Rat developmental toxicity including embryolethality and teratogenicity (mainly
ventricular septal defects and wavy ribs) were produced by
S-53482, an N-phenylimide
herbicide that inhibits
protoporphyrinogen oxidase (PPO) common to
chlorophyll and
heme biosynthesis. The sequence of key biological events in the mode of action has been elucidated as follows: inhibition of PPO interferes with normal
heme synthesis, which causes loss of blood cells leading to fetal
anemia, embryolethality and the development of malformations. In this study we investigated whether the rat is a relevant model for the assessment of the human hazard of the
herbicide. To study effects on
heme biosynthesis, human
erythroleukemia, human cord blood, and rat
erythroleukemia cells were treated with the
herbicide during red cell differentiation.
Protoporphyrin IX, a marker of PPO inhibition, and
heme were determined. We investigated whether synchronous maturation of primitive erythropoiesis, which can contribute to massive losses of embryonic blood, occurs in rats. The population of primitive erythroblasts was observed on gestational days 11 through 14.
Heme production was suppressed in rat erythroid cells. In contrast,
heme reduction was not seen in both human erythroid cells when PPO was inhibited. Rats underwent synchronous maturation in primitive erythropoiesis. Our results combined with epidemiological findings that patients with deficient PPO are not anemic led us to conclude that human erythroblasts are resistant to the
herbicide. It is suggested that the rat would be an inappropriate model for assessing the developmental toxicity of
S-53482 in humans as rats are specifically sensitive to PPO inhibition by the
herbicide.