scholarly journals Prenatal Exposure to Triclocarban Impairs ESR1 Signaling and Disrupts Epigenetic Status in Sex-Specific Ways as Well as Dysregulates the Expression of Neurogenesis- and Neurotransmitter-Related Genes in the Postnatal Mouse Brain

2021 ◽  
Vol 22 (23) ◽  
pp. 13121
Author(s):  
Agnieszka Wnuk ◽  
Joanna Rzemieniec ◽  
Karolina Przepiórska ◽  
Bernadeta Angelika Pietrzak ◽  
Marzena Maćkowiak ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Risk Factor ◽  
Prenatal Exposure ◽  
Prenatally Exposed ◽  
Protein Levels ◽  
Esr1 Gene ◽  
Mrna And Protein Expression ◽  
First Time ◽  
The Brain ◽  
Estrogen Receptor 1

Triclocarban is a highly effective and broadly used antimicrobial agent. Humans are continually exposed to triclocarban, but the safety of prenatal exposure to triclocarban in the context of neurodevelopment remains unknown. In this study, we demonstrated for the first time that mice that had been prenatally exposed to environmentally relevant doses of triclocarban had impaired estrogen receptor 1 (ESR1) signaling in the brain. These mice displayed decreased mRNA and protein expression levels of ESR1 as well as hypermethylation of the Esr1 gene in the cerebral cortex. Prenatal exposure to triclocarban also diminished the mRNA expression of Esr2, Gper1, Ahr, Arnt, Cyp19a1, Cyp1a1, and Atg7, and the protein levels of CAR, ARNT, and MAP1LC3AB in female brains and decreased the protein levels of BCL2, ARNT, and MAP1LC3AB in male brains. In addition, exposure to triclocarban caused sex-specific alterations in the methylation levels of global DNA and estrogen receptor genes. Microarray and enrichment analyses showed that, in males, triclocarban dysregulated mainly neurogenesis-related genes, whereas, in females, the compound dysregulated mainly neurotransmitter-related genes. In conclusion, our data identified triclocarban as a neurodevelopmental risk factor that particularly targets ESR1, affects apoptosis and autophagy, and in sex-specific ways disrupts the epigenetic status of brain tissue and dysregulates the postnatal expression of neurogenesis- and neurotransmitter-related genes.

scholarly journals Mn Inhibits GSH Synthesis via Downregulation of Neuronal EAAC1 and Astrocytic xCT to Cause Oxidative Damage in the Striatum of Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Xinxin Yang ◽  
Haibo Yang ◽  
Fengdi Wu ◽  
Zhipeng Qi ◽  
Jiashuo Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Dependent Manner ◽  
Protein Levels ◽  
Key Factor ◽  
Protein Sulfhydryl ◽  
Mrna And Protein Expression ◽  
The Brain

Excessive manganese (Mn) can accumulate in the striatum of the brain following overexposure. Oxidative stress is a well-recognized mechanism in Mn-induced neurotoxicity. It has been proven that glutathione (GSH) depletion is a key factor in oxidative damage during Mn exposure. However, no study has focused on the dysfunction of GSH synthesis-induced oxidative stress in the brain during Mn exposure. The objective of the present study was to explore the mechanism of Mn disruption of GSH synthesis via EAAC1 and xCT in vitro and in vivo. Primary neurons and astrocytes were cultured and treated with different doses of Mn to observe the state of cells and levels of GSH and reactive oxygen species (ROS) and measure mRNA and protein expression of EAAC1 and xCT. Mice were randomly divided into seven groups, which received saline, 12.5, 25, and 50 mg/kg MnCl2, 500 mg/kg AAH (EAAC1 inhibitor) + 50 mg/kg MnCl2, 75 mg/kg SSZ (xCT inhibitor) + 50 mg/kg MnCl2, and 100 mg/kg NAC (GSH rescuer) + 50 mg/kg MnCl2 once daily for two weeks. Then, levels of EAAC1, xCT, ROS, GSH, malondialdehyde (MDA), protein sulfhydryl, carbonyl, 8-hydroxy-2-deoxyguanosine (8-OHdG), and morphological and ultrastructural features in the striatum of mice were measured. Mn reduced protein levels, mRNA expression, and immunofluorescence intensity of EAAC1 and xCT. Mn also decreased the level of GSH, sulfhydryl, and increased ROS, MDA, 8-OHdG, and carbonyl in a dose-dependent manner. Injury-related pathological and ultrastructure changes in the striatum of mice were significantly present. In conclusion, excessive exposure to Mn disrupts GSH synthesis through inhibition of EAAC1 and xCT to trigger oxidative damage in the striatum.

scholarly journals Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia

2019 ◽  
Author(s):  
Sawako Shindo ◽  
Shih-Heng Chen ◽  
Saki Gotoh ◽  
Kosuke Yokobori ◽  
Hao Hu ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Inflammatory Cytokines ◽  
Estrogen Receptor Α ◽  
Microglia Activation ◽  
Immune Functions ◽  
Protein Levels ◽  
Brain Extracts ◽  
Anti Inflammatory ◽  
The Brain ◽  
Pro Inflammatory Cytokines

Abstract Background Estrogen has been suggested to regulate anti-inflammatory signaling in brain microglia through estrogen receptor α (ERα), the only resident immune cells of the brain. The mechanism of how ERα regulates is not well understood. Previously, ERα is phosphorylated at Ser216 in mouse neutrophils, regulating their infiltration into the uterus. Therefore, ERα has now been examined as to its phosphorylation in microglia to regulate their inflammatory functions.MethodsAn antibody against an anti-phospho-S216 peptide of ERα (αP-S216) was used for double immunofluorescence staining to detect to ERα in cultured microglia. A knock-in (KI) mouse line bearing the phosphorylation-blocked ERα mutation S216A (ERα KI) was generated to examine whether this phosphorylation regulate immune functions of microglia.ResultsPhosphorylated ERα at Ser216 was present in microglia but not astrocytes. Staining with an anti-Iba-1 antibody showed that microglia activation was augmented in substantial nigra of ERα KI brains. Lipopolysaccharide (LPS) treatments aggravated microglia activation in ERα KI brains, pro-inflammatory cytokines were increased while anti-inflammatory cytokines were decreased at mRNA and protein levels in whole brain extracts. These increases and decreases of cytokine proteins were also observed in LPS-treated microglia cultured from brains of ERα KI neonates. FACS analysis revealed that ERα KI mutation increased number of IL-6 producing microglia and apoptosis. ERα KI mice decreased motor connection ability in Rotarod tests.ConclusionsBlocking of Ser216 phosphorylation aggravated microglia activation and inflammation of mouse brain, thus confirming that phosphorylated ERα exerts anti-inflammatory functions. ERα KI mice enable us to further investigate the mechanism by which phosphorylated ERα regulates brain immunity and inflammation.

Estrogen Receptor Distribution in the Hippocampus and Prefrontal Cortex

2020 ◽  
pp. 11-23
Author(s):  
Annelyn Torres-Reveron ◽  
Wayne G. Brake ◽  
Teresa A. Milner
Keyword(s):  
Estrogen Receptor ◽  
Prefrontal Cortex ◽  
Estrogen Receptors ◽  
Estrogen Receptor Alpha ◽  
Estrogen Receptor Beta ◽  
Cognitive Behaviors ◽  
G Protein Coupled ◽  
The Brain ◽  
Anatomical Evidence ◽  
Estrogen Receptor 1

This chapter presents anatomical evidence for the distribution of estrogen receptors in the brain. First, the chapter presents a brief discussion of the historical findings that led to the discovery of nuclear and extranuclear estrogen receptors in the brain. A distribution pattern for each one of the receptors, estrogen receptor alpha (ERα‎), estrogen receptor beta (ERβ‎), and G-protein coupled estrogen receptor 1 (GPER1), is presented in sequential subsections. The discussion focuses on the hippocampus and prefrontal cortex areas, as these are largely involved in memory and cognitive behaviors, further discussed in other chapters in this book. In addition, co-localization studies with other neurotransmitter systems and molecules important for the functional activity of estrogen receptors is reviewed.

Estrogen Receptor 1 (ESR1) Gene Polymorphisms and Obesity Phenotypes in a Population of Young Adults

2017 ◽  
Vol 27 (8) ◽  
pp. 936-949 ◽  
Author(s):  
María Correa-Rodríguez ◽  
Jacqueline Schmidt-RioValle ◽  
Emilio González-Jiménez ◽  
Blanca Rueda-Medina
Keyword(s):  
Estrogen Receptor ◽  
Young Adults ◽  
Genetic Risk ◽  
Gene Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Esr1 Gene ◽  
Haplotype Frequencies ◽  
Genetic And Environmental Factors ◽  
Estrogen Receptor 1

Obesity is considered an increasingly serious health problem determined by multiple genetic and environmental factors. Estrogens have been found to play a major role in body weight and adiposity regulation through estrogen receptor 1 ( ESR1). The aim of this study was to determine whether genotype and haplotype frequencies of ESR1 polymorphisms are associated with body composition measures in a population of 572 young adults. A lack of significant association between genotypes of ESR1 gene polymorphisms and obesity phenotypes was seen after adjustment for confounding factors. Linkage disequilibrium (LD) analysis identified a single LD block for the ESR1 gene including PvuII and XbaI single-nucleotide polymorphisms (SNPs) (pairwise r2 = .66). None of the haplotypes identified revealed statistically significant associations with any of the obesity phenotypes. Our results suggest that polymorphisms of the ESR1 gene do not contribute significantly to the genetic risk for obesity phenotypes in a population of young Caucasian adults.

scholarly journals ESR1 gene status correlates with estrogen receptor protein levels measured by ligand binding assay and immunohistochemistry

2012 ◽  
Vol 6 (4) ◽  
pp. 428-436 ◽  
Author(s):  
Anne-Vibeke Laenkholm ◽  
Ann Knoop ◽  
Bent Ejlertsen ◽  
Tine Rudbeck ◽  
Maj-Britt Jensen ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Binding Assay ◽  
Receptor Protein ◽  
Ligand Binding Assay ◽  
Estrogen Receptor Protein ◽  
Protein Levels ◽  
Esr1 Gene ◽  
Gene Status

scholarly journals Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia

2020 ◽  
Author(s):  
Sawako Shindo ◽  
Shih-Heng Chen ◽  
Saki Gotoh ◽  
Kosuke Yokobori ◽  
Hao Hu ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Inflammatory Cytokines ◽  
Estrogen Receptor Α ◽  
Brain Diseases ◽  
Antibody Array ◽  
Mouse Uterus ◽  
Glia Cells ◽  
Protein Levels ◽  
Anti Inflammatory ◽  
The Brain

Abstract Background Estrogen receptor α (ERα) has been suggested to regulate anti-inflammatory signaling in brain microglia, the only resident immune cells in the brain. ERα conserves the phosphorylation motif at Ser216 within the DNA binding domain. Previously, Ser216 was found to be phosphorylated in neutrophils infiltrating into the mouse uterus and to enable ERα to regulate migration. Given the implication of this phosphorylation in immune regulation, ERα was examined in mouse microglia to determine if Ser216 is phosphorylated and regulates microglia’s inflammation. It was found that Ser216 was constitutively phosphorylated in microglia and demonstrated that in the absence of phosphorylated ERα in ERα KI brains microglia inflamed, confirming that phosphorylation confers ERα with anti-inflammatory capability. ERα KI mice were obese and weakened motor ability. Methods Mixed glia cells were prepared from brains of 2-days-old neonates and cultured to mature and isolate microglia. An antibody against an anti-phospho-S216 peptide of ERα (αP-S216) was used to detect phosphorylated ERα in double immunofluorescence staining with ERα antibodies and a microglia maker Iba-1 antibody. A knock-in (KI) mouse line bearing the phosphorylation-blocked ERα S216A mutation (ERα KI) was generated to examine inflammation-regulating functions of phosphorylated ERα in microglia. RT-PCR, antibody array, ELISA and FACS assays were employed to measure expressions of pro- or anti-inflammatory cytokines at their mRNA and protein levels. Rotarod tests were performed to examine motor connection ability.Results Double immune staining of mixed glia cells showed that ERα is phosphorylated at Ser216 in microglia, but not astrocytes. Immunohistochemistry with an anti-Iba-1 antibody showed that microglia cells were swollen and shortened branches in the substantial nigra (SN) of ERα KI brains, indicating the spontaneous activation of microglia as observed with those of lipopolysaccharide (LPS)-treated ERα WT brains. Pro-inflammatory cytokines were up-regulated in the brain of ERα KI brains as well as cultured microglia, whereas anti-inflammatory cytokines were down-regulated. FACS analysis showed that the number of IL-6 producing and apoptotic microglia increased in those prepared from ERα KI brains. Times of ERα KI mice on rod were shortened in Rotarod tests. Conclusions Blocking of Ser216 phosphorylation aggravated microglia activation and inflammation of mouse brain, thus confirming that phosphorylated ERα exerts anti-inflammatory functions. ERα KI mice enable us to further investigate the mechanism by which phosphorylated ERα regulates brain immunity and inflammation and brain diseases.

scholarly journals SNP analysis reveals estrogen receptor 1 (<i>ESR1</i>) gene variants associated with laying traits in quails

2015 ◽  
Vol 58 (2) ◽  
pp. 441-444 ◽  
Author(s):  
Y. Wu ◽  
A. L. Pan ◽  
J. S. Pi ◽  
Y. J. Pu ◽  
J. P. Du ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Snp Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Esr1 Gene ◽  
Intron 1 ◽  
Egg Number ◽  
Exon 1 ◽  
Polymerase Chain ◽  
Estrogen Receptor 1

Abstract. In this study, the estrogen receptor 1 (ESR1) gene was studied as a candidate gene for laying traits of two quail populations (the yellow-feather quail and chestnut-feather quail). Five pairs of primers were designed to detect single-nucleotide polymorphisms (SNPs) of exon 1, 2, 4, 8 and intron 1 of the ESR1 gene by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and sequencing methods. Only the products amplified from exon 8 displayed polymorphism. The results showed one novel variation: a variation in exon 8 of ESR1 gene (g.91C > T, KC977991 and KC977992). It was associated with some laying traits in two quail populations including egg weight, the age of first egg and egg number at 20 weeks. And the CC genotype was associated with superior egg number at 20 weeks. Therefore, we speculated that the variation in exon 8 of ESR1 gene may have an effect on laying traits in the abovementioned quail populations.

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