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.

大鼠发育毒性包括胚胎致死性和致畸性（主要是室间隔缺损和波状肋骨）由 S-53482 产生，一种N-苯基酰亚胺除草剂，可抑制叶绿素和血红素生物合成中常见的原卟啉原氧化酶 (PPO)。作用方式中关键生物学事件的顺序已阐明如下：抑制 PPO 会干扰正常的血红素合成，这会导致血细胞损失，从而导致胎儿贫血、胚胎死亡和畸形的发展。在这项研究中，我们调查了大鼠是否是评估除草剂对人类危害的相关模型。为了研究对血红素生物合成的影响，在红细胞分化过程中用除草剂处理人红白血病、人脐带血和大鼠红白血病细胞。测定了原卟啉 IX、PPO 抑制的标志物和血红素。我们研究了原始红细胞生成的同步成熟，这会导致胚胎血液大量流失，发生在大鼠身上。在妊娠第 11 天到第 14 天观察到原始成红细胞的数量。大鼠红细胞中的血红素产生受到抑制。相反，当 PPO 被抑制时，在两种人类红细胞中均未观察到血红素减少。大鼠在原始红细胞生成中经历了同步成熟。我们的结果与流行病学发现相结合，即缺乏 PPO 的患者并不贫血，这使我们得出结论，人类成红细胞对除草剂具有抗性。这表明大鼠将是评估 S-53482 对人类发育毒性的不合适模型，因为大鼠对除草剂的 PPO 抑制特别敏感。在妊娠第 11 天到第 14 天观察到原始成红细胞的数量。大鼠红细胞中的血红素产生受到抑制。相比之下，当 PPO 被抑制时，在两种人类红细胞中均未观察到血红素减少。大鼠在原始红细胞生成中经历了同步成熟。我们的结果与流行病学发现相结合，即缺乏 PPO 的患者并不贫血，这使我们得出结论，人类成红细胞对除草剂具有抗性。这表明大鼠将是评估 S-53482 对人类发育毒性的不合适模型，因为大鼠对除草剂的 PPO 抑制特别敏感。在妊娠第 11 天到第 14 天观察到原始成红细胞的数量。大鼠红细胞中的血红素产生受到抑制。相反，当 PPO 被抑制时，在两种人类红细胞中均未观察到血红素减少。大鼠在原始红细胞生成中经历了同步成熟。我们的结果与流行病学发现相结合，即缺乏 PPO 的患者并不贫血，这使我们得出结论，人类成红细胞对除草剂具有抗性。这表明大鼠将是评估 S-53482 对人类发育毒性的不合适模型，因为大鼠对除草剂的 PPO 抑制特别敏感。大鼠在原始红细胞生成中经历了同步成熟。我们的结果与流行病学发现相结合，即缺乏 PPO 的患者并不贫血，这使我们得出结论，人类成红细胞对除草剂具有抗性。这表明大鼠将是评估 S-53482 对人类发育毒性的不合适模型，因为大鼠对除草剂的 PPO 抑制特别敏感。大鼠在原始红细胞生成中经历了同步成熟。我们的结果与流行病学发现相结合，即缺乏 PPO 的患者并不贫血，这使我们得出结论，人类成红细胞对除草剂具有抗性。这表明大鼠将是评估 S-53482 对人类发育毒性的不合适模型，因为大鼠对除草剂的 PPO 抑制特别敏感。