{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:10:19Z","timestamp":1782778219379,"version":"3.54.5"},"reference-count":42,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DE032710, R01ES033345"],"award-info":[{"award-number":["R01DE032710, R01ES033345"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Teratogens and other environmental factors influence human birth defect risk, but our understanding of how they reach the developing conceptus is surprisingly limited. The placenta is often invoked as a key mediator of teratogenicity by acting as a physical barrier that can block or regulate the transfer of harmful substances to the embryo or fetus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this review, we compare the timing of teratogen susceptibility with the development of the placenta. Teratogenicity data from multiple published studies were plotted on a unified multi\u2010species developmental timeline to relate findings from animal models to human developmental timing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The critical periods for most teratogen\u2010induced structural birth defects, including fetal alcohol syndrome\u2010related defects, neural tube defects, orofacial clefts, and limb malformations translate to the 3rd to 6th week of human embryonic development, while the human hemochorial placenta matures later, between 8 and 12\u2009weeks of pregnancy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This developmental chronology challenges the seemingly pervasive notion that placental transfer capacity plays a major role in mediating teratogenicity and highlights the need to further investigate the barrier capacity of the structures that surround and protect the developing embryo (e.g., trophoblast, yolk sac) prior to formation of the definitive placenta, and when the embryo is most sensitive to teratogenic insult.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bdr2.2532","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T04:39:27Z","timestamp":1759207167000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Barrier to Understanding Teratogenicity: The Critical Periods of Sensitivity for Most Structural Birth Defects Precede the Established Hemochorial Placenta"],"prefix":"10.1002","volume":"117","author":[{"given":"Matthew A.","family":"Nangle","sequence":"first","affiliation":[{"name":"Department of Comparative Biosciences, School of Veterinary Medicine University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khush","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Medicine Lake Erie College of Osteopathic Medicine at Seton Hill  Greensburg Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathish","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, School of Veterinary Medicine University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1994-4090","authenticated-orcid":false,"given":"Robert J.","family":"Lipinski","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, School of Veterinary Medicine University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmaa063"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2020.00359"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0143-4004(05)80280-2"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)12859-0"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1001190311"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420380308"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1993.1041"},{"key":"e_1_2_11_9_1","first-page":"22","article-title":"Critical Periods for Prenatal Alcohol Exposure: Evidence From Animal and Human Studies","volume":"18","author":"Coles C.","year":"1994","journal-title":"Alcohol Health and Research World"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.84.3.536"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(87)90199-2"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j2249"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.42.083001.110955"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32372"},{"key":"e_1_2_11_15_1","first-page":"63","article-title":"The Effect of Teratogenic Antiserum on Yolk\u2010Sac Function in Rat Embryos Cultured In\u00a0Vitro","volume":"71","author":"Freeman S. 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