title: Mechanism of Developmental Effects in Rats Caused by an N-Phenylimide Herbicide: Transient Fetal Anemia and Sequelae during Mid-to-Late Gestation.
abstract: BACKGROUND
  Rat developmental toxicity including embryolethality and teratogenicity (mainly ventricular septal defects [VSDs] and wavy ribs) was produced by an N-phenylimide 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-specific 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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- and compound-specific differences corresponding to the developmental toxicity.
  
  
  CONCLUSIONS
  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.
authors: Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Konohana-ku, Osaka, Japan.
authors: Satoshi
authors: S
authors: Kawamura
authors: Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Konohana-ku, Osaka, Japan.
authors: Takafumi
authors: T
authors: Yoshioka
authors: Intellectual Property Department, Sumitomo Chemical Co. Ltd, Chuo-ku, Tokyo, Japan.
authors: Nobuaki
authors: N
authors: Mito
authors: Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Konohana-ku, Osaka, Japan.
authors: Noriyuki
authors: N
authors: Kishimoto
authors: Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Konohana-ku, Osaka, Japan.
authors: Masanao
authors: M
authors: Nakaoka
authors: Department of Pediatrics, University of Washington, Seattle, Washington.
authors: Alan G
authors: AG
authors: Fantel
mesh_terms: D000740:Anemia / Q000196:embryology* / Q000473:pathology*; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D004906:Erythrocyte Count; D005260:Female; D046689:Fetal Mortality; D005333:Fetus / Q000002:abnormalities* / Q000187:drug effects / Q000196:embryology* / Q000473:pathology; D006321:Heart / Q000187:drug effects / Q000196:embryology; D006418:Heme / Q000096:biosynthesis; D006454:Hemoglobins / Q000378:metabolism; D006540:Herbicides / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D007094:Imides / Q000737:chemistry / Q000633:toxicity*; D020128:Inhibitory Concentration 50; D010797:Phthalimides / Q000494:pharmacology; D011247:Pregnancy; D050768:Protoporphyrinogen Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011817:Rabbits; D017207:Rats, Sprague-Dawley; D012272:Ribs / Q000002:abnormalities / Q000196:embryology; D013045:Species Specificity
chemical_list: D048588:Benzoxazines; D001798:Blood Proteins; D006454:Hemoglobins; D006540:Herbicides; D007094:Imides; D010797:Phthalimides; D006418:Heme; D050768:Protoporphyrinogen Oxidase; C106487:flumioxazin
keywords: N-phenylimide herbicide; compound-specific difference; developmental toxicity; fetal anemia; humans; interventricular foramen; peak period; rabbits; rats; species difference; teratogenicity; ventricular septum defects; wavy ribs