase systems 7. Decreased motility, abnormal acrosome reaction, altered mitochondrial activities, and decreased fertilisation and embryo development were observed in the BPA-exposed spermatozoa 6,7. Similar adverse effects have also been reported in F1 spermatozoa following gestational exposure to BPA 13,14. These harmful effects appeared mostly because of the increased oxidative stress in BPA-treated spermatozoa as detected by elevated reactive oxygen species (ROS) levels 6,13,14. Furthermore, a few studies have reported an increase in BPA-induced oxidative stress in neuronal 15 and kidney cells 16. Although low levels of ROS are important for regulating normal sperm functions, such as capacitation 17 , acrosome reaction 18 ,
Journal of proteome research, 2017
Studies regarding bisphenol A (BPA) exposure and male (in)fertility have conventionally focused on modifications in ejaculated spermatozoa function from exposed individuals. However, mammalian spermatozoa are incapable of fertilization prior to achieving capacitation, the penultimate step in maturation. Therefore, it is necessary to investigate BPA-induced changes in capacitated spermatozoa and assess the consequences on subsequent fertilization. Here, we demonstrate the effect of gestational BPA exposure (50 μg/kg bw/day, 5 mg/kg bw/day, and 50 mg/kg bw/day) on the functions, biochemical properties, and proteomic profiles of F1 capacitated spermatozoa from adult mice. The data showed that high concentrations of BPA inhibited motility, motion kinematics, and capacitation of spermatozoa, perhaps because of increased lipid peroxidation and protein tyrosine nitration, and decreased intracellular ATP levels and protein kinase-A activity in spermatozoa. We also found that BPA compromised...
Toxicology, 2015
Reproductive physiology involves complex biological processes that can be disrupted by exposure to environmental contaminants. The effects of bisphenol A (BPA) on spermatogenesis and sperm quality is still unclear. The objective of this study was to investigate the reproductive toxicity of BPA at dosages considered to be safe (5 or 25 mg BPA/kg/day). We assessed multiple sperm parameters, the relative expression of genes involved in the central regulation of the hypothalamic-pituitary-testicular axis, and the serum concentrations of testosterone, estradiol, LH and FSH. BPA exposure reduced sperm production, reserves and transit time. Significant damage to the acrosomes and the plasma membrane with reduced mitochondrial activity and increased levels of defective spermatozoa may have compromised sperm function and caused faster movement through the epididymis. BPA exposure reduced the serum concentrations of testosterone, LH and FSH and increased the concentration of estradiol. The relative gene expression revealed an increase in gonadotropin releasing hormone receptor (Gnrhr), luteinizing hormone beta (Lhb), follicle stimulating hormone beta (Fshb), estrogen receptor beta (Esr2) and androgen receptor (Ar) transcripts in the pituitary and a reduction in estrogen receptor alpha (Esr1) transcripts in the hypothalamus. In this study, we demonstrated for the first time that adult male exposure to BPA caused a reduction in sperm production and specific functional parameters. The corresponding pattern of gene expression is indicative of an attempt by the pituitary to reestablish normal levels of LH, FSH and testosterone serum concentrations. In conclusion, these data suggest that at dosages previously considered nontoxic to reproductive function, BPA compromises the spermatozoa and disrupts the hypothalamic-pituitary-gonadal axis, causing a state of hypogonadotropic hypogonadism. 2015 Elsevier Ireland Ltd. All rights reserved.
Bisphenol A affects the maturation and fertilization competence of spermatozoa
Ecotoxicology and Environmental Safety, 2020
Although there are numerous studies on bisphenol A (BPA) on the testis and spermatozoa, the effect of BPA on the physiological link between the testis and maturation of spermatozoa has not been studied. To provide an optimal environment (acidic pH) for sperm maturation in the epididymis, clear cells secrete protons and principal cells reabsorb bicarbonate and the secreted proton. Because of its crucial role in sperm maturation and fertility, functional changes in the epididymis following BPA exposure must be considered to fully understand the mechanisms of BPA on male fertility. Here, we identified the adverse effects of BPA exposure during puberty in male mice. CD-1 male mice were gavaged daily with vehicle (corn oil) and 50 mg BPA/kg-BW for 6 weeks. We determined the changes in epididymis, functional sperm parameters including motility, capacitation status, tyrosine phosphorylation, and fertility-related protein expression and in vitro and in vivo fertility rate following BPA exposure. Expression of vacuolar-type H +-ATPase is necessary for the secretion of protons by clear cells of the caput epididymis and was directly down-regulated following BPA exposure, while there were no changes in the other epithelial cell types in the epididymis. Also, pERK 1/2 signaling pathway was increased significantly in the caput epididymis following BPA exposure. Consequently, the luminal pH slightly increased, resulting in premature capacitation of spermatozoa. Moreover, there was a significant loss of the acrosomal membrane following an increase of protein tyrosine phosphorylation, while PKA activity decreased during sperm capacitation. Fertility-related proteins also showed aberrant expression upon BPA exposure. These modifications resulted in decreased male fertility in vitro and in vivo.
Bisphenol-A Affects Male Fertility via Fertility-related Proteins in Spermatozoa
The xenoestrogen bisphenol-A (BPA) is a widespread environmental contaminant that has been studied for its impact on male fertility in several species of animals and humans. Growing evidence suggests that xenoestrogens can bind to receptors on spermatozoa and thus alter sperm function. The objective of the study was to investigate the effects of varying concentrations of BPA (0.0001, 0.01, 1, and 100 mMfor 6 h) on sperm function, fertilization, embryonic development, and on selected fertility-related proteins in spermatozoa. Our results showed that high concentrations of BPA inhibited sperm motility and motion kinematics by significantly decreasing ATP levels in spermatozoa. High BPA concentrations also increased the phosphorylation of tyrosine residues on sperm proteins involved in protein kinase A-dependent regulation and induced a precocious acrosome reaction, which resulted in poor fertilization and compromised embryonic development. In addition, BPA induced the down-regulation of b-actin and up-regulated peroxiredoxin-5, glutathione peroxidase 4, glyceraldehyde-3-phosphate dehydrogenase, and succinate dehydrogenase. Our results suggest that high concentrations of BPA alter sperm function, fertilization, and embryonic development via regulation and/or phosphorylation of fertility-related proteins in spermatozoa. We conclude that BPA-induced changes in fertility-related protein levels in spermatozoa may be provided a potential cue of BPA-mediated disease conditions.
Understanding the molecular mechanisms of bisphenol A action in spermatozoa
Clinical and Experimental Reproductive Medicine
Bisphenol A (BPA) is an endocrine-disrupting chemical that is capable of interfering with the normal function of the endocrine system in the body. Exposure to this chemical from BPA-containing materials and the environment is associated with deleterious health effects, including male reproductive abnormalities. A search of the literature demonstrated that BPA, as a toxicant, directly affects the cellular oxidative stress response machinery. Because of its hormone-like properties, it can also bind with specific receptors in target cells. Therefore, the tissue-specific effects of BPA mostly depend on its endocrine-disrupting capabilities and the expression of those particular receptors in target cells. Although studies have shown the possible mechanisms of BPA action in various cell types, a clear consensus has yet to be established. In this review, we summarize the mechanisms of BPA action in spermatozoa by compiling existing information in the literature.
Prenatal exposure to BPA substitution affects the adult male reproductive system in the offspring
Early exposure to bisphenol may result in adverse reproductive health in later life. The use of bisphenol S (BPS) has increased considerably after bisphenol A (BPA) is regulated worldwide. However, little is known about the fetal exposure to BPS compared with BPA and its effects on the reproductive system in the adult male offspring. Here, we investigated the effects of orally administered BPS and BPA (0.4, 4.0, 40.0 μg/kg bw/d) during gestation (gD4-21) on testicular development by evaluating the sperm DNA damage & methylation and testicular functions in the 90 d Wistar rats. Male offspring prenatally exposed to BPS (0.4 μg/kg) had higher plasma testosterone than BPA and control. The testis histology reveals thickened membrane by producing a wide interstitial gap between seminiferous tubules, increased testicular inflammation, oxidative stress, TIMP-1 expression, and decreased VCAM-1 expression. BPS promotes apoptosis by up-regulating IL-6, cleaved caspases, and a spike in sperm DNA fragmentation. Prenatal BPS exposure reduces sperm motility mediated via impaired PI3K-AKT signaling and increases testicular TEX11 expression in the offspring. Exposure of the fetus to BPS interferes developmental programming of the male reproductive system in the offspring. BPS could be an equally potent endocrine disruptor affecting male reproductive functions.
BISPHENOL A REDUCES FERTILIZING ABILITY AND MOTILITY BY COMPROMISING MITOCHONDRIAL FUNCTION OF SPERM
Bisphenol A (BPA) acts as an endocrine disruptor, affects animal reproductive success in vivo and affects sperm functions in vitro at environmentally relevant concentrations, leading to reduction in sperm motility and fertilizing ability in fish. The effect of in vitro BPA on avian sperm functions has not been explored. The present study examined the effect of environmentally relevant concentrations of BPA (0 mM, 0.18 mM, 0.37 mM, and 0.74 mM) on sperm functions in chicken in vitro. Sperm were exposed to concentrations of BPA for 30 min and analyzed for motility, fertilizing ability, live sperm percentage, and mitochondrial membrane potential (Dcm). Results showed that BPA at a concentration of 0.74 mM significantly decreased motility, fertilizing ability, live sperm count percentage, and sperm Dcm. Sperm motility was positively correlated with fertility (r ¼ 0.73, p 0.01), live sperm percentage (r ¼ 0.64, p 0.01), and high Dcm (r ¼ 0.44, p 0.01). A dose-dependent and time-dependent effect of BPA was observed on sperm motility at all BPA concentrations. However, sperm's fertilizing ability was unaffected in low BPA concentration (0.18 mM and 0.37 mM). A significantly higher percentage of moribund sperm was observed at 0.37 mM and 0.74 mM BPA compared with at 0.18 mM BPA, in the negative control, and in the vehicle control. The present study confirms that environmentally relevant concentrations of BPA are capable of compromising sperm functions, leading to reduction in fertilizing ability of chicken sperm. Environ Toxicol Chem 2015;9999:1-6. # 2015 SETAC