Exposure to podophyllotoxin inhibits oocyte meiosis by disturbing meiotic spindle formation

Abstract

Podophyllotoxin is used as medical cream which is widely applied to genital warts and molluscum contagiosum. Although previous study showed that podophyllotoxin had minimal toxicity, it was forbidden to use during pregnancy since it might be toxic to the embryos. In present study we used mouse as the model and tried to examine whether podophyllotoxin exposure was toxic to oocyte maturation, which further affected embryo development. Our results showed that podophyllotoxin exposure inhibited mouse oocyte maturation, showing with the failure of polar body extrusion, and the inhibitory effects of podophyllotoxin on oocytes was dose-depended. Further studies showed that the meiotic spindle formation was disturbed, the chromosomes were misaligned and the fluorescence signal of microtubule was decreased, indicating that podophyllotoxin may affect microtubule dynamics for spindle organization. Moreover, the oocytes which reached metaphase II under podophyllotoxin exposure also showed aberrant spindle morphology and chromosome misalignment, and the embryos generated from these oocytes showed low developmental competence. We also found that the localization of p44/42 MAPK and gamma-tubulin was disrupted, which further confirmed the effects of podophyllotoxin on meiotic spindle formation. In all, our results indicated that podophyllotoxin exposure could affect mouse oocyte maturation by disturbing microtubule dynamics and meiotic spindle formation.

Podophyllotoxin Exposure Affects Organelle Distribution and Functions in Mouse Oocyte Meiosis

“…Successful extrusion of PB1 is the last step of oocyte nuclear maturation ( Reyes and Ross, 2016 ). Our results suggest that POD exposure significantly causes declined oocyte quality in mice, showing with a reduction of the PB1 extrusion rate, which is similar to a previous report ( Hu et al, 2018 ). During oocyte maturation, the demand for new proteins that are accomplished by proper protein synthesis, folding, modification, and trafficking is increasing ( Guzel et al, 2017 ).…”

“…We speculate that there are two possible causes for the aberrant distribution of organelles in oocytes: one is that POD could prevent the assembly of tubulin into microtubules, which serve as a scaffold for organelle transport and positioning ( Ardalani et al, 2017 ; Meiring et al, 2020 ); another is that the disrupted spindle structure by microtubule disassembly may affect organelle location and function since they accumulate at the spindle periphery at the MI stage, and POD exposure can disrupt the spindle formation ( Coticchio et al, 2015 ; Hu et al, 2018 ). However, the deeper explanation for the alteration of the distribution after POD exposure still needs further mechanism study.…”

“…Similarly, POD has harmful effects on rat sperm maturation or fertility due to epididymal epithelial cell apoptosis induced by activating TNF-α and the caspase signaling pathway ( Xie et al, 2017 ). In females, in vitro tests confirm that exposure to POD can inhibit microtubule dynamics and meiotic spindle formation, which leads to low oocyte maturing rates and early embryonic developmental competence ( Hu et al, 2018 ). Moreover, porcine oocytes exposed to POD are also subjected to oxidative stress, apoptosis, abnormal spindle formation, and chromosome abnormality ( Jiang et al, 2020 ).…”

Podophyllotoxin Isolated from Podophyllum peltatum Induces G2/M Phase Arrest and Mitochondrial-Mediated Apoptosis in Esophageal Squamous Cell Carcinoma Cells

“…According to a 2018 study, weight loss and other side effects were not observed when Free PT was treated in mice xenografts to assess antitumor activity [21]. In previous reports, PT, a natural phytochemical compound, has been showed to inhibit cancers, including cervical carcinoma, breast, and prostate cancers [22,23]. Although the anti-neoplastic efficacy of PT against numerous cancers has been reported [2], its efficacy and precise pharmacological mechanisms in ESCC were not reported until now.…”

Editorial: Meiosis: From Molecular Basis to Medicine

“…Podophyllotoxin (POD) is a well characterized lignan, derivatives of which are widely used in clinical treatment due to their strong antitumor and antivirus activities ( Ardalani et al, 2017 ; Zálešák et al, 2019 ). Exposure to POD can inhibit microtubule dynamics and lead to abnormal meiotic spindle formation, which influences oocyte development and maturation ( Hu et al, 2018 ; Jiang et al, 2020 ). A research article in this Research Topic by Lu et al illustrated that exposure to POD might disrupt protein synthesis, transport, degradation, and ATP production through its effects on the distribution and functions of organelles during mouse oocyte meiotic maturation.…”