{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:13:06Z","timestamp":1762866786786},"reference-count":86,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2016,2,10]],"date-time":"2016-02-10T00:00:00Z","timestamp":1455062400000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research Pt B"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Rat developmental toxicity including embryolethality and teratogenicity (mainly ventricular septal defects [VSDs] and wavy ribs) was produced by an <jats:italic>N<\/jats:italic>\u2010phenylimide herbicide that inhibits protoporphyrinogen oxidase (PPO) common to chlorophyll and heme biosynthesis. Major characteristics of the developmental toxicity included species difference between rats and rabbits, compound\u2010specific difference among structurally similar herbicides, and sensitive period. Protoporphyrin accumulation in treated fetuses closely correlated with the major characteristics. Iron deposits in erythroblastic mitochondria and degeneration of erythroblasts were observed in treated rat fetuses. In this study we investigated fetal anemia and subsequent developmental effects in rats, and inhibition of PPO in rats, rabbits, and humans by the herbicides in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fetuses were treated on gestational day (GD) 12 and removed on GDs 13 through 20. All litters were examined externally. One half of litters were examined for blood and skeletal development, and the other half for interventricular foramen closure. Effects on PPO were determined in mitochondria from embryos and adult livers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fetal anemia in rats was evident on GDs 13 through 16. Subsequently, enlarged heart, delayed closure of the foramen, reduced serum protein, and retarded rib ossification were observed. In vitro PPO inhibition exhibited species\u2010 and compound\u2010specific differences corresponding to the developmental toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We propose that developmental toxicity results from PPO inhibition in primitive erythroblasts, causing transient fetal anemia followed by death. Compensatory enlargement of the fetal heart results in failure of interventricular foramen closure and VSD. Reduced serum protein leads to delayed ossification and wavy ribs<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdrb.21172","type":"journal-article","created":{"date-parts":[[2016,2,11]],"date-time":"2016-02-11T21:01:22Z","timestamp":1455224482000},"page":"45-59","source":"Crossref","is-referenced-by-count":6,"title":["Mechanism of Developmental Effects in Rats Caused by an <i>N<\/i>\u2010Phenylimide Herbicide: Transient Fetal Anemia and Sequelae during Mid\u2010to\u2010Late Gestation"],"prefix":"10.1002","volume":"107","author":[{"given":"Satoshi","family":"Kawamura","sequence":"first","affiliation":[{"name":"Environmental Health Science Laboratory Sumitomo Chemical Co. Ltd  Konohana\u2010ku Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takafumi","family":"Yoshioka","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory Sumitomo Chemical Co. 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