Close Link between Protoporphyrin IX Accumulation and Developmental Toxicity Induced by <i>N</i>‐Phenylimide Herbicides in Rats

Kawamura, Satoshi; Kato, Takeshi; Fantel, Alan G.

doi:10.1002/bdrb.21133

Cited by 9 publications

(8 citation statements)

References 24 publications

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“…Since other plant PPO inhibitors, diphenyl ether‐type herbicides, inhibit mouse liver mitochondrial PPO (Matringe et al., , ), we assumed that the N ‐phenylimide herbicides act by suppressing PPO in embryonic heme biosynthesis. Previous studies (Kawamura et al., , ) demonstrated a close link between the developmental toxicity of the herbicides and PPIX accumulation, presumably resulting from embryonic PPO inhibition. The major characteristics of developmental toxicity, species‐ and compound‐specific differences and the peak period of sensitivity, corresponded closely to that of PPIX accumulation in embryos.…”

Section: Discussionmentioning

confidence: 90%

“…Since other plant PPO inhibitors, diphenyl ether-type herbicides, inhibit mouse liver mitochondrial PPO (Matringe et al, 1989a(Matringe et al, , 1989b, we assumed that the N-phenylimide herbicides act by suppressing PPO in embryonic heme biosynthesis. Previous studies (Kawamura et al, 1996a(Kawamura et al, , 2014b) demonstrated a close link between the developmental toxicity of the herbicides and PPIX accumulation, presumably resulting Fig. 10.…”

Section: Ppo Inhibition Is the Primary Factor For Developmental Toxicmentioning

confidence: 89%

“…Remarkable PPIX accumulation was observed in rat embryos, sensitive to S‐53482 developmental toxicity, but not in insensitive rabbit embryos, following treatment with S‐53482 at 1000 mg/kg on GD 12 (Kawamura et al., ). The developmentally toxic compounds, S‐53482 and S‐23121, caused PPIX accumulation in rat embryos, while the nontoxic compound, S‐23031, did not at 1000 mg/kg on GD 12 (Kawamura et al., ). The peak period of PPIX accumulation corresponded to that of developmental effects when single oral treatments of S‐53482 were given to rats at 400 mg/kg on GDs 10 through 15 (Kawamura et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…The developmentally toxic compounds, S‐53482 and S‐23121, caused PPIX accumulation in rat embryos, while the nontoxic compound, S‐23031, did not at 1000 mg/kg on GD 12 (Kawamura et al., ). The peak period of PPIX accumulation corresponded to that of developmental effects when single oral treatments of S‐53482 were given to rats at 400 mg/kg on GDs 10 through 15 (Kawamura et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…These herbicides differently inhibit PPOs from different sources such as plants, yeasts, and mice. Therefore, we investigated a possible link between developmental toxicity and PPIX accumulation presumably resulting from PPO inhibition (Kawamura et al., , ). We determined whether there are species‐ and compound‐specific differences in PPIX accumulation in rat and rabbit embryos and how these differences correlate with developmental toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of Developmental Effects in Rats Caused by an N‐Phenylimide Herbicide: Transient Fetal Anemia and Sequelae during Mid‐to‐Late Gestation

Kawamura

Yoshioka

Mito

et al. 2016

Birth Defects Research Pt B

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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. Birth Defects Res (Part B) 107:45-59, 2016. C 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 90%

Section: Ppo Inhibition Is the Primary Factor For Developmental Toxicmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mechanism of Developmental Effects in Rats Caused by an N‐Phenylimide Herbicide: Transient Fetal Anemia and Sequelae during Mid‐to‐Late Gestation

Kawamura

Yoshioka

Mito

et al. 2016

Birth Defects Research Pt B

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ProtoporphyrinogenIXOxidase Inhibitors

Žagar

Liebl

Theodoridis

et al. 2019

Modern Crop Protection Compounds

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Species-specific developmental toxicity in rats and rabbits: Generation of a reference compound list for development of alternative testing approaches

Teixidó

Krupp

Amberg

et al. 2018

Reproductive Toxicology

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For regulatory information requirements, developmental toxicity testing is often conducted in two mammalian species. In order to provide a set of reference compounds that could be used to explore alternative approaches to supersede testing in a second species, a retrospective data analysis was conducted. The aim was to identify compounds for which species sensitivity differences between rats and rabbits are not caused by maternal toxicity or toxicokinetic differences. A total of 330 compounds were analysed and classified according to their species-specific differences. A lack of concordance between rat and rabbit was observed in 24% of the compounds, of which 10% were found to be selective developmental toxicants in one of the species. In contrast to previously published analyses the presented comparison is based entirely on publically data allowing validating and comparing alternative approaches for developmental toxicity testing. Furthermore, this list could be useful to identify mechanisms leading to species differences.

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Close Link between Protoporphyrin IX Accumulation and Developmental Toxicity Induced by N‐Phenylimide Herbicides in Rats

Abstract: The developmentally toxic compounds caused PPIX accumulation in embryos. The peak period of PPIX accumulation corresponded to that of developmental effects. This correlation suggests a close link between PPO inhibition and developmental abnormality.

Cited by 9 publications

References 24 publications

Mechanism of Developmental Effects in Rats Caused by an N‐Phenylimide Herbicide: Transient Fetal Anemia and Sequelae during Mid‐to‐Late Gestation

Mechanism of Developmental Effects in Rats Caused by an N‐Phenylimide Herbicide: Transient Fetal Anemia and Sequelae during Mid‐to‐Late Gestation

ProtoporphyrinogenIXOxidase Inhibitors

Species-specific developmental toxicity in rats and rabbits: Generation of a reference compound list for development of alternative testing approaches

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