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Cytochrome P450 1B1 (EC (CYPIB1) (Hydroperoxy icosatetraenoate dehydratase) (EC


Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts.

Experimental and/or epidemiological studies suggest that prenatal exposure to bisphenol A (BPA) may delay fetal lung development and maturation and increase the susceptibility to childhood respiratory disease. However, the underlying mechanisms remain to be elucidated. In our previous study with cultured human fetal lung fibroblasts (HFLF), we demonstrated that 24-h exposure to 1 and 100 µM BPA increased GPR30 protein in the nuclear fraction. Exposure to 100 μM BPA had no effects on cell viability, but increased cytoplasmic expression of ERβ and release of GDF-15, as well as decreased release of IL-6, ET-1, and IP-10 through suppression of NFκB phosphorylation. By performing global gene expression and pathway analysis in this study, we identified molecular pathways, gene networks, and key molecules that were affected by 100, but not 0.01 and 1 µM BPA in HFLF. Using multiple genomic and proteomic tools, we confirmed these changes at both gene and protein levels. Our data suggest that 100 μM BPA increased CYP1B1 and HSD17B14 gene and protein expression and release of endogenous estradiol, which was associated with increased ROS production and DNA double-strand breaks, upregulation of genes and/or proteins in steroid synthesis and metabolism, and activation of Nrf2-regulated stress response pathways. In addition, BPA activated ATM-p53 signaling pathway, resulting in increased cell cycle arrest at G1 phase, senescence and autophagy, and decreased cell proliferation in HFLF. The results suggest that prenatal exposure to BPA at certain concentrations may affect fetal lung development and maturation, and thereby affecting susceptibility to childhood respiratory diseases.

MeSH Terms

  • 17-Hydroxysteroid Dehydrogenases
  • Air Pollutants, Occupational
  • Autophagy
  • Benzhydryl Compounds
  • Cell Cycle Checkpoints
  • Cellular Senescence
  • Cytochrome P-450 CYP1B1
  • Estradiol
  • Fibroblasts
  • Humans
  • Lung
  • NF-E2-Related Factor 2
  • Phenols
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • Up-Regulation


  • ATM signaling
  • Autophagy
  • Bisphenol A
  • CYP1B1
  • Cell cycle arrest
  • DNA double-strand breaks
  • Estradiol release
  • G1/S transition
  • HSD17B14
  • Human fetal lung fibroblasts
  • Nrf2
  • ROS
  • Senescence
  • Steroid synthesis and metabolism
  • p53
  • γ-H2AX

Target disruption of ribosomal protein pNO40 accelerates aging and impairs osteogenic differentiation of mesenchymal stem cells.

pNO40/PS1D, a novel nucleolar protein, has been characterized as a core protein of eukaryotic 60S ribosome and at least two splicing forms of pNO40 mRNAs with alternative starting sites have been identified. Through production of knockout (ko) mice with either exon 2 (△E2), exon 4 (△E4) or △E2 E4 targeted disruption we identified a cryptic splicing product occurring in the ko tissues examined which in general cannot be observed in regular RT-PCR detection of wild-type (wt) animals. Among ko animals, △E4 null embryos exhibited prominent senescence-associated β-galactosidase (SA-β-gal) staining, a marker for senescent cells, in notochord, forelimbs and heart while bone marrow-derived mesenchymal stem cells (MSCs) from △E4 null mice developed accelerated aging and osteogenic differentiation defects compared to those from wt and other isoform mutant mice. Examination of the causal relationship between pNO40 deficiency and MSC-accelerated aging revealed △E4 null disruption in MSCs elicits high levels of ROS and elevated expression levels of p16 and Rb but not p53. Further analysis with iTraq identified CYP1B1, a component of the cytochrome p450 system, as a potential molecule mediating ROS generation in pNO40 deficient MSCs. We herein established a mouse model of MSC aging through pNO40-targeted depletion and demonstrated the effects of loss of pNO40 on bone homeostasis.

MeSH Terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Cellular Senescence
  • Cytochrome P-450 CYP1B1
  • Mesenchymal Stem Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins
  • Osteoblasts
  • Osteogenesis
  • Reactive Oxygen Species


  • Aging
  • Knockout mice
  • Mesenchymal stem cells
  • Osteogenesis
  • pNO40

Expression of genes for AhR and Nrf2 signal pathways in the retina of OXYS rats during the development of retinopathy and melatonin-induced changes in this process.

Modulation of oxidative stress is one of the experimental approaches to the therapy of age-related macular degeneration. Melatonin holds much promise in this respect. It was hypothesized that the efficiency of melatonin in age-related macular degeneration is associated with its ability to modulate gene expression for the AhR and Nrf2 signal pathways. Experiments were performed on premature aging OXYS rats, which serve as a reliable model of age-related macular degeneration in humans. We studied the effect of melatonin on gene mRNA for the AhR and Nrf2 signal pathways. Melatonin was shown to decrease the level of mRNA for AhR-dependent genes of CYP1A2 and CYP1B1 cytochromes in the retina, but had no effect on the content of mRNA for Nrf2-dependent genes in OXYS rats.

MeSH Terms

  • Aging
  • Animals
  • Antioxidants
  • Basic Helix-Loop-Helix Transcription Factors
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP1B1
  • Cytochromes
  • Disease Models, Animal
  • Gene Expression Regulation, Developmental
  • Humans
  • Macular Degeneration
  • Male
  • Melatonin
  • NF-E2-Related Factor 2
  • Oxidative Stress
  • Progeria
  • RNA, Messenger
  • Rats
  • Rats, Transgenic
  • Rats, Wistar
  • Receptors, Aryl Hydrocarbon
  • Retina
  • Signal Transduction