Tubacin alleviate the reproductive toxicity of deoxynivalenol in mouse oocytes and zygotes via strengthening microtubule stability

Deoxynivalenol (DON) is one of the most common food contaminants, widely present in grain products. Studies using murine and porcine models show deoxynivalenol exposure impairs oocyte maturation and mitochondrial function; however, the exact mechanisms remain unclear. In the present study, we found DON exposure markedly altered the microtubule nucleation-associated proteins expression pattern of oocytes, while supplementation of Tubacin recovered the progress of oocyte maturation, as well as the expression of KIF11 and TPX2, which are key factors for microtubule nucleation and spindle stabilization. More importantly, with the in vivo TUBB8 oocyte-specific knock-in model which introduced the human β-tubulin isotype into the most widely used mouse model, we found inhibition of HDAC6 activity reconstructed morphologically normal spindles and drastically recovered polar-body extrusion rate by culturing with the specific HDAC6 inhibitor Tubacin in DON-exposed oocytes. Mechanistically, DON represses mRNA translation and disrupts ribosomal function. In our investigation, DON interfered with fertilized egg cleavage by disrupting microtubule and microfilament networks, and Tubacin enhanced microtubule acetylation, stabilizing the network and rescuing developmental arrest. Taken together, these findings elucidated the rescue effects of Tubacin on DON-induced reproductive toxicity in oocytes, and validated our TUBB8 oocyte-specific knock-in mouse model as a rapid evaluation of exposure and potential treatment of environmental pollutants to female reproductive health.