Melatonin orchestrates cAMP-PKA signaling to alleviate zearalenone-impaired the estradiol synthesis in mammal ovary.

The present study aimed to investigate the toxic effects of zearalenone (ZEN) on the mammal ovaries and its impact on estradiol (E2) synthesis, as well as to explore the detoxifying role of melatonin (MT) on ZEN. Firstly, we reanalyzed the transcriptome data between ZEN-exposed piglet ovaries and corresponding control group. We identified 3124 differentially expressed genes (DEGs), implying that ZEN significantly altered ovarian gene expression patterns. These DEGs were then subjected to GO and KEGG analyses, parts of which were specifically enriched in the production of ovarian hormones. By using an in vitro mouse granulosa cells (mGCs) model, we found that ZEN significantly reduced cell viability, increased intracellular ROS levels, and decreased mitochondrial membrane potential, with a significant downregulation of mRNA expression levels of E2 synthesis genes (Cyp19a1, Cyp11a1, Star and Hsd3b) (P < 0.05). Specially, MT was able to reverse the abovementioned indicators by increasing intracellular cAMP content, thus activating the cAMP-PKA pathway. In mice model, ZEN caused the swelling of mouse vulva, and significantly reduced sex hormone level in serum including E2, progesterone (PROG), follicle stimulating hormone (FSH), luteinizing hormone (LH), and the expression of E2 synthesis genes (P < 0.05), excepting for gonadotropin releasing hormone (GnRH) levels, which were significant increased. Of note, MT significantly recovered serum levels of E2, PROG, GnRH, and the expression of E2 synthesis genes to the normal level by activating the cAMP-PKA pathway. In summary, ZEN altered piglet ovarian gene expression patterns, and disrupted gene expression involving in E2 synthesis; ZEN caused oxidative stress and E2 synthesis disorders in mGCs, and disturbed the secretion of reproductive hormones in mice, leading to endocrine disruption with reproductive toxicity; Whereas, MT could partially alleviate the disturbances in E2 synthesis induced by ZEN through the cAMP-PKA pathway, suggesting MT as a potential remedy to alleviate the reproductive toxicity of ZEN.