{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:32:49Z","timestamp":1791581569095,"version":"4.3.4"},"reference-count":51,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2018,9,3]],"date-time":"2018-09-03T00:00:00Z","timestamp":1535932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007045","name":"Secretar\u00eda de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n del Distrito Federal","doi-asserted-by":"publisher","award":["PICSA12-086"],"award-info":[{"award-number":["PICSA12-086"]}],"id":[{"id":"10.13039\/501100007045","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Consejo Nacional de Ciencia y Tecnolog\u00eda CONACYT\/FONCICYT","award":["267755"],"award-info":[{"award-number":["267755"]}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["326697"],"award-info":[{"award-number":["326697"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>During embryonic development, some hypoxia occurs due to incipient vascularization. Under hypoxic conditions, gene expression is mainly controlled by hypoxia-inducible factor 1 (HIF-1). The activity of this transcription factor can be altered by the exposure to a variety of compounds; among them is cadmium (Cd), a nephrotoxic heavy metal capable of crossing the placenta and reaching fetal kidneys. The goal of the study was to determine Cd effects on HIF-1 on embryonic kidneys. Pregnant Wistar rats were exposed to a mist of isotonic saline solution or CdCl2 (DDel = 1.48 mg Cd\/kg\/day), from gestational day (GD) 8 to 20. Embryonic kidneys were obtained on GD 21 for RNA and protein extraction. Results show that Cd exposure had no effect on HIF-1\u03b1 and prolyl hydroxylase 2 protein levels, but it reduced HIF-1 DNA-binding ability, which was confirmed by a decrease in vascular endothelial growth factor (VEGF) mRNA levels. In contrast, the protein levels of VEGF were not changed, which suggests the activation of additional regulatory mechanisms of VEGF protein expression to ensure proper kidney development. In conclusion, Cd exposure decreases HIF-1-binding activity, posing a risk on renal fetal development.<\/jats:p>","DOI":"10.3390\/toxics6030053","type":"journal-article","created":{"date-parts":[[2018,9,3]],"date-time":"2018-09-03T10:50:51Z","timestamp":1535971851000},"page":"53","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Intrauterine Exposure to Cadmium Reduces HIF-1 DNA-Binding Ability in Rat Fetal Kidneys"],"prefix":"10.3390","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9682-8627","authenticated-orcid":false,"given":"Tania","family":"Jacobo-Estrada","sequence":"first","affiliation":[{"name":"Departamento de Toxicolog\u00eda, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, 07360 Ciudad de M\u00e9xico, Mexico"},{"name":"Departamento de Sociedad y Pol\u00edtica Ambiental, CIIEMAD, Instituto Polit\u00e9cnico Nacional, 07340 Ciudad de M\u00e9xico, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4154-6088","authenticated-orcid":false,"given":"Mariana","family":"Cardenas-Gonzalez","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitzi Paola","family":"Santoyo-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Departamento de Toxicolog\u00eda, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, 07360 Ciudad de M\u00e9xico, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Thevenod","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pathophysiology and Toxicology and ZBAF (Center for Biomedical Education and Research), Faculty of Health-School of Medicine, Witten\/Herdecke University, 58448 Witten, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0378-3675","authenticated-orcid":false,"given":"Olivier","family":"Barbier","sequence":"additional","affiliation":[{"name":"Departamento de Toxicolog\u00eda, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional, 07360 Ciudad de M\u00e9xico, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1002\/bdr2.1142","article-title":"Hypoxia: From placental development to fetal programming","volume":"109","author":"Fajersztajn","year":"2017","journal-title":"Birth Defects Res."},{"key":"ref_2","first-page":"75","article-title":"Embriology and teratology","volume":"2","author":"Baker","year":"1979","journal-title":"The Laboratory Rat"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/sj.ki.5000062","article-title":"Expression of hypoxia-inducible transcription factors in developing human and rat kidneys","volume":"69","author":"Bernhardt","year":"2006","journal-title":"Kidney Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.biocel.2004.08.012","article-title":"Hypoxia-inducible factor 1: Regulation by hypoxic and non-hypoxic activators","volume":"37","author":"Dery","year":"2005","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1681\/ASN.2008070804","article-title":"HIF in kidney disease and development","volume":"20","author":"Gunaratnam","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1097\/01.ASN.0000013925.19218.7B","article-title":"Loss of the VEGF(164) and VEGF(188) isoforms impairs postnatal glomerular angiogenesis and renal arteriogenesis in mice","volume":"13","author":"Mattot","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1172\/JCI119416","article-title":"Vascular endothelial growth factor is an essential molecule for mouse kidney development: Glomerulogenesis and nephrogenesis","volume":"99","author":"Kitamoto","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.cardiores.2004.09.032","article-title":"Transcriptional regulation of the vascular endothelial growth factor gene\u2014A concert of activating factors","volume":"65","author":"Pouyssegur","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.2131\/jts.37.1035","article-title":"Participation of metal transporters in cadmium transport from mother rat to fetus","volume":"37","author":"Nakamura","year":"2012","journal-title":"J. Toxicol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"149","DOI":"10.2131\/jts.37.149","article-title":"Health effects of low-level cadmium intake and the role of metallothionein on cadmium transport from mother rats to fetus","volume":"37","author":"Nakamura","year":"2012","journal-title":"J. Toxicol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"F1450","DOI":"10.1152\/ajprenal.00223.2007","article-title":"Cadmium causes delayed effects on renal function in the offspring of cadmium-contaminated pregnant female rats","volume":"293","author":"Jacquillet","year":"2007","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1002\/jat.3286","article-title":"Evaluation of kidney injury biomarkers in rat amniotic fluid after gestational exposure to cadmium","volume":"36","author":"Barbier","year":"2016","journal-title":"J. Appl. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4198","DOI":"10.1046\/j.1432-1327.2000.01453.x","article-title":"Cadmium blocks hypoxia-inducible factor (HIF)-1-mediated response to hypoxia by stimulating the proteasome-dependent degradation of HIF-1alpha","volume":"267","author":"Chun","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1093\/toxsci\/kfs327","article-title":"Hypoxia-response element (hre)-directed transcriptional regulation of the rat lysyl oxidase gene in response to cobalt and cadmium","volume":"132","author":"Gao","year":"2013","journal-title":"Toxicol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3743","DOI":"10.1182\/blood.V96.12.3743","article-title":"Cadmium and platinum suppression of erythropoietin production in cell culture: Clinical implications","volume":"96","author":"Horiguchi","year":"2000","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1093\/toxsci\/kfr256","article-title":"Cadmium increases HIF-1 and VEGF expression through ROS, ERK, and AKT signaling pathways and induces malignant transformation of human bronchial epithelial cells","volume":"125","author":"Jing","year":"2012","journal-title":"Toxicol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s00204-003-0444-0","article-title":"Suppression of erythropoietin gene expression by cadmium depends on inhibition of HIF-1, not stimulation of GATA-2","volume":"77","author":"Obara","year":"2003","journal-title":"Arch. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.aquatox.2010.05.013","article-title":"Effects of cadmium on anaerobic energy metabolism and mRNA expression during air exposure and recovery of an intertidal mollusk Crassostrea virginica","volume":"99","author":"Ivanina","year":"2010","journal-title":"Aquat. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.cbd.2010.10.003","article-title":"Molecular characterization and mRNA expression of two key enzymes of hypoxia-sensing pathways in eastern oysters Crassostrea virginica (Gmelin): Hypoxia-inducible factor alpha (HIF-alpha) and HIF-prolyl hydroxylase (PHD)","volume":"6","author":"Piontkivska","year":"2011","journal-title":"Comp. Biochem. Physiol. Part D Genomics Proteomics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.aquatox.2010.04.015","article-title":"Effects of cadmium on hypoxia-induced expression of hemoglobin and erythropoietin in larval sheepshead minnow, cyprinodon variegatus","volume":"99","author":"Dangre","year":"2010","journal-title":"Aquat. Toxicol."},{"key":"ref_21","unstructured":"Agency for Toxic Substances and Disease Registry (2012). Toxicological Profile for Cadmium."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/BF00364654","article-title":"Early signs of oral and inhalative cadmium uptake in rats","volume":"40","author":"Prigge","year":"1978","journal-title":"Arch. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0378-4274(84)90045-6","article-title":"Behavioral alterations in offspring of female rats repeatedly exposed to cadmium oxide by inhalation","volume":"22","author":"Baranski","year":"1984","journal-title":"Toxicol. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0378-4274(02)00007-3","article-title":"Maternal-fetal distribution of cadmium in the guinea pig following a low dose inhalation exposure","volume":"129","author":"Trottier","year":"2002","journal-title":"Toxicol. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1530\/JME-12-0024","article-title":"Tissue-specific selection of stable reference genes for real-time pcr normalization in an obese rat model","volume":"48","author":"Cabiati","year":"2012","journal-title":"J. Mol. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ejphar.2012.03.032","article-title":"Testosterone replacement therapy promotes angiogenesis after acute myocardial infarction by enhancing expression of cytokines HIF-1a, SDF-1a and VEGF","volume":"684","author":"Chen","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/j.1745-7270.2006.00174.x","article-title":"Differential and reciprocal regulation between hypoxia-inducible factor-alpha subunits and their prolyl hydroxylases in pulmonary arteries of rat with hypoxia-induced hypertension","volume":"38","author":"Chen","year":"2006","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1681\/ASN.2005090918","article-title":"High glucose blunts vascular endothelial growth factor response to hypoxia via the oxidative stress-regulated hypoxia-inducible factor\/hypoxia-responsible element pathway","volume":"17","author":"Katavetin","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_29","first-page":"332","article-title":"New data on toxic metal intoxication (Cd, Pb, and Hg in particular) and mg status during pregnancy","volume":"7","author":"Semczuk","year":"2001","journal-title":"Med. Sci. Monit."},{"key":"ref_30","first-page":"3375","article-title":"Carcinogenic metals induce hypoxia-inducible factor-stimulated transcription by reactive oxygen species-independent mechanism","volume":"60","author":"Salnikow","year":"2000","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Yao, Y.X., Lu, Y.H., Chen, W.C., Jiang, Y.P., Cheng, T., Ma, Y.P., Lu, L., and Dai, W. (2014). Cobalt and nickel stabilize stem cell transcription factor oct4 through modulating its sumoylation and ubiquitination. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086620"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10508","DOI":"10.3390\/ijerph120910508","article-title":"Low-dose cadmium upregulates vegf expression in lung adenocarcinoma cells","volume":"12","author":"Liu","year":"2015","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.bbamcr.2005.05.007","article-title":"Accumulation and nuclear import of HIF1 alpha during high and low oxygen concentration in skeletal muscle cells in primary culture","volume":"1745","author":"Kubis","year":"2005","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0014-5793(99)01359-9","article-title":"Hypoxia-induced activation of HIF-1: Role of HIF-1alpha-hsp90 interaction","volume":"460","author":"Minet","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"29936","DOI":"10.1074\/jbc.M204733200","article-title":"Hsp90 regulates a von hippel lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway","volume":"277","author":"Isaacs","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1158\/0008-5472.CAN-09-0448","article-title":"JNK1 mediates degradation HIF-1alpha by a VHL-independent mechanism that involves the chaperones Hsp90\/Hsp70","volume":"70","author":"Zhang","year":"2010","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0378-4274(02)00205-9","article-title":"Expression of Hsp90 in the human kidney and in proximal tubule cells exposed to heat, sodium arsenite and cadmium chloride","volume":"133","author":"Somji","year":"2002","journal-title":"Toxicol. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1379\/1466-1268(1998)003<0188:CEOHSP>2.3.CO;2","article-title":"Constitutive expression of heat shock proteins Hsp90, Hsc70, Hsp70 and Hsp60 in neural and non-neural tissues of the rat during postnatal development","volume":"3","author":"Brown","year":"1998","journal-title":"Cell Stress Chaperones"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1002\/bdrb.10044","article-title":"Mercury, cadmium, and arsenite enhance heat shock protein synthesis in chick embryos prior to embryotoxicity","volume":"68","author":"Papaconstantinou","year":"2003","journal-title":"Birth Defects Res. B Dev. Reprod. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/0300-483X(93)90081-3","article-title":"Stress protein synthesis induced by cadmium-cysteine in rat kidney","volume":"85","author":"Goering","year":"1993","journal-title":"Toxicology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s12011-015-0348-x","article-title":"The co-induced effects of molybdenum and cadmium on antioxidants and heat shock proteins in duck kidneys","volume":"168","author":"Xia","year":"2015","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S1532-0456(01)00216-2","article-title":"Identification of two Hsp90 genes in carp","volume":"129","author":"Hermesz","year":"2001","journal-title":"Comp. Biochem. Physiol. C Toxicol. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/jbt.10015","article-title":"A comparison of 60, 70, and 90 kDa stress protein expression in normal rat NRK-52 and human HK-2 kidney cell lines following in vitro exposure to arsenite and cadmium alone or in combination","volume":"16","author":"Madden","year":"2002","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1023\/A:1007600511094","article-title":"Glucocorticoid receptor-Hsp90 interaction in the liver cytosol of cadmium-intoxicated rats","volume":"16","author":"Dundjerski","year":"2000","journal-title":"Cell Biol. Toxicol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1124\/mol.108.051516","article-title":"Copper regulation of hypoxia-inducible factor-1 activity","volume":"75","author":"Feng","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.toxlet.2004.12.009","article-title":"Effects of cadmium exposure during pregnancy on trace elements in fetal rat liver and kidney","volume":"156","author":"Kuriwaki","year":"2005","journal-title":"Toxicol. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1289\/ehp.792897","article-title":"Some effects of oral ingestion of cadmium on zinc, copper, and iron metabolism","volume":"28","author":"Petering","year":"1979","journal-title":"Environ. Health Perspect."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1007\/BF00295164","article-title":"Effect of oral cadmium administration to female rats during pregnancy on zinc, copper, and iron content in placenta, foetal liver, kidney, intestine, and brain","volume":"56","author":"Sowa","year":"1985","journal-title":"Arch. Toxicol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/S0013-9351(87)80006-3","article-title":"Effect of cadmium on prenatal development and on tissue cadmium, copper, and zinc concentrations in rats","volume":"42","author":"Baranski","year":"1987","journal-title":"Environ. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.taap.2015.09.004","article-title":"Exposure of chick embryos to cadmium changes the extra-embryonic vascular branching pattern and alters expression of VEGF-A and VEGF-R2","volume":"289","author":"Gheorghescu","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7997","DOI":"10.1093\/nar\/gkt539","article-title":"VEGF-A mrna processing, stability and translation: A paradigm for intricate regulation of gene expression at the post-transcriptional level","volume":"41","author":"Arcondeguy","year":"2013","journal-title":"Nucleic Acids Res."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/6\/3\/53\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:18:30Z","timestamp":1760195910000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/6\/3\/53"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,3]]},"references-count":51,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,9]]}},"alternative-id":["toxics6030053"],"URL":"https:\/\/doi.org\/10.3390\/toxics6030053","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,3]]}}}