Folate deficiency mediates ovarian dysfunction through appetite and inflammatory pathways

The long-established link between nutrition and reproduction is known to have critical consequences for reproductive function. However, the available experimental data on the effects of folate deficiency on ovarian health remains scarce. It is still unclear whether folate deficiency is directly responsible for causing ovarian-dysfunction and, if so, what are the underlying mechanisms. Therefore, our objective was to establish evidence for association between folate deficiency, hormone dynamics, and ovarian function using in vivo model. Folate-deprived female zebrafish were developed using intraperitoneal administration of methotrexate (MTX; DHFR inhibitor) and were used to study the possible implications of folate deprivation on ovarian health. Changes in the expression of transcripts regulating appetite and ovarian function was observed. We observed that folate deprivation resulted in impaired appetite behaviour and alteration in its regulatory gene expression. Due to folate deficiency, the neuroendocrine function of the brain was affected that resulted in altered reproductive hormone levels. Histology of ovary shows follicles arrested in primary oocyte stage and scarring of tissue is seen. Furthermore, elevated lipid peroxidation and catalase enzyme activity along with increased IL-6, indicates folate deficiency induced oxidative stress and inflammation in ovary as one of the possible mechanisms to aid- ovarian dysfunction. Our study provides experimental evidence, using an in vivo folate-deficient fish model, that underscores the essential role of folate in maintaining reproductive health. The intricate relationship between folate deficiency, appetite regulation, and its impact on the synthesis and release of female reproductive hormones calls for deeper investigation, particularly through studies involving mammalian models.