PMID- 26865470
OWN - NLM
STAT- MEDLINE
DCOM- 20161114
LR  - 20171116
IS  - 1542-9741 (Electronic)
IS  - 1542-9733 (Linking)
VI  - 107
IP  - 1
DP  - 2016 Feb
TI  - Mechanism of Developmental Effects in Rats Caused by an N-Phenylimide Herbicide: 
      Transient Fetal Anemia and Sequelae during Mid-to-Late Gestation.
PG  - 45-59
LID - 10.1002/bdrb.21172 [doi]
AB  - 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. CONCLUSION: 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.
CI  - (c) 2016 Wiley Periodicals, Inc.
FAU - Kawamura, Satoshi
AU  - Kawamura S
AD  - Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Konohana-ku, 
      Osaka, Japan.
FAU - Yoshioka, Takafumi
AU  - Yoshioka T
AD  - Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Konohana-ku, 
      Osaka, Japan.
FAU - Mito, Nobuaki
AU  - Mito N
AD  - Intellectual Property Department, Sumitomo Chemical Co. Ltd, Chuo-ku, Tokyo, 
      Japan.
FAU - Kishimoto, Noriyuki
AU  - Kishimoto N
AD  - Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Konohana-ku, 
      Osaka, Japan.
FAU - Nakaoka, Masanao
AU  - Nakaoka M
AD  - Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Konohana-ku, 
      Osaka, Japan.
FAU - Fantel, Alan G
AU  - Fantel AG
AD  - Department of Pediatrics, University of Washington, Seattle, Washington.
LA  - eng
PT  - Journal Article
DEP - 20160210
PL  - United States
TA  - Birth Defects Res B Dev Reprod Toxicol
JT  - Birth defects research. Part B, Developmental and reproductive toxicology
JID - 101155115
RN  - 0 (Benzoxazines)
RN  - 0 (Blood Proteins)
RN  - 0 (Hemoglobins)
RN  - 0 (Herbicides)
RN  - 0 (Imides)
RN  - 0 (Phthalimides)
RN  - 42VZT0U6YR (Heme)
RN  - EC 1.3.3.4 (Protoporphyrinogen Oxidase)
RN  - L0PX7OGI22 (flumioxazin)
SB  - IM
MH  - Anemia/*embryology/*pathology
MH  - Animals
MH  - Benzoxazines/pharmacology
MH  - Blood Proteins/metabolism
MH  - Erythrocyte Count
MH  - Female
MH  - Fetal Mortality
MH  - Fetus/*abnormalities/drug effects/*embryology/pathology
MH  - Heart/drug effects/embryology
MH  - Heme/biosynthesis
MH  - Hemoglobins/metabolism
MH  - Herbicides/chemistry/*toxicity
MH  - Humans
MH  - Imides/chemistry/*toxicity
MH  - Inhibitory Concentration 50
MH  - Phthalimides/pharmacology
MH  - Pregnancy
MH  - Protoporphyrinogen Oxidase/antagonists & inhibitors/metabolism
MH  - Rabbits
MH  - Rats, Sprague-Dawley
MH  - Ribs/abnormalities/embryology
MH  - Species Specificity
OTO - NOTNLM
OT  - N-phenylimide herbicide
OT  - compound-specific difference
OT  - developmental toxicity
OT  - fetal anemia
OT  - humans
OT  - interventricular foramen
OT  - peak period
OT  - rabbits
OT  - rats
OT  - species difference
OT  - teratogenicity
OT  - ventricular septum defects
OT  - wavy ribs
EDAT- 2016/02/13 06:00
MHDA- 2016/11/15 06:00
CRDT- 2016/02/12 06:00
PHST- 2015/12/10 00:00 [received]
PHST- 2016/01/20 00:00 [accepted]
PHST- 2016/02/12 06:00 [entrez]
PHST- 2016/02/13 06:00 [pubmed]
PHST- 2016/11/15 06:00 [medline]
AID - 10.1002/bdrb.21172 [doi]
PST - ppublish
SO  - Birth Defects Res B Dev Reprod Toxicol. 2016 Feb;107(1):45-59. doi: 
      10.1002/bdrb.21172. Epub 2016 Feb 10.