{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:27:31Z","timestamp":1791044851007,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Akiyama Life Science Foundation 2018","award":["102-045"],"award-info":[{"award-number":["102-045"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>Intrauterine inflammation can cause infertility by disrupting reproductive function. The pathogenesis underlying this process may primarily involve endotoxins from lipopolysaccharides (LPS), which are produced by Gram-negative bacteria. However, the long-term effects of endotoxins in mammalian pregnancy following LPS exposure during fertilization have not been clarified. In this study, we performed experiments to analyze the influence of LPS on early embryonic development and fetal development in mice. Mice uteruses were examined for the expression of genes related to the inflammatory response. The expression of Il-1\u03b2 and Il-6 increased following the administration of 200 and 1000 \u00b5g\/kg LPS. Exposure to LPS using in vitro fertilization (IVF) significantly decreased the embryonic developmental rate. A concentration of 100 \u00b5g\/kg LPS significantly increased the placental weight and fetal crown \u2013rump length (CRL), whereas a concentration of 200 \u00b5g\/kg LPS significantly decreased the placenta weight and fetal weight in vivo. These findings indicate that maternal LPS during fertilization affects fetal development until the late stage of pregnancy. Thus, maternal endotoxins may affect epigenetic inheritance during embryonic development from the early to late stages of pregnancy.<\/jats:p>","DOI":"10.3390\/ani13071135","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T02:34:54Z","timestamp":1679625294000},"page":"1135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["LPS Administration during Fertilization Affects Epigenetic Inheritance during Embryonic Development"],"prefix":"10.3390","volume":"13","author":[{"given":"Sangwoo","family":"Kim","sequence":"first","affiliation":[{"name":"Graduate School of Animal and Veterinary Sciences and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erina","family":"Yoneda","sequence":"additional","affiliation":[{"name":"Graduate School of Animal and Veterinary Sciences and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kisaki","family":"Tomita","sequence":"additional","affiliation":[{"name":"Graduate School of Animal and Veterinary Sciences and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsunori","family":"Kayano","sequence":"additional","affiliation":[{"name":"Graduate School of Animal and Veterinary Sciences and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Graduate School of Animal and Veterinary Sciences and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoki","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Graduate School of Animal and Veterinary Sciences and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Graduate School of Animal and Veterinary Sciences and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Muranishi","sequence":"additional","affiliation":[{"name":"Graduate School of Animal and Veterinary Sciences and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eaat6114","DOI":"10.1126\/sciimmunol.aat6114","article-title":"Immune Responses at the Maternal-Fetal Interface","volume":"4","author":"Ander","year":"2019","journal-title":"Sci. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1471-0528.2010.02773.x","article-title":"Unique Alterations in Infection-Induced Immune Activation during Pregnancy","volume":"118","author":"Witkin","year":"2011","journal-title":"BJOG"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1093\/humupd\/dmv041","article-title":"The Role of Infection in Miscarriage","volume":"22","author":"Giakoumelou","year":"2016","journal-title":"Hum. Reprod. Update"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"R169","DOI":"10.1530\/REP-17-0406","article-title":"Disruption of Female Reproductive Function by Endotoxins","volume":"155","author":"Bidne","year":"2020","journal-title":"Reproduction"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1439-0531.2009.01465.x","article-title":"Mechanisms of Infertility Associated with Clinical and Subclinical Endometritis in High Producing Dairy Cattle","volume":"44","author":"Sheldon","year":"2009","journal-title":"Reprod. Domest. Anim."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.theriogenology.2022.04.030","article-title":"Peroxisome Proliferator-Activated Receptor Gamma Ligands Regulate the Expression of Inflammatory Mediators in Porcine Endometrium during LPS-Induced Inflammation","volume":"187","author":"Mierzejewski","year":"2022","journal-title":"Theriogenology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1095\/biolreprod.109.077370","article-title":"Defining Postpartum Uterine Disease and the Mechanisms of Infection and Immunity in the Female Reproductive Tract in Cattle","volume":"81","author":"Sheldon","year":"2009","journal-title":"Biol. Reprod."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s00404-004-0623-0","article-title":"Comprehending the Role of LPS in Gram-Negative Bacterial Vaginosis: Ogling into the Causes of Unfulfilled Child-Wish","volume":"270","author":"Deb","year":"2004","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/ecosalplus.ESP-0001-2018","article-title":"Function and Biogenesis of Lipopolysaccharides","volume":"8","author":"Bertani","year":"2018","journal-title":"EcoSal Plus"},{"key":"ref_10","first-page":"128","article-title":"Ex Vivo Lipopolysaccharide (LPS)-Induced TNF-a, IL-1b, IL-6 and PGE 2 Secretion in Whole Blood from Type 1 Diabetes Mellitus Patients with or without Aggressive Periodontitis","volume":"14","author":"Araya","year":"2003","journal-title":"Eur. Cytokine Netw."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/intimm\/dxh186","article-title":"Toll-like Receptors in Innate Immunity","volume":"17","author":"Takeda","year":"2005","journal-title":"Int. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.smim.2006.12.004","article-title":"TLR Signaling","volume":"19","author":"Kawai","year":"2007","journal-title":"Semin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S53","DOI":"10.1016\/j.ajog.2015.08.041","article-title":"Chronic Inflammation of the Placenta: Definition, Classification, Pathogenesis, and Clinical Significance","volume":"213","author":"Kim","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0739-7240(01)00098-4","article-title":"Endotoxin Induces Delayed Ovulation Following Endocrine Aberration during the Proestrous Phase in Holstein Heifers","volume":"20","author":"Suzuki","year":"2001","journal-title":"Domest. Anim. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.theriogenology.2011.05.001","article-title":"Immediate and Carryover Effects of Gram-Negative and Gram-Positive Toxin-Induced Mastitis on Follicular Function in Dairy Cows","volume":"76","author":"Lavon","year":"2011","journal-title":"Theriogenology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1262\/jrd.2013-124","article-title":"Lipopolysaccharide (LPS) Inhibits Steroid Production in Theca Cells of Bovine Follicles In Vitro: Distinct Effect of LPS on Theca Cell Function in Pre-and Post-Selection Follicles","volume":"60","author":"Fumie","year":"2014","journal-title":"J. Reprod. Dev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0378-4320(02)00248-8","article-title":"Relationship between Endotoxin and Prostaglandin (PGE2 and PGFM) Concentrations and Ovarian Function in Dairy Cows with Puerperal Endometritis","volume":"76","author":"Mateus","year":"2003","journal-title":"Anim. Reprod. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1530\/REP-07-0229","article-title":"Ovarian Follicular Cells Have Innate Immune Capabilities That Modulate Their Endocrine Function","volume":"134","author":"Herath","year":"2007","journal-title":"Reproduction"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.anireprosci.2013.11.005","article-title":"Lipopolysaccharide in Ovarian Follicular Fluid Influences the Steroid Production in Large Follicles of Dairy Cows","volume":"144","author":"Magata","year":"2014","journal-title":"Anim. Reprod. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.anireprosci.2019.04.004","article-title":"Effects of Follicular Fluid of Preovulatory Follicles of Repeat Breeder Dairy Cows with Subclinical Endometritis on Oocyte Developmental Competence","volume":"205","author":"Heidari","year":"2019","journal-title":"Anim. Reprod. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3228","DOI":"10.1210\/me.2006-0194","article-title":"Induced Expression of Pattern Recognition Receptors in Cumulus Oocyte Complexes: Novel Evidence for Innate Immune-like Functions during Ovulation","volume":"20","author":"Shimada","year":"2006","journal-title":"Mol. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.tox.2007.02.010","article-title":"Effects of Low-Dose Lipopolysaccharide (LPS) Pretreatment on LPS-Induced Intra-Uterine Fetal Death and Preterm Labor","volume":"234","author":"Xu","year":"2007","journal-title":"Toxicology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1016\/j.theriogenology.2010.05.019","article-title":"Polymyxin B Neutralizes Bacteria-Released Endotoxin and Improves the Quality of Boar Sperm during Liquid Storage and Cryopreservation","volume":"74","author":"Okazaki","year":"2010","journal-title":"Theriogenology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/rmb2.12355","article-title":"Male Advantage Observed for in Vitro Fertilization Mouse Embryos Exhibiting Early Cleavage","volume":"20","author":"Kawase","year":"2021","journal-title":"Reprod. Med. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1274\/jmor.33.3","article-title":"The Early History of the TYH Medium for in Vitro Fertilization of Mouse Ova","volume":"33","author":"Toyoda","year":"2016","journal-title":"J. Mamm. Ova. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1530\/jrf.0.0170399","article-title":"Complete Development in Vitro of the Pre-Implantation Stages of the Mouse in a Simple Chemically Defined Medium","volume":"17","author":"Whitten","year":"1968","journal-title":"J. Reprod. Fertil."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1046\/j.0936-6768.2003.00465.x","article-title":"Effects of Glucose Concentration on in Vitro Fertilization in BALB\/c Mice","volume":"38","author":"Wu","year":"2003","journal-title":"Reprod. Domest. Anim."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/aji.12438","article-title":"Chronic Endometritis: Potential Cause of Infertility and Obstetric and Neonatal Complications","volume":"75","author":"Kitaya","year":"2016","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"hoac023","DOI":"10.1093\/hropen\/hoac023","article-title":"Diagnosing Chronic Endometritis: When Simplification Fails to Clarify","volume":"2022","author":"Murtinger","year":"2022","journal-title":"Hum. Reprod. Open"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.1600-0897.2011.00986.x","article-title":"Peptidoglycan Induces Necrosis and Regulates Cytokine Production in Murine Trophoblast Stem Cells","volume":"66","author":"Rose","year":"2011","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/2049-1891-3-7","article-title":"Tumor Necrosis Factor Alpha Inhibits In Vitro Bovine Embryo Development through a Prostaglandin Mediated Mechanism","volume":"3","author":"Lauren","year":"2012","journal-title":"J. Anim. Sci. Biotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/jog.13498","article-title":"Interleukin-6 Regulates Expression of Fos and Jun Genes to Affect the Development of Mouse Preimplantation Embryos","volume":"44","author":"Yu","year":"2018","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4316316","DOI":"10.1155\/2017\/4316316","article-title":"Elevated Glucose and Interleukin-1 \u03b2 Differentially Affect Retinal Microglial Cell Proliferation","volume":"2017","author":"Baptista","year":"2017","journal-title":"Mediators Inflamm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.domaniend.2017.08.004","article-title":"Human IL6 Stimulates Bovine Satellite Cell Proliferation through a Signal Transducer and Activator of Transcription 3 (STAT3)-Dependent Mechanism","volume":"62","author":"Brandt","year":"2018","journal-title":"Domest. Anim. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wiliams, C.L., Teeling, J.L., Perry, H.V., and Fleming, T.P. (2011). Mouse Maternal Systemic Inflammation at the Zygote Stage Causes Blunted Cytokine Responsiveness in Lipopolysaccharide-Challenged Adult Offspring. BMC Biol, 9.","DOI":"10.1186\/1741-7007-9-49"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0165-0378(98)00078-3","article-title":"Intrauterine Infusion of Bacterial Lipopolysaccharide (LPS) Prior to Mating Has No Adverse Effect on Fertility, Fetal Survival and Fetal Development","volume":"42","author":"Wenbio","year":"1999","journal-title":"J. Reprod. Immuol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.ejogrb.2007.08.016","article-title":"Proliferative Responses in the Placenta after Endotoxin Exposure in Preterm Fetal Sheep","volume":"138","author":"Garnier","year":"2008","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.mvr.2016.10.001","article-title":"Cdc42 Regulates LPS-Induced Proliferation of Primary Pulmonary Microvascular Endothelial Cells via ERK Pathway","volume":"109","author":"Lv","year":"2017","journal-title":"Microvasc. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s00011-016-1004-4","article-title":"Curcumin Inhibits Placental Inflammation to Ameliorate LPS-Induced Adverse Pregnancy Outcomes in Mice via Upregulation of Phosphorylated Akt","volume":"66","author":"Zhou","year":"2017","journal-title":"Inflamm. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s00412-018-0659-8","article-title":"Ki-67: More than a Proliferation Marker","volume":"127","author":"Sun","year":"2018","journal-title":"Chromosoma"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1158\/0008-5472.CAN-16-0707","article-title":"Cell-Cycle Regulation Accounts for Variability in Ki-67 Expression Levels","volume":"77","author":"Sobecki","year":"2017","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"BSR20190386","DOI":"10.1042\/BSR20190386","article-title":"Nicotine Protects Fetus against LPS-Induced Fetal Growth Restriction through Ameliorating Placental Inflammation and Vascular Development in Late Pregnancy in Rats","volume":"39","author":"Bao","year":"2019","journal-title":"Biosci. Rep."}],"container-title":["Animals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2615\/13\/7\/1135\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:01:30Z","timestamp":1760122890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2615\/13\/7\/1135"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,23]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ani13071135"],"URL":"https:\/\/doi.org\/10.3390\/ani13071135","relation":{},"ISSN":["2076-2615"],"issn-type":[{"value":"2076-2615","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,23]]}}}