Division of Biology and Medicine, Brown University, Providence, Rhode Island.
Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility Fellowship Program, Women and Infants Hospital of Rhode Island, Providence, Rhode Island; Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Department of Obstetrics and Gynecology, Wright State University, Dayton, Ohio.
F S Sci. 2024 May;5(2):141-153. doi: 10.1016/j.xfss.2023.10.003. Epub 2023 Oct 29.
To investigate the long-term effects of in utero taxane exposure on exposed daughters' ovarian reserve and reproductive potential.
Pregnant dams were treated with a single, human-relevant animal-equivalent dose of saline, docetaxel, or paclitaxel at embryonic day 16.5. In utero-exposed daughters were aged to multiple postnatal time points for ovarian and endocrine analysis or were bred to assess fertility and fecundity. Granddaughters of treated dams were assessed also for ovarian follicle composition and atresia.
Laboratory study.
C57BL/6 mice.
INTERVENTION(S): In utero exposure to saline, docetaxel, or paclitaxel.
MAIN OUTCOME MEASURE(S): Ovarian follicle composition, rates of follicle atresia, and rates of multioocyte follicles were analyzed in all exposure groups. Serum hormone levels and oocyte retrieval outcomes following ovarian hyperstimulation were also assessed. Finally, animals from all exposure groups were bred with the number of litters, pups per litter, live births, interlitter time interval, and age at the last litter analyzed.
RESULT(S): We found that docetaxel and paclitaxel exposure in utero results in ovarian toxicity later in life, significantly affecting folliculogenesis as well as increasing the rate of follicular abnormalities, including follicle atresia and multioocyte follicles. Furthermore, viability staining indicates that the ovaries of daughters exposed to taxanes in utero demonstrate a significantly higher number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive follicles. Hormone measurements also revealed that serum follicle-stimulating hormone concentration was significantly altered in taxane-exposed daughters, with the ratio of luteinizing hormone to follicle-stimulating hormone significantly elevated, specifically after paclitaxel exposure, coincident with the inability of these animals to properly respond to ovarian stimulation. Breeding studies over the course of a year also suggest that these taxane-exposed mice are fertile, although the duration of their fertility is shortened and they produce significantly fewer litters. Finally, ovarian effects are apparent in granddaughters of mice treated with docetaxel, suggesting persistent and multigenerational effects of taxane exposure.
CONCLUSION(S): Our studies demonstrate that in utero exposure to taxane-based therapy during late gestation has a significant effect on the long-term reproductive health of exposed daughters (as well as their daughters) and will be instrumental in helping clinicians better understand which chemotherapies for maternal malignancy are least detrimental to a developing fetus.
研究宫内紫杉醇暴露对暴露女儿卵巢储备和生殖潜能的长期影响。
在胚胎第 16.5 天，用单次人类相关动物等效剂量的生理盐水、多西紫杉醇或紫杉醇处理妊娠母体。对宫内暴露的女儿进行多个产后时间点的卵巢和内分泌分析，或进行繁殖以评估生育力和繁殖力。还评估了经处理的母体的孙女的卵巢卵泡组成和闭锁。
实验室研究。
C57BL/6 小鼠。
宫内暴露于生理盐水、多西紫杉醇或紫杉醇。
分析所有暴露组的卵巢卵泡组成、卵泡闭锁率和多卵卵泡率。还评估了卵巢过度刺激后血清激素水平和卵母细胞回收结果。最后，对所有暴露组的动物进行繁殖，分析产仔数、每窝产仔数、活产数、产仔间隔和最后一窝的年龄。
我们发现，宫内多西紫杉醇和紫杉醇暴露会导致女儿在以后的生活中发生卵巢毒性，显著影响卵泡发生，增加卵泡异常的发生率，包括卵泡闭锁和多卵卵泡。此外，末端脱氧核苷酸转移酶 dUTP 缺口末端标记阳性卵泡的数量表明，暴露于紫杉醇的女儿的卵巢明显增加。激素测量还表明，暴露于紫杉醇的女儿的血清卵泡刺激素浓度明显改变，黄体生成素与卵泡刺激素的比值显著升高，特别是在紫杉醇暴露后，这些动物无法对卵巢刺激做出适当反应。一年的繁殖研究也表明，这些暴露于紫杉醇的小鼠具有生育能力，尽管它们的生育能力持续时间缩短，产仔数明显减少。最后，在接受多西紫杉醇治疗的小鼠的孙女中也出现了卵巢效应，表明紫杉醇暴露具有持续和多代效应。
我们的研究表明，妊娠晚期宫内接受基于紫杉烷的治疗会对暴露女儿（及其女儿）的长期生殖健康产生重大影响，并将有助于临床医生更好地了解哪些治疗母亲恶性肿瘤的化疗对发育中的胎儿的危害最小。
