{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T12:05:32Z","timestamp":1779710732734,"version":"3.53.1"},"reference-count":96,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic exposure to fine particulate matter (PM2.5) derived from residential wood combustion is a major environmental health concern in southern Chile and other cold-climate regions. Although PM2.5 has been linked to adverse reproductive outcomes, it remains unclear whether sustained exposure induces pregestational uterine alterations that compromise reproductive competence before the first pregnancy. This study evaluated the effects of chronic wood smoke-derived PM2.5 exposure on uterine morphology and molecular markers in nulliparous rats. A two-generation exposure model was used to assess cumulative effects. Second-generation (G2) female Sprague Dawley rats continuously exposed from conception were housed in filtered air (FA, control; n=12) or PM2.5-containing ambient air (NFA; n=12) until reproductive maturity (82 days). Uterine horns were analyzed by histology, planimetry, immunohistochemistry, immunofluorescence, and second harmonic generation microscopy. Markers of hypoxia, inflammation, extracellular matrix remodeling, angiogenesis, proliferation, apoptosis, and DNA repair were quantified. Chronic PM2.5 exposure increased hypoxia-inducible factor 1\u03b1, tumor necrosis factor-\u03b1, vascular endothelial growth factor A, and collagen types I, III, and IV, while transforming growth factor-\u03b2 expression and Ki-67-positive proliferating cells were reduced. Exposed rats showed increased apoptosis and decreased nuclear expression of O6-methylguanine-DNA methyltransferase, indicating impaired DNA repair capacity. Second harmonic generation imaging demonstrated increased collagen deposition with marked fibrillar disorganization. These findings indicate that chronic wood smoke-derived PM2.5 exposure induces hypoxia-driven structural and molecular alterations in the uterus of nulliparous rats before first pregnancy, including extracellular matrix remodeling, inflammatory imbalance, angiogenic dysregulation, reduced proliferation, and compromised DNA repair, suggesting early disruption of uterine homeostasis and increased susceptibility to adverse reproductive outcomes.<\/jats:p>","DOI":"10.3390\/ijms27104289","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:04:36Z","timestamp":1778601876000},"page":"4289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Uterine Vulnerability to Environmental PM2.5: Chronic Wood Smoke Exposure Alters Morphogenesis Before First Pregnancy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6643-5935","authenticated-orcid":false,"given":"Francisca","family":"Villarroel","sequence":"first","affiliation":[{"name":"Laboratory of Animal & Experimental Morphology, Institute of Biology, Faculty of Sciences, Pontificia Universidad Cat\u00f3lica de Valpara\u00edso, Valpara\u00edso 2362807, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1050-7636","authenticated-orcid":false,"given":"Eder","family":"Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology and Stem Cells NeuroCellT, Department of Cellular Biology, Faculty of Biological Sciences, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070386, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9432-6311","authenticated-orcid":false,"given":"Nikol","family":"Ponce","sequence":"additional","affiliation":[{"name":"PhD Program in Morphological Sciences, Universidad de La Frontera, Temuco 4811230, Chile"},{"name":"Center of Excellence in Surgical and Morphological Studies (CEMyQ), Universidad de La Frontera, Temuco 4811230, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7762-1417","authenticated-orcid":false,"given":"Francisco","family":"Nualart","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology and Stem Cells NeuroCellT, Department of Cellular Biology, Faculty of Biological Sciences, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070386, Chile"},{"name":"Center for Advanced Microscopy CMA BIO-BIO, Universidad de Concepci\u00f3n, Concepci\u00f3n 4070386, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5357-3086","authenticated-orcid":false,"given":"Felipe","family":"Ram\u00edrez-Cepeda","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunolog\u00eda, Institute of Biology, Faculty of Sciences, Pontificia Universidad Cat\u00f3lica de Valpara\u00edso, Valpara\u00edso 2362807, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3883-5188","authenticated-orcid":false,"given":"Luis","family":"Mercado","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunolog\u00eda, Institute of Biology, Faculty of Sciences, Pontificia Universidad Cat\u00f3lica de Valpara\u00edso, Valpara\u00edso 2362807, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4979-115X","authenticated-orcid":false,"given":"Maria","family":"Miglino","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, Universidade de Mar\u00edlia (UNIMAR), Mar\u00edlia 17525-902, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2273-0904","authenticated-orcid":false,"given":"Paulo","family":"Salinas","sequence":"additional","affiliation":[{"name":"Laboratory of Animal & Experimental Morphology, Institute of Biology, Faculty of Sciences, Pontificia Universidad Cat\u00f3lica de Valpara\u00edso, Valpara\u00edso 2362807, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2021). WHO Global Air Quality Guidelines: Particulate Matter (PM2.5 and PM10), Ozone, Nitrogen Dioxide, Sulfur Dioxide and Carbon Monoxide, World Health Organization. Available online: https:\/\/www.who.int\/publications\/i\/item\/9789240034228."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Manisalidis, I., Stavropoulou, E., Stavropoulos, A., and Bezirtzoglou, E. (2020). Environmental and health impacts of air pollution: A review. Front. Public Health, 8.","DOI":"10.3389\/fpubh.2020.00014"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"361","DOI":"10.5194\/essd-14-361-2022","article-title":"High-resolution inventory of atmospheric emissions from transport, industrial, energy, mining, and residential activities in Chile","volume":"14","author":"Alamos","year":"2022","journal-title":"Earth Syst. Sci. Data"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.atmosenv.2015.08.087","article-title":"Contributions to cities\u2019 ambient particulate matter (PM): A systematic review of local source contributions at global level","volume":"120","author":"Karagulian","year":"2015","journal-title":"Atmos. Environ."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.3155\/1047-3289.59.12.1481","article-title":"Particulate air pollution and health effects for cardiovascular and respiratory causes in Temuco, Chile: A wood-smoke-polluted urban area","volume":"59","author":"Sanhueza","year":"2009","journal-title":"J. Air Waste Manag. Assoc."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Salinas, P., Ponce, N., del Sol, M., and V\u00e1squez, B. (2025). Impact of PM2.5 Exposure from Wood Combustion on Reproductive Health: Implications for Fertility, Ovarian Function, and Fetal Development. Toxics, 13.","DOI":"10.3390\/toxics13040238"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108610","DOI":"10.1016\/j.reprotox.2024.108610","article-title":"Exposure to fine particulate matter 2.5 from wood combustion smoke causes vascular changes in placenta and reduce fetal size","volume":"127","author":"Villarroel","year":"2024","journal-title":"Reprod. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Orru, H., Olstrup, H., Kukkonen, J., Lopez-Aparicio, S., Segersson, D., Geels, C., Tamm, T., Riikonen, K., Maragkidou, A., and Sigsgaard, T. (2022). Health impacts of PM2.5 originating from residential wood combustion in four Nordic cities. BMC Public Health, 22.","DOI":"10.1186\/s12889-022-13622-x"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"097010","DOI":"10.1289\/EHP849","article-title":"Randomized trial of interventions to improve childhood asthma in homes with wood-burning stoves","volume":"125","author":"Noonan","year":"2017","journal-title":"Environ. Health Perspect."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1007\/s00204-013-1071-z","article-title":"Comparison of wood smoke PM2.5 obtained from the combustion of fir and beech pellets on inflammation and DNA damage in A549 and THP-1 human cell lines","volume":"87","author":"Corsini","year":"2013","journal-title":"Arch. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1080\/08958370600985875","article-title":"Woodsmoke health effects: A review","volume":"19","author":"Naeher","year":"2007","journal-title":"Inhal. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1080\/10937400290070062","article-title":"The toxicology of inhaled woodsmoke","volume":"5","author":"Zelikoff","year":"2002","journal-title":"J. Toxicol. Environ. Health B Crit. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1136\/jech-2023-220594","article-title":"Air pollution and environmental epidemiological evidence in Chile: Alerts for decision-makers and citizens","volume":"78","author":"Cortes","year":"2024","journal-title":"J. Epidemiol. Community Health"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12989-023-00526-w","article-title":"Type 1 diabetes and diet-induced obesity predispose C57BL\/6J mice to PM2.5-induced lung injury: A comparative study","volume":"20","author":"Chen","year":"2023","journal-title":"Part. Fibre Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107003","DOI":"10.1289\/EHP12110","article-title":"Exposure to particulate matter air pollution and age of menarche in a nationwide cohort of U.S. girls","volume":"131","author":"Hood","year":"2023","journal-title":"Environ. Health Perspect."},{"key":"ref_16","first-page":"200217","article-title":"PM2.5 and cardiovascular diseases: State-of-the-art review","volume":"19","author":"Krittanawong","year":"2023","journal-title":"Int. J. Cardiol. Cardiovasc. Risk Prev."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Chen, H., Oliver, B.G., Pant, A., Olivera, A., Poronnik, P., Pollock, C.A., and Saad, S. (2021). Particulate matter, an intrauterine toxin affecting foetal development and beyond. Antioxidants, 10.","DOI":"10.3390\/antiox10050732"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"111281","DOI":"10.1016\/j.ecoenv.2020.111281","article-title":"Maternal PM2.5 exposure and abnormal placental nutrient transport","volume":"207","author":"Zhu","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s13148-019-0713-2","article-title":"Air pollution and DNA methylation: Effects of exposure in humans","volume":"11","author":"Rider","year":"2019","journal-title":"Clin. Epigenetics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1039\/C6EM00148C","article-title":"Source identification, apportionment and toxicity of indoor and outdoor PM2.5 airborne particulates in a region characterised by wood burning","volume":"18","author":"Gatica","year":"2016","journal-title":"Environ. Sci. Process. Impacts"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ecoenv.2016.01.030","article-title":"The health effects of ambient PM2.5 and potential mechanisms","volume":"128","author":"Feng","year":"2016","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.tox.2006.04.038","article-title":"Activation of different pathways of apoptosis by air pollution particulate matter (PM2.5) in human epithelial lung cells (L132) in culture","volume":"225","author":"Dagher","year":"2006","journal-title":"Toxicology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1002\/tox.23476","article-title":"Tussilagone protects acute lung injury from PM2.5 via alleviating HIF-1\u03b1\/NF-\u03baB-mediated inflammatory response","volume":"37","author":"Lin","year":"2022","journal-title":"Environ. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1080\/17435390.2022.2083995","article-title":"PM2.5 induce the defective efferocytosis and promote atherosclerosis via HIF-1\u03b1 activation in macrophage","volume":"16","author":"Liang","year":"2022","journal-title":"Nanotoxicology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1080\/17435390.2021.1917716","article-title":"MiR-939-5p suppresses PM2.5-induced endothelial injury via targeting HIF-1\u03b1 in HAECs","volume":"15","author":"Liang","year":"2021","journal-title":"Nanotoxicology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1093\/humupd\/dmaa053","article-title":"Adaptations of the human placenta to hypoxia: Opportunities for interventions in fetal growth restriction","volume":"27","author":"Colson","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1177\/1933719118815589","article-title":"Maternal oxidative stress, placental morphometry, and fetal growth in diabetic rats exposed to cigarette smoke","volume":"26","author":"Sinzato","year":"2019","journal-title":"Reprod. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.2174\/1381612054065747","article-title":"The role and modulation of the oxidative balance in pregnancy","volume":"11","author":"Biondi","year":"2005","journal-title":"Curr. Pharm. Des."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1016\/S0002-9440(10)64849-3","article-title":"Onset of maternal arterial blood flow and placental oxidative stress: A possible factor in human early pregnancy failure","volume":"157","author":"Jauniaux","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"169555","DOI":"10.1016\/j.scitotenv.2023.169555","article-title":"Impact of antioxidants on PM2.5 oxidative potential, radical level, and cytotoxicity","volume":"912","author":"Wang","year":"2024","journal-title":"Sci. Total Environ."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"111492","DOI":"10.1016\/j.ecoenv.2020.111492","article-title":"The relationship between long-term exposure to PM2.5 and hypertension in women: A meta-analysis","volume":"208","author":"Ma","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1089\/jwh.2018.7182","article-title":"Residential exposure to PM2.5 and ozone and progression of subclinical atherosclerosis among women transitioning through menopause: The Study of Women\u2019s Health Across the Nation","volume":"28","author":"Duan","year":"2019","journal-title":"J. Womens Health"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"103929","DOI":"10.1016\/j.jri.2023.103929","article-title":"Chronic poor healing wounds of post cesarean scar diverticulum: Altered angiogenesis and immunobiology","volume":"157","author":"Guo","year":"2023","journal-title":"J. Reprod. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Yu, X., Xu, J., Song, B., Zhu, R., Liu, J., Liu, Y.F., and Ma, Y.J. (2024). The role of epigenetics in women\u2019s reproductive health: The impact of environmental factors. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1399757"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13148-019-0688-z","article-title":"Air pollution-induced placental alterations: An interplay of oxidative stress, epigenetics, and the aging phenotype?","volume":"11","author":"Saenen","year":"2019","journal-title":"Clin. Epigenetics"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Villarroel, F., Ramirez, E., Ponce, N., Nualart, F., and Salinas, P. (2025). Impact of PM2.5 emitted by wood smoke on the expression of glucose transporter 1 (GLUT1) and sodium-dependent vitamin C transporter 2 (SVCT2) in the rat placenta: A pregestational and gestational exposure study. Antioxidants, 14.","DOI":"10.3390\/antiox14091050"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"647","DOI":"10.4067\/s0717-95022024000300647","article-title":"Histological and endocrine effects of chronic exposure to PM2.5 derived from wood smoke in the uterus of nulliparous adult rats","volume":"42","author":"Villarroel","year":"2024","journal-title":"Int. J. Morphol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/aje\/kwae152","article-title":"Ambient exposure to fine particulate matter with oxidative potential affects oxidative stress biomarkers in pregnancy","volume":"194","author":"Meng","year":"2025","journal-title":"Am. J. Epidemiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1097\/EDE.0000000000000126","article-title":"Air pollution and risk of uterine leiomyomata","volume":"25","author":"Mahalingaiah","year":"2014","journal-title":"Epidemiology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1161\/CIRCRESAHA.116.309279","article-title":"Exposure to fine particulate air pollution is associated with endothelial injury and systemic inflammation","volume":"119","author":"Pope","year":"2016","journal-title":"Circ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/aji.12417","article-title":"Placental regulation of inflammation and hypoxia after TNF-\u03b1 infusion in mice","volume":"74","author":"Bobek","year":"2015","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"114481","DOI":"10.1016\/j.biopha.2023.114481","article-title":"Ovatodiolide inhibits SARS-CoV-2 replication and ameliorates pulmonary fibrosis through suppression of the TGF-\u03b2\/T\u03b2Rs signaling pathway","volume":"161","author":"Chiou","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_43","first-page":"911","article-title":"Relaci\u00f3n entre polimorfismo BsmI y perfil de metilaci\u00f3n del gen VDR, g\u00e9nero, perfil metab\u00f3lico, estr\u00e9s oxidativo e inflamaci\u00f3n en adolescentes","volume":"38","author":"Lucena","year":"2021","journal-title":"Nutr. Hosp."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41467-017-02375-6","article-title":"Hypoxia and hypoxia inducible factor-1\u03b1 are required for normal endometrial repair during menstruation","volume":"9","author":"Maybin","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1056\/NEJMra0910283","article-title":"Hypoxia and inflammation","volume":"364","author":"Eltzschig","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_46","first-page":"3810","article-title":"Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition","volume":"117","author":"Higgins","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"120017","DOI":"10.1016\/j.envpol.2022.120017","article-title":"Long-term exposure to PM2.5 aggravates pulmonary fibrosis and acute lung injury by disrupting Nrf2-mediated antioxidant function","volume":"313","author":"Zhao","year":"2022","journal-title":"Environ. Pollut."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate is an inflammatory signal that induces IL-1\u03b2 through HIF-1\u03b1","volume":"496","author":"Tannahill","year":"2013","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1095\/biolreprod.114.117929","article-title":"Role of uterine contraction in regeneration of the murine postpartum endometrium","volume":"91","author":"Yoshii","year":"2014","journal-title":"Biol. Reprod."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1002\/jcp.24331","article-title":"TNF\u03b1 induces expression of HIF-1\u03b1 mRNA and protein but inhibits hypoxic stimulation of HIF-1 transcriptional activity in airway smooth muscle cells","volume":"228","author":"Tsapournioti","year":"2013","journal-title":"J. Cell. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e12646","DOI":"10.1111\/aji.12646","article-title":"The female reproduction and senescence nexus","volume":"77","author":"Marquez","year":"2017","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1530\/rep.1.00433","article-title":"Endometrial tumor necrosis factor alpha (TNFalpha) is a likely mediator of early luteal phase mifepristone-mediated negative effector action on the preimplantation embryo","volume":"129","author":"Lalitkumar","year":"2005","journal-title":"Reproduction"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1093\/humrep\/dei315","article-title":"Tumour necrosis factor-alpha up-regulates macrophage migration inhibitory factor expression in endometrial stromal cells via the nuclear transcription factor NF-kappaB","volume":"21","author":"Cao","year":"2006","journal-title":"Hum. Reprod."},{"key":"ref_54","first-page":"415","article-title":"Compartmentalization of TNF Receptor 1 Signaling","volume":"21","author":"Tchikov","year":"2004","journal-title":"Immunity"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1124\/mol.107.042176","article-title":"Tumor necrosis factor-alpha regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor kappaB in human endometriotic epithelial cells","volume":"73","author":"Grund","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"108491","DOI":"10.1016\/j.reprotox.2023.108491","article-title":"Chronic exposure of mice to phthalates enhances TGF beta signaling and promotes uterine fibrosis","volume":"122","author":"Shukla","year":"2023","journal-title":"Reprod. Toxicol."},{"key":"ref_57","first-page":"270","article-title":"Hypoxia induces endothelial mesenchymal transition in pulmonary vascular remodeling","volume":"42","author":"Zhang","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1017\/S2040174413000299","article-title":"Increased collagen deposition in the heart of chronically hypoxic ovine fetuses","volume":"4","author":"Thompson","year":"2013","journal-title":"J. Dev. Orig. Health Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s42825-022-00087-2","article-title":"The role of extracellular matrix on unfavorable maternal\u2013fetal interface: Focusing on the function of collagen in human fertility","volume":"4","author":"Liu","year":"2022","journal-title":"J. Leather Sci. Eng."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1016\/j.ajpath.2012.02.004","article-title":"Recent developments in myofibroblast biology: Paradigms for connective tissue remodeling","volume":"180","author":"Hinz","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1007\/978-0-387-74672-2_7","article-title":"The effects of relaxin on extracellular matrix remodeling in health and fibrotic disease","volume":"Volume 612","author":"Samuel","year":"2007","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1007\/s43032-022-01083-x","article-title":"Endometriosis: Cellular and Molecular Mechanisms Leading to Fibrosis","volume":"30","author":"Vannuzzi","year":"2023","journal-title":"Reprod. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ajog.2005.12.059","article-title":"A new hypothesis about the origin of uterine fibroids based on gene expression profiling with microarrays","volume":"195","author":"Leppert","year":"2006","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Ma, J., Gao, W., and Li, D. (2023). Recurrent implantation failure: A comprehensive summary from etiology to treatment. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1061766"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1093\/humrep\/deae259","article-title":"Particulate air pollution at the time of oocyte retrieval is independently associated with reduced odds of live birth in subsequent frozen embryo transfers","volume":"40","author":"Leathersich","year":"2025","journal-title":"Hum. Reprod."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6170936","DOI":"10.1155\/2019\/6170936","article-title":"HB-EGF ameliorates oxidative stress-mediated uterine decidualization damage","volume":"2019","author":"Yu","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.yexcr.2008.07.025","article-title":"HB-EGF: A unique mediator of embryo-uterine interactions during implantation","volume":"315","author":"Lim","year":"2009","journal-title":"Exp. Cell Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e23494","DOI":"10.1002\/jbt.23494","article-title":"Induction of heme oxygenase-1 antagonizes PM2.5-induced pulmonary VEGFA expression through regulating HIF-1\u03b1","volume":"37","author":"Xu","year":"2023","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Fan, X., Muruganandan, S., Shallie, P.D., Dhal, S., Petitt, M., and Nayak, N.R. (2021). VEGF maintains maternal vascular space homeostasis in the mouse placenta through modulation of trophoblast giant cell functions. Biomolecules, 11.","DOI":"10.3390\/biom11071062"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1093\/rheumatology\/ker327","article-title":"Hypoxia differentially affects IL-1\u03b2-stimulated MMP-1 and MMP-13 expression of fibroblast-like synoviocytes in an HIF-1\u03b1-dependent manner","volume":"51","author":"Lee","year":"2012","journal-title":"Rheumatology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12967-021-03031-w","article-title":"Integrative analysis and experiments to explore angiogenesis regulators correlated with poor prognosis, immune infiltration and cancer progression in lung adenocarcinoma","volume":"19","author":"Cai","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Don, E.E., Middelkoop, M.A., Hehenkamp, W.J., Mijatovic, V., Griffioen, A.W., and Huirne, J.A. (2023). Endometrial angiogenesis in abnormal uterine bleeding and infertility in patients with uterine fibroids: A systematic review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087011"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1093\/humupd\/dmt042","article-title":"The role of angiogenic factors in fibroid pathogenesis: Potential implications for future therapy","volume":"20","author":"Tal","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"ref_74","first-page":"111","article-title":"Association of PM2.5 and its components with endometriosis among women undergoing assisted reproductive technology: A case-control study in Anhui, China","volume":"30","author":"Peng","year":"2024","journal-title":"Hum. Ecol. Risk Assess."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.ijheh.2019.02.004","article-title":"The effects of exposure to air pollution on the development of uterine fibroids","volume":"222","author":"Lin","year":"2019","journal-title":"Int. J. Hyg. Environ. Health"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"143144","DOI":"10.1016\/j.cej.2023.143144","article-title":"An anti-fibroblast adhesion and anti-inflammatory hydrogel film combined with VEGF for intrauterine adhesion prevention","volume":"466","author":"Liu","year":"2023","journal-title":"Chem. Eng. J."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Setiawan, A., Anwar, R., Syamsunarno, M.R.A.A., Mose, J.C., Santoso, B., Maskoen, A.M., Permadi, W., Setiabudiawan, B., Dhamayanti, M., and Hidayat, Y.M. (2023). Epigenetic regulation interplays with endometriosis pathogenesis in low-birth-weight patients via the progesterone receptor B\u2013VEGF\u2013DNMT1 axis. Diagnostics, 13.","DOI":"10.3390\/diagnostics13122085"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1080\/10715762.2022.2061967","article-title":"Hypoxia induces proliferation via NOX4-mediated oxidative stress and TGF-\u03b23 signaling in uterine leiomyoma cells","volume":"56","author":"Reschke","year":"2022","journal-title":"Free Radic. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"C775","DOI":"10.1152\/ajpcell.00279.2015","article-title":"Regulation of cell proliferation by hypoxia-inducible factors","volume":"309","author":"Hubbi","year":"2015","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_80","first-page":"6071","article-title":"Knockdown of miR-27a reduces TGF\u03b2-induced EMT and H2O2-induced oxidative stress through regulating mitochondrial autophagy","volume":"15","author":"Zhao","year":"2023","journal-title":"Am. J. Transl. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1016\/j.fertnstert.2017.04.015","article-title":"Oxidative stress: A key regulator of leiomyoma cell survival","volume":"107","author":"Fletcher","year":"2017","journal-title":"Fertil. Steril."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s10815-010-9419-2","article-title":"Impact of short-term preconceptional exposure to particulate air pollution on treatment outcome in couples undergoing in vitro fertilization and embryo transfer (IVF\/ET)","volume":"27","author":"Perin","year":"2010","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"168843","DOI":"10.1016\/j.scitotenv.2023.168843","article-title":"Causal effects of exposure to ambient air pollution on cancer risk: Insights from genetic evidence","volume":"912","author":"Li","year":"2024","journal-title":"Sci. Total Environ."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Stoccoro, A., Nicoli, V., Copped\u00e8, F., Grossi, E., Fedrizzi, G., Menotta, S., Lorenzoni, F., Caretto, M., Carmignani, A., and Pistolesi, S. (2023). Prenatal environmental stressors and DNA methylation levels in placenta and peripheral tissues of mothers and neonates evaluated by applying artificial neural networks. Genes, 14.","DOI":"10.3390\/genes14040836"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Sabolova, G., Spakova, I., Artimovic, P., Bohus, P., Rabajdova, M., and Marekova, M. (2024). The pivotal role of the key angiogenic factors in the development of endometrioid pathologies of the uterus and ovary. Cancers, 16.","DOI":"10.3390\/cancers16162772"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Kim, J.H., Hwang, K.H., Kim, S.H., Kim, H.J., Kim, J.M., Lee, M.Y., Cha, S.K., and Lee, J. (2024). Particulate matter-induced neurotoxicity: Unveiling the role of NOX4-mediated ROS production and mitochondrial dysfunction in neuronal apoptosis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25116116"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Zeng, Y., Li, M., Zou, T., Chen, X., Li, Q., Li, Y., Ge, L., Chen, S., and Xu, H. (2021). The impact of particulate matter (PM2.5) on human retinal development in hESC-derived retinal organoids. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.607341"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Luo, M., Tan, X., Wang, Y., Chen, G., and Lan, L. (2023). Household polluting cooking fuels and adverse birth outcomes: An updated systematic review and meta-analysis. Front. Public Health, 11.","DOI":"10.3389\/fpubh.2023.978556"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1111\/ina.12144","article-title":"Effect of indoor air pollution from biomass and solid fuel combustion on symptoms of preeclampsia\/eclampsia in Indian women","volume":"25","author":"Agrawal","year":"2015","journal-title":"Indoor Air"},{"key":"ref_90","unstructured":"IQAir (2023, June 02). First in Air Quality, 2022. Available online: https:\/\/www.iqair.com\/world-air-quality-report."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2158244019863563","DOI":"10.1177\/2158244019863563","article-title":"Examining patterns of air quality perception: A cluster analysis for southern Chilean cities","volume":"9","author":"Boso","year":"2019","journal-title":"SAGE Open"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"306","DOI":"10.4209\/aaqr.2013.10.0316","article-title":"Short term health effects of particulate matter: A comparison between wood smoke and multi-source polluted urban areas in Chile","volume":"15","author":"Cortes","year":"2015","journal-title":"Aerosol Air Qual. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.envpol.2018.01.085","article-title":"Indoor PM2.5 in an urban zone with heavy wood smoke pollution: The case of Temuco, Chile","volume":"236","author":"Jorquera","year":"2018","journal-title":"Environ. Pollut."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.envres.2009.03.006","article-title":"Chronic exposure to fine particulate matter emitted by traffic affects reproductive and fetal outcomes in mice","volume":"109","author":"Veras","year":"2009","journal-title":"Environ. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"119255","DOI":"10.1016\/j.atmosenv.2022.119255","article-title":"Spatial distribution of particulate matter on winter nights in Temuco, Chile: Studying the impact of residential wood-burning using mobile monitoring","volume":"286","author":"Blanco","year":"2022","journal-title":"Atmos. Environ."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1093\/bioinformatics\/btaa847","article-title":"Colour deconvolution: Stain unmixing in histological imaging","volume":"37","author":"Landini","year":"2021","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4289\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T12:00:24Z","timestamp":1779710424000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,12]]},"references-count":96,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104289"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104289","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,12]]}}}