{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:20:09Z","timestamp":1790785209730,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2005,6,6]],"date-time":"2005-06-06T00:00:00Z","timestamp":1118016000000},"content-version":"vor","delay-in-days":4084,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratology"],"published-print":{"date-parts":[[1994,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hydroxyurea (HU) is a potent mammalian teratogen. Within 2\u20134 hours after maternal injection, HU causes 1) a rapid episode of embryonic cell death and 2) profound inhibition of embryonic DNA synthesis. A variety of antioxidants delays the onset of embryonic cell death and reduces the incidence of birth defects. Antioxidants do not block the inhibition of DNA synthesis, indicating that early embryonic cell death is not caused by inhibited DNA synthesis. We have suggested that some HU molecules may react within the embryo to produce H2O2 and subsequent free radicals, including the very reactive hydroxyl free radical. The free radicals could cause the early cell death; antioxidants are believed to terminate the aberrant free radical reactions resulting in lessened developmental toxicity. To investigate whether hydroxyl free radicals cause the early episode of cell death, pregnant New Zealand white rabbits were injected subcutaneously on gestational day 12 with a teratogenic dose of HU (650 mg\/kg) in the presence or absence of 550 mg\/kg of D\u2013mannitol (Man), a specific scavenger of hydroxyl free radicals. Osmotic control rabbits received HU plus 550 mg\/kg of xylose (Xyl, a nonactive aldose). At term, the teratologic effects of HU were ameliorated by Man as evidenced by decreased incidences of the expected limb malformations. Xyl exerted no demonstrable effect on HU teratogenesis. Histological examination of limb buds at 3\u20138 hours after maternal injection, showed that Man delayed the onset of HU\u2013induced cell death by as much as 4 hours. Xyl had no effect. That Man acts within the embryo was shown by performing intracoelomic injections on alternate implantation sites with Man, Xyl, or saline followed by subcutaneous injection of the pregnant doe with HU. Embryos were harvested 3\u20138 hours later. Limb buds from saline\u2013 and Xyl\u2013injected embryos exhibited the typical pattern of widespread HU\u2013induced cell death at 3\u20134 hours, whereas Man\u2013injected embryos did not exhibit cell death until 5\u20138 hours. These results are consistent with those reported for antioxidant\u2013mediated amelioration of HU\u2013induced developmental toxicity and with the hypothesis that hydroxyl free radicals are the proximate reactive species in HU\u2013induced early embryonic cell death. \u00a9 1994 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/tera.1420490404","type":"journal-article","created":{"date-parts":[[2005,6,11]],"date-time":"2005-06-11T12:01:53Z","timestamp":1118491313000},"page":"248-259","source":"Crossref","is-referenced-by-count":75,"title":["D\u2010mannitol, a specific hydroxyl free radical scavenger, reduces the developmental toxicity of hydroxyurea in rabbits"],"prefix":"10.1002","volume":"49","author":[{"given":"John M.","family":"Desesso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony R.","family":"Scialli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald C.","family":"Goeringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,6,6]]},"reference":[{"key":"e_1_2_1_2_1","first-page":"125","volume-title":"Superoxide Dismutase","author":"Allen A. 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