scholarly journals Multigenerational and transgenerational impact of paternal bisphenol A exposure on male fertility in a mouse model

2020 ◽  
Vol 35 (8) ◽  
pp. 1740-1752 ◽  
Author(s):  
Md Saidur Rahman ◽  
Won-Ki Pang ◽  
Do-Yeal Ryu ◽  
Yoo-Jin Park ◽  
Myung-Geol Pang
Keyword(s):  
Dna Methylation ◽  
Bisphenol A ◽  
Large Scale ◽  
Corn Oil ◽  
Sperm Count ◽  
Future Generations ◽  
High Dose ◽  
Male Mice ◽  
Paternal Exposure ◽  
Methylation Patterns

Abstract 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.

scholarly journals The Effect of Exposure to Bisphenol A on Spermatozoon and the Expression of Tight Junction Protein Occludin in Male Mice

Dose-Response ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 155932582092674
Author(s):  
Tingshuai Cao ◽  
Yuanchao Cao ◽  
Hongqiang Wang ◽  
Peitao Wang ◽  
Xinsheng Wang ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Tight Junction ◽  
Sperm Motility ◽  
Corn Oil ◽  
Sperm Count ◽  
High Dose ◽  
Male Mice ◽  
Irreversible Damage ◽  
Junction Protein ◽  
Higher Doses

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.

scholarly journals Microwave Assisted DNA Hydrolysis for Global Methylation Analysis by Gas Chromatography/Tandem Mass Spectrometry

2018 ◽  
Vol 62 (2) ◽  
Author(s):  
Karla Viridiana Castro-Cerritos ◽  
Julio Cesar Torres-Elguera ◽  
Jaqueline Capataz-Tafur ◽  
Erick Adrian Juarez-Arellano ◽  
Adolfo Lopez-Torres
Keyword(s):  
Dna Methylation ◽  
Large Scale ◽  
Limit Of Detection ◽  
Multiple Reaction Monitoring ◽  
Good Alternative ◽  
Detection Methods ◽  
Mass Analyzer ◽  
Global Methylation ◽  
Epigenetic Events ◽  
Methylation Patterns

<div><p class="Abstract">The analysis of the global DNA methylation, calculated as the percentage of 5-methylcytosine (5mC) over the total sum of cytosines, is a well stablished biomarker for monitoring large scale epigenetic events in organisms. DNA purification, hydrolysis, separation and detection methods are critical steps to determine this biomarker. In the present work is proposed a robust procedure for DNA acid-hydrolysis assisted by microwave that provides identical DNA methylation patterns that enzymatic hydrolysis and better release of 5mC than acid classic method. The quantification was performed using a gas chromatographer coupled to a mass spectrometer with triple quadrupole as mass analyzer (GC-TQ-MS/MS) using multiple reaction monitoring (MRM) mode for the trimethylsilyl-derivates of nucleobases; following the transitions of 254→238, 240→170 and 254→238, 254→184 (m/z) for C and 5mC respectively, was achieved a limit of detection of 0.46 fmol for C and 0.41 fmol for 5mC. The proposed procedure is capable of determine 0.004% of 5mC in 50 ng of DNA in a chromatographic time of 10 minutes, being a good alternative to LC-MS/MS analysis.</p></div>

Investigation of the effects of bisphenol-A exposure on lymphoid system in prenatal stage

2020 ◽  
Vol 36 (7) ◽  
pp. 502-513
Author(s):  
Işil Aydemir ◽  
Caner Özbey ◽  
Oktay Özkan ◽  
Şadiye Kum ◽  
Mehmet İbrahim Tuğlu
Keyword(s):  
Lymph Node ◽  
Bisphenol A ◽  
Tissue Damage ◽  
Corn Oil ◽  
Histopathological Examination ◽  
Female Rats ◽  
Male Rats ◽  
High Dose ◽  
Organ Function ◽  
Pregnant Rats

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.

scholarly journals Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference

2019 ◽  
Author(s):  
Paul J. Hop ◽  
René Luijk ◽  
Lucia Daxinger ◽  
Maarten van Iterson ◽  
Koen F. Dekkers ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Large Scale ◽  
Population Genomics ◽  
Epigenetic Modification ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Genome Wide ◽  
Scale Population ◽  
Genes Encoding ◽  
Methylation Patterns

SUMMARYDNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identified 818 genes that influence DNA methylation patterns in blood using large-scale population genomics data. By employing genetic instruments as causal anchors, we identified directed associations between gene expression and distant DNA methylation levels, whilst ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. We found that DNA methylation patterns are commonly shaped by transcription factors that consistently increase or decrease DNA methylation levels. However, we also observed genes encoding proteins without DNA binding activity with widespread effects on DNA methylation (e.g. NFKBIE, CDCA7(L) and NLRC5) and we suggest plausible mechanisms underlying these findings. Many of the reported genes were unknown to influence DNA methylation, resulting in a comprehensive resource providing insights in the principles underlying epigenetic regulation.

124 THE REGULATION OF CALCIUM TRANSPORT GENE EXPRESSIONS DURING PREGNANCY AFTER EXPOSURE TO OCTYLPHENOL AND BISPHENOL A

2013 ◽  
Vol 25 (1) ◽  
pp. 209
Author(s):  
S. Kim ◽  
E. B. Jeung
Keyword(s):  
Bisphenol A ◽  
Calcium Transport ◽  
Corn Oil ◽  
Urinary Calcium ◽  
High Dose ◽  
Dependent Manner ◽  
Gene Expressions ◽  
Protein Levels ◽  
Pregnant Mice ◽  
Serum And Urine

Octylphenol (OP) is a degradation product of alkylphenol ethoxylates that are widely used to in rubber, pesticides, and paints. Bisphenol A (BPA) is an organic compound with two functional phenol groups and used to make polycarbonate plastic and epoxy resins, along with other applications. OP and BPA are known as endocrine disruptors that can induce inappropriate estrogenic action, and may disturb natural calcium metabolism. In the present study, the effects of OP and BPA on the calcium levels of serum and urine, and calcium transport genes were investigated in the duodenum and kidney of the pregnant mice. From 6.5 to 16.5 days post-coitus (dpc), 5 pregnant mice for each group were orally given with ethylestradiol (EE, 0.2 mg kg–1 day –1), OP (15, 45, or 135 mg kg–1 day–1) or BPA (5 or 50 mg kg–1 day –1) dissolved in corn oil. The duodenum, kidney, blood, and urine were obtained from the mice at day 18.5 of pregnancy. As a result, serum and urinary calcium levels were decreased by OP and BPA in a dose-dependent manner. The mRNA expression levels of calcium transport genes TRPV6 and CaBP-9k were decreased in the kidney after treatment with OP and BPA, while duodenal expression of TRPV6 was reduced by a high dose of BPA. The protein levels of these genes showed similar pattern with those of mRNA in the kidney and duodenum. The data were analyzed using a one-way ANOVA. P < 0.05 was considered statistically significant. Taken together, OP and BPA altered gene expressions associated with calcium transport in the pregnant mice, which may cause reduced serum and urine calcium levels. These results suggest that estrogenic actions of OP and BPA may lead to influence the calcium levels during pregnancy in the mice.

scholarly journals Comparative analysis of genome-wide DNA methylation identifies patterns that associate with conserved transcriptional programs in osteosarcoma

2020 ◽  
Author(s):  
Lauren J. Mills ◽  
Milcah C. Scott ◽  
Pankti Shah ◽  
Anne R. Cunanan ◽  
Archana Deshpande ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Large Scale ◽  
Immune Cell ◽  
Cell Types ◽  
Structural Variations ◽  
Canine Osteosarcoma ◽  
Genome Wide ◽  
Highly Correlated ◽  
Murine Osteosarcoma ◽  
Methylation Patterns

AbstractOsteosarcoma is an aggressive tumor of the bone that primarily affects young adults and adolescents. Osteosarcoma is characterized by genomic chaos and heterogeneity. While inactivation of tumor suppressor p53 TP53 is nearly universal other high frequency mutations or structural variations have not been identified. Despite this genomic heterogeneity, key conserved transcriptional programs associated with survival have been identified across human, canine and induced murine osteosarcoma. The epigenomic landscape, including DNA methylation, plays a key role in establishing transcriptional programs in all cell types. The role of epigenetic dysregulation has been studied in a variety of cancers but has yet to be explored at scale in osteosarcoma. Here we examined genome-wide DNA methylation patterns in 24 human and 44 canine osteosarcoma samples identifying groups of highly correlated DNA methylation marks in human and canine osteosarcoma samples. We also link specific DNA methylation patterns to key transcriptional programs in both human and canine osteosarcoma. Building on previous work, we built a DNA methylation-based measure for the presence and abundance of various immune cell types in osteosarcoma. Finally, we determined that the underlying state of the tumor, and not changes in cell composition, were the main driver of differences in DNA methylation across the human and canine samples.SignificanceThis is the first large scale study of DNA methylation in osteosarcoma and lays the ground work for the exploration of DNA methylation programs that help establish conserved transcriptional programs in the context of different genomic landscapes.

scholarly journals Cluster mean-field theory accurately predicts statistical properties of large-scale DNA methylation patterns

2021 ◽  
Author(s):  
Lyndsay Kerr ◽  
Duncan Sproul ◽  
Ramon Grima
Keyword(s):  
Dna Methylation ◽  
Large Scale ◽  
Field Model ◽  
Mean Field ◽  
Statistical Properties ◽  
Stochastic Simulations ◽  
Model Parameters ◽  
Mean Field Model ◽  
Mean Field Models ◽  
Methylation Patterns

The accurate establishment and maintenance of DNA methylation patterns is vital for mammalian development and disruption to these processes causes human disease. Our understanding of DNA methylation mechanisms has been facilitated by mathematical modelling, particularly stochastic simulations. Mega-base scale variation in DNA methylation patterns is observed in development, cancer and ageing and the mechanisms generating these patterns are little understood. However, the computational cost of stochastic simulations prevents them from modelling such large genomic regions. Here we test the utility of three different mean-field models to predict large-scale DNA methylation patterns. By comparison to stochastic simulations, we show that a cluster mean-field model accurately predicts the statistical properties of steady-state DNA methylation patterns, including the mean and variance of methylation levels calculated across a system of CpG sites, as well as the covariance and correlation of methylation levels between neighbouring sites. We also demonstrate that a cluster mean-field model can be used within an approximate Bayesian computation framework to accurately infer model parameters from data. As mean-field models can be solved numerically in a few seconds, our work demonstrates their utility for understanding the processes underpinning large-scale DNA methylation patterns.

Reduction in semen quality after mixed exposure to bisphenol A and isobutylparaben in utero and during lactation periods

2016 ◽  
Vol 35 (8) ◽  
pp. 902-911 ◽  
Author(s):  
Yun-Jung Yang ◽  
Yeon-Pyo Hong ◽  
Soo Ahn Chae
Keyword(s):  
Bisphenol A ◽  
Corn Oil ◽  
Semen Quality ◽  
Sperm Count ◽  
Male Reproduction ◽  
Female Rats ◽  
Epididymal Sperm ◽  
Low Level ◽  
Developmental Characteristics ◽  
Mixed Exposure

This study was performed to determine the effect of low-level exposure to a mixture of bisphenol A (BPA) and isobutylparaben (IBP) on male reproduction. Corn oil, BPA (0.05 mg/kg/day), IBP (2.5 mg/kg/day), and a BPA/IBP mixture (BPA 0.05 mg/kg/day and IBP 2.5 mg/kg/day) were administered once daily by oral gavage to female rats for 5 weeks from gestation day 6 to lactation day 21. Male pups were killed at postnatal day 70 and examined for developmental characteristics, body weight, testis and epididymis weight, steroid hormones, epididymal sperm count and motility, and histological changes in testis and epididymis. The BPA/IBP mixture produced a significant downregulation of epididymal sperm count and motility. BPA or IBP alone also reduced epididymal sperm count and motility compared to control. These results indicate that exposure to low-level BPA/IBP mixture, which showed no notable physiological response in early life stages, can decrease semen quality in adulthood.

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