Prenatal Exposure to Bisphenol A, E, and S Induces Transgenerational Effects on Male Reproductive Functions in Mice

2019 ◽  
Vol 172 (2) ◽  
pp. 303-315 ◽  
Author(s):  
Mingxin Shi ◽  
Allison E Whorton ◽  
Nikola Sekulovski ◽  
James A MacLean ◽  
Kanako Hayashi
Keyword(s):  
Prenatal Exposure ◽  
Corn Oil ◽  
Epigenetic Modification ◽  
Serum Levels ◽  
Dna Methyltransferases ◽  
Control Treatment ◽  
Mrna Levels ◽  
Transgenerational Effects ◽  
Adult Testis ◽  
Neonatal Testis

Abstract 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.

Prenatal Exposure to Bisphenol A, E, and S Induces Transgenerational Effects on Female Reproductive Functions in Mice

2019 ◽  
Vol 170 (2) ◽  
pp. 320-329 ◽  
Author(s):  
Mingxin Shi ◽  
Allison E Whorton ◽  
Nikola Sekulovski ◽  
James A MacLean ◽  
Kanako Hayashi
Keyword(s):  
Prenatal Exposure ◽  
Corn Oil ◽  
Follicular Development ◽  
Control Treatment ◽  
Serum Estradiol ◽  
Transgenerational Effects ◽  
Vaginal Plug ◽  
Estrous Cyclicity ◽  
Estradiol 17Β ◽  
Bpa Analogs

Abstract 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.

Negative Correlation Between Serum Levels of Homocysteine and Apolipoprotein M

2019 ◽  
Vol 19 (2) ◽  
pp. 120-126
Author(s):  
J. Wei ◽  
Y. Yu ◽  
Y. Feng ◽  
J. Zhang ◽  
Q. Jiang ◽  
...  
Keyword(s):  
Negative Correlation ◽  
Hepg2 Cells ◽  
Serum Levels ◽  
Significant Negative Correlation ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Apolipoprotein M ◽  
Protein Mass ◽  
Protein Levels ◽  
Phosphoinositide 3 Kinase

Background: Homocysteine (Hcy) has been suggested as an independent risk factor for atherosclerosis. Apolipoprotein M (apoM) is a constituent of the HDL particles. The goal of this study was to examine the serum levels of homocysteine and apoM and to determine whether homocysteine influences apoM synthesis. Methods: Serum levels of apoM and Hcy in 17 hyperhomocysteinemia (HHcy) patients and 19 controls were measured and their correlations were analyzed. Different concentrations of homocysteine (Hcy) and LY294002, a specific phosphoinositide 3- kinase (PI3K) inhibitor, were used to treat HepG2 cells. The mRNA levels were determined by RT-PCR and the apoM protein mass was measured by western blot. Results: We found that decreased serum apoM levels corresponded with serum HDL levels in HHcy patients, while the serum apoM levels showed a statistically significant negative correlation with the serum Hcy levels. Moreover, apoM mRNA and protein levels were significantly decreased after the administration of Hcy in HepG2 cells, and this effect could be abolished by addition of LY294002. Conclusions: resent study demonstrates that Hcy downregulates the expression of apoM by mechanisms involving the PI3K signal pathway.

scholarly journals DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors

2020 ◽  
Author(s):  
Jing Wei ◽  
Jia Cheng ◽  
Nicholas J Waddell ◽  
Zi-Jun Wang ◽  
Xiaodong Pang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Epigenetic Modification ◽  
Substantial Reduction ◽  
Dna Methyltransferases ◽  
Male Rats ◽  
Neural Pathways ◽  
Dnmt Inhibitors ◽  
Synaptic Functions

Abstract Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here, we found that male rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory, heightened aggression, and hyperlocomotion, were partially attenuated by Dnmt3a expression in PFC of stressed animals. Finally, we found that there were genome-wide DNA methylation changes and transcriptome alterations in PFC of stressed rats, both of which were enriched at several neural pathways, including glutamatergic synapse and microtubule-associated protein kinase signaling. These results have therefore recognized the potential role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive and emotional processes.

scholarly journals Addition of Olive Leaf Extract to a Mixture of Algae and Extra Virgin Olive Oils Decreases Fatty Acid Oxidation and Synergically Attenuates Age-Induced Hypertension, Sarcopenia and Insulin Resistance in Rats

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1066
Author(s):  
Daniel González-Hedström ◽  
María de la Fuente-Fernández ◽  
Teresa Priego ◽  
Ana Isabel Martín ◽  
Sara Amor ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vascular Function ◽  
Virgin Olive Oil ◽  
Serum Levels ◽  
Acid Oxidation ◽  
Antioxidant Compounds ◽  
Mrna Levels ◽  
Omega 3 ◽  
Olive Leaf ◽  
Leaf Extracts

Olive-derived products, such as virgin olive oil (EVOO) and/or olive leaf extracts (OLE), exert anti-inflammatory, insulin-sensitizing and antihypertensive properties and may be useful for stabilizing omega 3 fatty acids (n-3 PUFA) due to their high content in antioxidant compounds. In this study, the addition of OLE 4:0.15 (w/w) to a mixture of algae oil (AO) rich in n-3 PUFA and EVOO (25:75, w/w) prevents peroxides formation after 12 months of storage at 30 °C. Furthermore, the treatment with the oil mixture (2.5 mL/Kg) and OLE (100 mg/Kg) for 24 month old Wistar rats in 21 days improved the lipid profile, increased the HOMA-IR and decreased the serum levels of miRNAs 21 and 146a. Treatment with this new nutraceutical also prevented age-induced insulin resistance in the liver, gastrocnemius and visceral adipose tissue by decreasing the mRNA levels of inflammatory and oxidative stress markers. Oil mixture + OLE also attenuated the age-induced alterations in vascular function and prevented muscle loss by decreasing the expression of sarcopenia-related markers. In conclusion, treatment with a new nutraceutical based on a mixture of EVOO, AO and OLE is a useful strategy for improving the stability of n-3 PUFA in the final product and to attenuate the cardiometabolic and muscular disorders associated with aging.

scholarly journals Sustained high expression of multiple APOBEC3 cytidine deaminases in systemic lupus erythematosus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Danielle Perez-Bercoff ◽  
Hélène Laude ◽  
Morgane Lemaire ◽  
Oliver Hunewald ◽  
Valérie Thiers ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Cell Death ◽  
Lupus Erythematosus ◽  
Immunosuppressive Treatment ◽  
Elevated Serum ◽  
Serum Levels ◽  
Chronic Inflammatory Disease ◽  
Mrna Levels ◽  
Systemic Lupus ◽  
Inflammatory Conditions

AbstractAPOBEC3 (A3) enzymes are best known for their role as antiviral restriction factors and as mutagens in cancer. Although four of them, A3A, A3B, A3F and A3G, are induced by type-1-interferon (IFN-I), their role in inflammatory conditions is unknown. We thus investigated the expression of A3, and particularly A3A and A3B because of their ability to edit cellular DNA, in Systemic Lupus Erythematosus (SLE), a chronic inflammatory disease characterized by high IFN-α serum levels. In a cohort of 57 SLE patients, A3A and A3B, but also A3C and A3G, were upregulated ~ 10 to 15-fold (> 1000-fold for A3B) compared to healthy controls, particularly in patients with flares and elevated serum IFN-α levels. Hydroxychloroquine, corticosteroids and immunosuppressive treatment did not reverse A3 levels. The A3AΔ3B polymorphism, which potentiates A3A, was detected in 14.9% of patients and in 10% of controls, and was associated with higher A3A mRNA expression. A3A and A3B mRNA levels, but not A3C or A3G, were correlated positively with dsDNA breaks and negatively with lymphopenia. Exposure of SLE PBMCs to IFN-α in culture induced massive and sustained A3A levels by 4 h and led to massive cell death. Furthermore, the rs2853669 A > G polymorphism in the telomerase reverse transcriptase (TERT) promoter, which disrupts an Ets-TCF-binding site and influences certain cancers, was highly prevalent in SLE patients, possibly contributing to lymphopenia. Taken together, these findings suggest that high baseline A3A and A3B levels may contribute to cell frailty, lymphopenia and to the generation of neoantigens in SLE patients. Targeting A3 expression could be a strategy to reverse cell death and the generation of neoantigens.

Prenatal exposure to a phthalate mixture leads to multigenerational and transgenerational effects on uterine morphology and function in mice

2020 ◽  
Vol 93 ◽  
pp. 178-190 ◽  
Author(s):  
Kailiang Li ◽  
Monika Liszka ◽  
Changqing Zhou ◽  
Emily Brehm ◽  
Jodi A. Flaws ◽  
...  
Keyword(s):  
Prenatal Exposure ◽  
Transgenerational Effects ◽  
And Function

scholarly journals X chromosome escapee genes are involved in ischemic sexual dimorphism through epigenetic modification of inflammatory signals

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Shaohua Qi ◽  
Abdullah Al Mamun ◽  
Conelius Ngwa ◽  
Sharmeen Romana ◽  
Rodney Ritzel ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
X Chromosome ◽  
Epigenetic Modification ◽  
Artery Occlusion ◽  
Sexually Dimorphic ◽  
Mrna Levels ◽  
Young Females ◽  
Human Stroke ◽  
Histone H3k4 ◽  
Cerebral Artery Occlusion

Abstract Background Stroke is a sexually dimorphic disease. Previous studies have found that young females are protected against ischemia compared to males, partially due to the protective effect of ovarian hormones, particularly estrogen (E2). However, there are also genetic and epigenetic effects of X chromosome dosage that contribute to stroke sensitivity and neuroinflammation after injury, especially in the aged. Genes that escape from X chromosome inactivation (XCI) contribute to sex-specific phenotypes in many disorders. Kdm5c and kdm6a are X escapee genes that demethylate H3K4me3 and H3K27me3, respectively. We hypothesized that the two demethylases play critical roles in mediating the stroke sensitivity. Methods To identify the X escapee genes involved in stroke, we performed RNA-seq in flow-sorted microglia from aged male and female wild type (WT) mice subjected to middle cerebral artery occlusion (MCAO). The expression of these genes (kdm5c/kdm6a) were confirmed in four core genotypes (FCG) mice and in post-mortem human stroke brains by immunohistochemistry (IHC), Western blot, and RT-PCR. Chromatin immunoprecipitation (ChIP) assays were conducted to detect DNA levels of inflammatory interferon regulatory factor (IRF) 4/5 precipitated by histone H3K4 and H3K27 antibodies. Manipulation of kdm5c/kdm6a expression with siRNA or lentivirus was performed in microglial culture, to determine downstream pathways and examine the regulatory roles in inflammatory cytokine production. Results Kdm5c and kdm6a mRNA levels were significantly higher in aged WT female vs. male microglia, and the sex difference also existed in ischemic brains from FCG mice and human stroke patients. The ChIP assay showed the IRF 4/5 had higher binding levels to demethylated H3K4 or H3K27, respectively, in female vs. male ischemic microglia. Knockdown or over expression of kdm5c/kdm6a with siRNA or lentivirus altered the methylation of H3K4 or H3K27 at the IRF4/5 genes, which in turn, impacted the production of inflammatory cytokines. Conclusions The KDM-Histone-IRF pathways are suggested to mediate sex differences in cerebral ischemia. Epigenetic modification of stroke-related genes constitutes an important mechanism underlying the ischemic sexual dimorphism.

scholarly journals Stochastic Modeling Reveals Kinetic Heterogeneity in Post-replication DNA Methylation

2019 ◽  
Author(s):  
Luis Busto-Moner ◽  
Julien Morival ◽  
Arjang Fahim ◽  
Zachary Reitz ◽  
Timothy L. Downing ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Dna Methylation ◽  
Rate Constants ◽  
Cytosine Methylation ◽  
Temporal Dynamics ◽  
Epigenetic Modification ◽  
Embryonic Stem ◽  
Likelihood Estimation ◽  
Dna Methyltransferases ◽  
Methylation Patterns

AbstractDNA methylation is a heritable epigenetic modification that plays an essential role in mammalian development. Genomic methylation patterns are dynamically maintained, with DNA methyltransferases mediating inheritance of methyl marks onto nascent DNA over cycles of replication. A recently developed experimental technique employing immunoprecipitation of bromodeoxyuridine labeled nascent DNA followed by bisulfite sequencing (Repli-BS) measures post-replication temporal evolution of cytosine methylation, thus enabling genome-wide monitoring of methylation maintenance. In this work, we combine statistical analysis and stochastic mathematical modeling to analyze Repli-BS data from human embryonic stem cells. We estimate site-specific kinetic rate constants for the restoration of methyl marks on >10 million uniquely mapped cytosines within the CpG (cytosine-phosphate-guanine) dinucleotide context across the genome using Maximum Likelihood Estimation. We find that post-replication remethylation rate constants span approximately two orders of magnitude, with half-lives of per-site recovery of steady-state methylation levels ranging from shorter than ten minutes to five hours and longer. Furthermore, we find that kinetic constants of maintenance methylation are correlated among neighboring CpG sites. Stochastic mathematical modeling provides insight to the biological mechanisms underlying the inference results, suggesting that enzyme processivity and/or collaboration can produce the observed kinetic correlations. Our combined statistical/mathematical modeling approach expands the utility of genomic datasets and disentangles heterogeneity in methylation patterns arising from replication-associated temporal dynamics versus stable cell-to-cell differences.

scholarly journals Synthesis and Metabolism of Thyroid Hormones Is Preferentially Maintained in Selenium-Deficient Transgenic Mice

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1306-1313 ◽  
Author(s):  
Lutz Schomburg ◽  
Cornelia Riese ◽  
Marten Michaelis ◽  
Emine Griebert ◽  
Marc O. Klein ◽  
...  
Keyword(s):  
Thyroid Gland ◽  
Thyroid Hormones ◽  
Knockout Mice ◽  
Serum Levels ◽  
Mrna Levels ◽  
Normal Range ◽  
Growth Defects ◽  
Low Levels

The thyroid gland is rich in selenium (Se) and expresses a variety of selenoproteins that are involved in antioxidative defense and metabolism of thyroid hormones (TH). Se deficiency impairs regular synthesis of selenoproteins and adequate TH metabolism. We recently generated mice that lack the plasma Se carrier, selenoprotein P (SePP). SePP-knockout mice display decreased serum Se levels and manifest growth defects and neurological abnormalities partly reminiscent of thyroid gland dysfunction or profound hypothyroidism. Thus, we probed the TH axis in developing and adult SePP-knockout mice. Surprisingly, expression of Se-dependent 5′-deiodinase type 1 was only slightly altered in liver, kidney, or thyroid at postnatal d 60, and 5′-deiodinase type 2 activity in brain was normal in SePP-knockout mice. Thyroid gland morphology, thyroid glutathione peroxidase activity, thyroid Se concentration, and serum levels of TSH, T4, or T3 were within normal range. Pituitary TSHβ transcripts and hepatic 5′-deiodinase type 1 mRNA levels were unchanged, indicating regular T3 bioactivity in thyrotropes and hepatocytes. Cerebellar granule cell migration as a sensitive indicator of local T3 action during development was undisturbed. Collectively, these findings demonstrate that low levels of serum Se or SePP in the absence of other challenges do not necessarily interfere with regular functioning of the TH axis. 5′-deiodinase isozymes are preferentially supplied, and Se-dependent enzymes in the thyroid are even less-dependent on serum levels of Se or SePP than in brain. This indicates a top priority of the thyroid gland and its selenoenzymes with respect to the hierarchical Se supply within the organism.

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