ABSTRACT
CONTEXT: Despite the absence of progesterone receptor protein in human endometrial endothelial cells (HEECs), endometria of women receiving long-acting progestin-only contraceptives (LAPCs) display reduced uterine blood flow, elevated reactive oxygen species generation, increased angiogenesis, and irregularly distributed, enlarged, fragile microvessels resulting in abnormal uterine bleeding. OBJECTIVE: We propose that paracrine factors from LAPC-treated human endometrial stromal cells (HESCs) impair HEEC functions by shifting the balance between HEEC viability and death in favor of the latter. DESIGN AND SETTING: Proliferation, apoptosis, and transcriptome analyses were performed in HEECs treated with conditioned medium supernatant (CMS) derived from HESCs treated with estradiol (E2) ± medroxyprogesterone acetate or etonogestrel under normoxia or hypoxia. Mass spectrometry interrogated the CMS secretome while immunostaining for neuronal pentraxin-1 (NPTX1), cleaved caspase-3, and cytochrome c was performed in cultured HEECs and paired endometria from women using LAPCs. MAIN OUTCOME: HEEC apoptosis and its underlying mechanism. RESULTS: HESC CMS from E2 + medroxyprogesterone acetate or E2 + etonogestrel incubations under hypoxia induced HEEC apoptosis (P < .05), whereas mass spectrometry of the CMS revealed increased NPTX1 secretion (P < .05). Endothelial cleaved caspase-3 and stromal NPTX1 immunoreactivity were significantly higher in LAPC-treated endometria (P < .001). Transcriptomics revealed AKT signaling inhibition and mitochondrial dysfunction in HEECs incubated with HESC CMS. In vitro analyses proved that CMS decreased HEEC AKT phosphorylation (P < .05) and that recombinant NPTX1 (P < .05) or NPTX1 + H2O2 (P < .001) increase HEEC apoptosis and cytosolic cytochrome c levels. CONCLUSIONS: LAPC-enhanced NPTX1 secretion and reactive oxygen species generation in HESCs impair HEEC survival resulting in a loss in vascular integrity, demonstrating a novel paracrine mechanism to explain LAPC-induced abnormal uterine bleeding.
Subject(s)
Apoptosis/drug effects , C-Reactive Protein/metabolism , Contraceptive Agents, Female/administration & dosage , Endometrium/drug effects , Nerve Tissue Proteins/metabolism , Progestins/administration & dosage , Stromal Cells/drug effects , Caspase 3/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Contraceptive Agents, Female/adverse effects , Culture Media, Conditioned/pharmacology , Cytochromes c/metabolism , Endometrium/cytology , Endothelial Cells/cytology , Endothelial Cells/drug effects , Estradiol/adverse effects , Estradiol/pharmacology , Female , Humans , Medroxyprogesterone Acetate/adverse effects , Medroxyprogesterone Acetate/pharmacology , Microvessels/metabolism , Paracrine Communication/drug effects , Paracrine Communication/physiology , Progestins/adverse effects , Reactive Oxygen Species/metabolism , Stromal Cells/metabolismABSTRACT
The effects of eight transition metals were studied in a nitrifying system to investigate the relationship between the ionic characteristics of metals and their toxicity to nitrifiers. The cumulative oxygen consumption and the cumulative carbon dioxide production were monitored throughout each respirometric batch run to determine the toxicity of metals to nitrifiers. Several quantitative cationic-activity relationship (QCAR) models were developed on the basis of these different toxicity endpoints using quantum chemical descriptors. Descriptors were calculated with density functional theory (DFT) at the B3LYP/LANL2DZ level using the Gaussian 03W software. Additionally, the same descriptors were recalculated using another basis set, B3LYP/SDD, to test the impact of the basis set on prediction of toxicity. Of the calculated descriptors, mainly the gaseous phase descriptors explained significant variances in both toxicity endpoints. However, the energy of the polarized solute-solvent (E(PSS)) was the most important common descriptors in modelling labile toxicity. A combination of the aqueous phase energy of the highest occupied molecular orbital (E(HOMO(aq))) and the maximum value for the energy of the lowest unoccupied molecular orbital of the most important metal species (E(LUMO)C(max)) produced the best two-descriptor model for both pTO(2) and pTCO(2). The electron donor/acceptor ability of metals and the electron acceptor ability of metal species (E(LUMO)C(max)) seemed to be important in explaining toxicity in aqueous media regardless of the measured endpoints for nitrifiers.
Subject(s)
Bacteria/drug effects , Ions/chemistry , Metals/toxicity , Nitrogen/metabolism , Oxygen Consumption/drug effects , Transition Elements/toxicity , Carbon Dioxide/metabolism , Humans , Models, Theoretical , Oxidation-Reduction/drug effects , Quantitative Structure-Activity RelationshipSubject(s)
Frameshift Mutation/genetics , Membrane Proteins/genetics , Neoplasm Proteins/genetics , Photosensitivity Disorders/genetics , Skin Diseases, Genetic/diagnosis , Adolescent , Blister/congenital , Blister/pathology , DNA Mutational Analysis , Female , Humans , Pedigree , Phenotype , Photosensitivity Disorders/congenital , Siblings , Syndrome , TurkeyABSTRACT
Ophthalmo-acromelic syndrome type Waardenburg is an extremely rare autosomal recessive syndrome comprising eye malformations ranging from true anophthalmia to mild microphthalmia with acromelic malformations. We report a case of ophthalmo-acromelic syndrome type Waardenburg diagnosed prenatally.
