Vincristine-induced alterations in ovarian function and oocyte quality: Modulation by dichloroacetate

Vincristine (VCR) is used in chemotherapy regimens and is generally considered to present low gonadotoxicity; however, its effects on ovarian function and oocyte quality are still to be wholly understood. Dichloroacetate (DCA), a metabolic modulator that promotes pyruvate dehydrogenase (PDH) activation, may influence the ovarian response to chemotherapeutic agents. Adult female C57BL/6 mice were randomly assigned to four groups: control, VCR, DCA, and VCR + DCA. During weeks 1-3, subjects received DCA via drinking water, and VCR was injected intraperitoneally during weeks 2-3. Short-term effects (at the end of week 3) were evaluated using ovarian histological and immunohistochemical analyses, including FOXO3a, anti-Müllerian hormone (AMH), cleaved caspase-3, Ki-67, and oxidative stress markers. Effects on oocyte number, diameter, and meiotic spindle morphology were evaluated in week 7 (Long-term effects). VCR was found to disrupt estrous cyclicity, reduce the number of growing follicles, and increase follicular atresia. These changes were associated with decreased AMH signaling and heightened cytoplasmic localization of FOXO3a, suggesting enhanced primordial follicle activation. VCR also increased the ovarian catalase levels. Long-term effects included reduced ovulation rate and alterations in oocyte diameter and meiotic spindle length. Combined treatment with DCA exacerbated the loss of growing follicles and reduced ovulatory rate, although some oocyte parameters, such as spindle length, were comparable to those in controls. Therefore, we propose that VCR induces significant alterations in ovarian function and oocyte quality that may persist beyond treatment. In contrast, DCA exhibits a dual effect, potentially aggravating follicular depletion while improving specific aspects of oocyte morphology.