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This study comprehensively evaluated the reproductive safety of Ramulus Mori (Sangzhi) alkaloids (SZ-A) in rats, analyzed the toxicokinetics of the main active ingredient 1-deoxynojirimycin (DNJ) during embryo-fetal development, and determined the no-observed-adverse-effect level. Reproductive toxicity assessment was conducted in three stages (this study was reviewed and approved by the Institutional Animal Care and Use Committee of Beijing Union-Genius Pharmaceutical Technology Development Co., Ltd., ethics numbers: SN22072-DS, SN21288-DS, SN22074-DS). In stage Ⅰ, rats were orally administered SZ-A at doses of 100, 200 and 500 mg·kg-1 (calculated as total alkaloids) to evaluate its effects on fertility and early embryonic development, including sperm count and motility in males, as well as mating and pregnancy rates in females. In stage Ⅱ, pregnant rats were given SZ-A by gavage at 100, 200 and 500 mg·kg-1 to examine its impact on maternal health, embryo-fetal development, and fetal growth, while DNJ concentrations in maternal plasma, placenta and fetus were measured. In stage Ⅲ, pregnant rats were orally administered SZ-A at doses of 250, 500 and 750 mg·kg-1. Indicators were examined to evaluate perinatal safety, including maternal reproductive function; offspring growth and development, behavior and learning/memory function, reproductive function; and F2 embryonic development. The results showed that SZ-A had no adverse effects on fertility, early embryonic development in both male and female rats, and on embryo-fetal development in pregnant rats. The plasma exposure of DNJ in pregnant rats showed a linear relationship with the administered dose. However, only limited distribution of DNJ was observed in the placenta, and the drug was undetectable in whole fetal tissues. At all tested doses, SZ-A showed no reproductive toxicity. This was evidenced by normal sex ratio, growth and development, and reproductive function in the F1 generation; embryonic development of the F2 generation was also unaffected. The no-observed-adverse-effect level (NOAEL) of SZ-A over the entire reproductive cycle in rats was determined to be 500 mg·kg-1, indicating favorable safety. This finding provides essential reproductive safety data to support the potential clinical application of SZ-A in special populations such as diabetic patients of childbearing age, gestational diabetes mellitus (GDM), and patients with polycystic ovary syndrome (PCOS).
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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