Podophyllotoxin Exposure Affects Organelle Distribution and Functions in Mouse Oocyte Meiosis

Abstract

Podophyllotoxin (POD) is one of the most characterized lignans that is commonly found in podophyllum, and its preparations and derivatives are widely used in clinical treatment due to strong antitumor and antivirus activities. POD has been reported for its neurotoxicity, liver toxicity, and potential reproductive toxicity. In the present study, we investigated the effects of POD on the organelles of mouse oocytes during meiosis. Our results showed that exposure to POD significantly reduced the developmental competence of mouse oocytes. Further analysis revealed that the endoplasmic reticulum (ER) failed to accumulate to the spindle periphery, suggesting that POD exposure might affect protein synthesis during oocyte meiotic maturation. Similarly, abnormal Golgi apparatus distribution was found after POD exposure, which could be confirmed by the aberrant localization of Rab11a-related vesicles, indicating that POD induced vesicle-based protein transport disorder. We also found the aberrant accumulation of lysosomes in the cytoplasm of POD-exposed oocytes, which implied that POD might lead to aberrant protein degradation. Moreover, the perinuclear distribution of mitochondria was also significantly disturbed, indicating the mitochondrial dysfunction after POD exposure. In all, our study illustrated that exposure to POD might disrupt protein synthesis, transport, degradation, and ATP production by its effects on the distribution and functions of organelles during mouse oocyte meiotic maturation.

Cellular Distribution and Ultrastructural Changes in HaCaT Cells, Induced by Podophyllotoxin and Its Novel Fluorescent Derivative, Supported by the Molecular Docking Studies

“…In contrast, following PPT incubation, the ER underwent significant changes, manifested as dilation of the ER cisternae, which was observed at 24 h and progressed further at 48 h. Vacuole formation likely represented extreme dilation of ER cisternae. Those morphological changes were consistent with ER stress, pointing towards the possible involvement of this mechanism in the initiation of programmed cell death in those cells, similar to previous reports [ 15 , 37 , 38 ]. ER stress is characterized by the accumulation of unfolded and/or misfolded proteins within the ER lumen, a process that can be triggered by the expression of abnormal proteins, proteasome inhibition, nutrient deficiency, hypoxia, calcium depletion, and other conditions.…”

Acrylamide Exposure Destroys the Distribution and Functions of Organelles in Mouse Oocytes

“…For example, exposure to zearalenone leads to the abnormal distribution of the Golgi apparatus in porcine oocytes, which causes the decrease in the maturation rate of porcine oocytes and affects the quality of porcine oocytes ( Wang et al, 2021 ). Podophyllotoxin can cause the Golgi apparatus fragment of mouse oocytes and vesicle transport defects, thus causing the meiosis failure of mouse oocytes ( Lu et al, 2021 ). Lysosomes are round organelles formed by a monolayer covering various acid hydrolases ( Lie and Nixon, 2018 ), which mainly participate in the metabolic activities of various substances in cells ( Albanese et al, 2019 ).…”

Chemistry and Biology of Podophyllotoxins: An Update

“…As described in Figure 2, cleisindosides A (3), cleisindosides B (4), cleisindosides C (5), cleisindosides D (6), cleisindosides E (7), cleisindosides F (8), picroburseranin (9) and 7-hydroxypicropolygamain (10) were isolated from the fruits of Cleistanthus indochinensis. Among them, compounds 5, 9 and 10 were highly cytotoxic to oral epidermoid carcinoma KB cells with IC 50 values of 7.5, 0.062, and 10.8 μM, respectively.…”

“…[9] In addition, PPT was toxic to mouse oocyte organelles by affecting its meiosis. [10] Previously, we reported total synthesis, biotransformation, structural modifications, and bioactivities of PPT and its derivatives until 2015. Additionally, the isolation of new PPT analogues from plants was summarized by September 2014.…”

“…However, PPT was a reproductive toxicant by affecting the early embryonic development through DNA damage [9] . In addition, PPT was toxic to mouse oocyte organelles by affecting its meiosis [10] . Previously, we reported total synthesis, biotransformation, structural modifications, and bioactivities of PPT and its derivatives until 2015.…”