Reproductive toxicity of JJH201501 in rats: Perinatal study

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY Birth Defects Research Pub Date : 2024-01-19 DOI:10.1002/bdr2.2303

Menghan Sun, Peng Yue, Hongqun Qiao

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Abstract

Introduction

In this study, JJH201501 was examined for reproductive toxicity during the perinatal period to support its safety as a novel serotonergic agent (5-HT) antidepressant. Pregnant Sprague–Dawley rats (F0, n = 24/group) were continuously exposed to 0 (control), 6, 18, and 60 mg/kg body weight/day of JJH201501 by intragastric administration from gestation day 15 to lactation day 21.

Methods

During this period, maternal toxicity was evaluated based on clinical signs, body weight, feed intake, delivery condition, litter parameters, and necropsy, with body weight, sex ratios, malformation incidence, physical, and neurodevelopmental assessments conducted on all offspring rats. Ten pups (male:female 1:1) from each dam within each dose group on postnatal day 4 (PND4) were randomly selected. One pair was evaluated for behavior evaluations (F1a) after PND35, one for reproduction performance (F1b) after 10 weeks, and three for organ weight and deformities (F1c) on PND35. After successful mating, F1b male rats were weighed and dissected to assess reproductive organ weight and sperm motility. Pregnant F1b rats were weighed and monitored for food intake twice weekly until laparotomy on GD14, which recorded live/dead fetuses, resorptions, implantations, corpora lutea, and uterine weight. Some statistical differences were found between the JJH-treated and control groups in maternal weight, food consumption, and F1 body weight and water maze performance.

Results

Autopsy results showed that JJH201501 had a low cardiac index effect in F0, with no significant histopathological changes detected. Only one F1 offspring died in the high-dose group throughout the experiment. Due to the lack of dose-dependent effects and the consistent growth pattern of these alterations, the study findings do not suggest any toxicological significance for the observed results.

Conclusion

In conclusion, the no-observed-adverse-effect level of JJH201501 for perinatal rats is about 60 mg/kg b.w./day.

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JJH201501 对大鼠的生殖毒性：围产期研究

引言本研究检测了 JJH201501 在围产期的生殖毒性，以支持其作为新型血清素能（5-HT）抗抑郁剂的安全性。从妊娠期第 15 天到哺乳期第 21 天，通过胃内给药的方式，对怀孕的 Sprague-Dawley 大鼠（F0，n = 24/组）连续暴露于 0（对照组）、6、18 和 60 毫克/千克体重/天的 JJH201501。方法在此期间，根据临床症状、体重、进食量、分娩状况、产仔参数和尸体解剖评估母体毒性，并对所有后代大鼠进行体重、性别比例、畸形发生率、体格和神经发育评估。在每个剂量组中，随机抽取出生后第 4 天（PND4）每只母鼠的 10 只幼鼠（雌雄比例为 1:1）。一对在出生后第 35 天进行行为评估（F1a），一对在 10 周后进行繁殖性能评估（F1b），三对在出生后第 35 天进行器官重量和畸形评估（F1c）。交配成功后，对 F1b 雄性大鼠进行称重和解剖，以评估生殖器官重量和精子活力。对怀孕的 F1b 大鼠每周称重两次，并监测其进食情况，直到 GD14 进行剖腹探查，记录活胎/死胎、再殖、植入、黄体和子宫重量。JJH处理组和对照组在母体体重、食量、F1体重和水迷宫表现方面存在一些统计学差异。结果解剖结果显示，JJH201501 对 F0 的心脏指数影响较低，未发现明显的组织病理学变化。在整个实验过程中，高剂量组仅有一只 F1 后代死亡。由于缺乏剂量依赖性影响以及这些变化的一致生长模式，研究结果并不表明所观察到的结果具有任何毒理学意义。结论总之，JJH201501 对围产期大鼠的无观测不良效应水平约为 60 毫克/千克体重/天。

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来源期刊

Birth Defects Research Medicine-Embryology

CiteScore

3.60

自引率

9.50%

发文量

153

期刊介绍： The journal Birth Defects Research publishes original research and reviews in areas related to the etiology of adverse developmental and reproductive outcome. In particular the journal is devoted to the publication of original scientific research that contributes to the understanding of the biology of embryonic development and the prenatal causative factors and mechanisms leading to adverse pregnancy outcomes, namely structural and functional birth defects, pregnancy loss, postnatal functional defects in the human population, and to the identification of prenatal factors and biological mechanisms that reduce these risks. Adverse reproductive and developmental outcomes may have genetic, environmental, nutritional or epigenetic causes. Accordingly, the journal Birth Defects Research takes an integrated, multidisciplinary approach in its organization and publication strategy. The journal Birth Defects Research contains separate sections for clinical and molecular teratology, developmental and reproductive toxicology, and reviews in developmental biology to acknowledge and accommodate the integrative nature of research in this field. Each section has a dedicated editor who is a leader in his/her field and who has full editorial authority in his/her area.