Podophyllotoxin Exposure Causes Spindle Defects and DNA Damage-Induced Apoptosis in Mouse Fertilized Oocytes and Early Embryos

Abstract

Podophyllotoxin (PPT) is a kind of lignans extracted from the roots and stems of the genus Podophyllum from the tiller family, and it has been widely used in the treatment of condyloma acuminatum, multiple superficial epithelioma in the clinics. However, PPT has been reported to be toxic and can cause liver defects and other organ poisoning. In addition, emerging evidences also indicate that PPT has reproductive toxicity and causes female reproduction disorders. In this study, we used fertilized oocytes and tried to explore the effects of PPT on the early embryonic development with the mouse model. The results showed that exposure to PPT had negative effects on the cleavage of zygotes. Further analysis indicated that PPT could disrupt the organization of spindle and chromosome arrangement at the metaphase of first cleavage. We also found that PPT exposure to the zygotes induced excessive reactive oxygen species (ROS), suggesting the occurrence of oxidative stress. Moreover, in the PPT-exposed embryos, there was positive γH2A.X and Annexin-V signals, indicating that PPT induced embryonic DNA damage and early apoptosis. In conclusion, our results suggested that PPT could affect spindle formation and chromosome alignment during the first cleavage of mouse embryos, and its exposure induced DNA damage-mediated oxidative stress which eventually led to embryonic apoptosis, indicating the toxic effects of PPT on the early embryo development.

Biosynthesis, total synthesis, and pharmacological activities of aryltetralin-type lignan podophyllotoxin and its derivatives

“…Further studies suggest that PTOX may destroy the spindle organization and affect the arrangement of chromosomes in the middle of the first mitosis. 87 Joseph summarized previous studies and found that the reason for etoposide's inhibiting activity of DNA synthesis is related to the inhibition of the mitotic cycle, especially at the stage of late S and G2. 88…”

Scutellarin-induced A549 cell apoptosis depends on activation of the transforming growth factor-β1/smad2/ROS/caspase-3 pathway

“…Intracellular ROS induces DNA damage and cell apoptosis [29]. Scutellarin has different effects on the accumulation of ROS in normal cells and tumor cells.…”

Transcriptional Profiling of Porcine Blastocysts Produced In Vitro in a Chemically Defined Culture Medium

“…This situation is reflected in this study where different genes related to oxidative stress were upregulated in IVP embryos, including essential genes involved in the protection of cells against free radicals such as GSS , GPX4 , GSTA , MGST1 [ 67 ], TXN , TXNIP , NXN [ 68 ], SOD1 [ 69 ] and SESN1 [ 70 ]. One of the main consequences of this overexposure to different types of free radicals is the damage that they cause to DNA [ 71 ], which has been confirmed in both oocytes [ 72 ] and embryos [ 73 , 74 , 75 ]. In that sense, in this study, we observed how, independent of the culture type, IVP embryos overexpressed genes involved in DNA repair processes.…”