Exogenous estrogen partially rescues progesterone deficiency and autophagosome enlargement in Mcoln1^(-/-)mouse model with lysosomal storage disorder  

作　　者：Zidao Wang Yuehuan Li Christian L.Andersen Ahmed E.El Zowalaty Jonathan M.Hancock Taylor E.Martin Elizabeth W.Howerth Suvitha Viswanathan Haeyeun Byun Xiaoqin Ye 

机构地区：[1]Department of Physiology and Pharmacology,College of Veterinary Medicine,University of Georgia,Athens,GA 30602,USA [2]Interdisciplinary Toxicology Program,University of Georgia,Athens,GA 30602,USA [3]Department of Pathology,College of Veterinary Medicine,University of Georgia,Athens,GA 30602,USA [4]Department of Obstetrics,Gynecology and Women's Health,University of Missouri,Columbia,MO 65211,USA [5]Bejing Institute of Collaborative Innovation,Beijing 100094,China [6]Department of Pharmacology and Toxicology,Faculty of Pharmacy,Zagazig University,Zagazig44519,Egypt

出　　处：《Reproductive and Developmental Medicine》2024年第4期197-205,共9页生殖与发育医学(英文版)

基　　金：the Offfce of the Vice President for Research,Interdisciplinary Toxicology Program,and Department of Physiology and Pharmacology at the University of Georgia,and the National Institutes of Health(grants NIH R01HD065939[co-funded by ORWH and NICHD],R03HD097384,and R03 HD100652 to X.Y.)for ffnancial support;Serum P4 and E2 levels were determined at The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core,which is supported by the Eunice Kennedy Shriver NICHD/NIH(NCTRI)Grant P50-HD28934.

摘　　要：Objective:FemaleMcoln1^(-/-)mice exhibit progressive progesterone(P4)deficiency,luteal cell degeneration,and premature embryo implantation failure at 5 months old.We attempted to rescue embryo implantation in non-virginMcoln1^(-/-)mice(5-6 months old)with exogenous P4 treatment on days 1.5 post-coitum(D1.5),D2.5,and D3.5,and observed partially restored luteal cell morphology on D4.5,but unexpectedly found 17β-estradiol(E2)contamination in the P4 working solution.In this study,we aim to investigate exogenous P4 and/or E2 for the partial recovery of luteal cell morphology in infertileMcoln1^(-/-)mice.Methods:Control and non-virginMcoln1^(-/-)mice(5-6 months old)were treated with newly ordered vehicle,P4,E2,or P4+E2 on D1.5 and D2.5 and dissected on D3.5 for P4 and E2 measurements,ovary histology,immunofluorescence,lipid droplet staining,and transmission electron microscopy.Results:E2 treatment significantly increased serum P4 levels in D3.5Mcoln1^(-/-)mice.E2 and P4+E2 treatments,but not P4 treatment alone,largely improved the morphology of D3.5Mcoln1^(-/-)corpora lutea,indicated by a more contiguous web-like collagen IV expression pattern,increased heat shock protein 60 expression,and reduced accumulation of large lipid droplets.Transmission electron microscopy revealed extremely enlarged autophagosomes and lipid droplets,lysosomes with lamellar structures,and mitochondria with reduced cristae in vehicle-treated D3.5Mcoln1^(-/-)luteal cells,while in E2-treated D3.5Mcoln1^(-/-)luteal cells,extremely enlarged autophagosomes and lipid droplets were reduced,indicating improved luteal cell ultrastructure.Conclusion:These findings reveal protective effects of high levels of exogenous E2 on P4 production and lysosomal function inMcoln1^(-/-)luteal cells.

关 键 词：TRPML1/Mcoln1 Corpus luteum PROGESTERONE ESTROGEN Heat shock protein 60 Collagen IV Transmission electron microscopy AUTOPHAGOSOME Lipid droplet 

分 类 号：R73[医药卫生—肿瘤]