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Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Gossypol impairs reproduction in both sexes, inducing mitochondrial dysfunction, irregular cycles, and fewer ovarian follicles, leading to decreased fertility rates. The present investigation was undertaken to evaluate the toxicological effects of (+)-gossypol powder, a substance derived from cottonseed in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The mice were divided into four groups: a control group receiving pure dimethyl sulfoxide (DMSO) and three treatment groups receiving 20, 40, or 80\u00a0mg\/kg gossypol dissolved in DMSO. The mice were treated daily via oral gavage for 14\u00a0days and subjected to clinical observation. At study completion, physical, hematological, and histopathological (ovary, testis, liver, lung, kidney, and spleen) evaluations were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with the control treatment, gossypol treatment adversely affected routine blood parameters and histopathology (p &amp;lt; 0.05). Routine blood tests revealed significantly elevated neutrophil granulocytes and monocytes, along with a marked decrease in lymphocytes. Furthermore, gossypol treatment inhibited spermatogenesis, caused follicular degeneration in the ovaries, and induced tissue damage in the liver, kidney, lung, and spleen. Furthermore, transcriptome sequencing of ovaries, testes, and livers from mice treated with DMSO or 80\u00a0mg\/kg gossypol was performed to investigate the molecular mechanisms of reproductive damage. Eighteen cDNA libraries were constructed and yielded 113.6\u00a0Gb of raw reads, which were filtered to obtain 112.4\u00a0Gb of high-quality clean reads. The analysis identified 639 differentially expressed genes (DEGs). Consecutively, weighted gene coexpression network analysis (WGCNA) revealed a strong correlation between the blue module hub gene <jats:italic>ENSMUSG00000048138<\/jats:italic> (<jats:italic>Dmrt2<\/jats:italic>) and mouse blood test results. <jats:italic>Dmrt2<\/jats:italic> gene expression was confirmed by RT-qPCR and GFP expression analysis. Lentivirus-mediated <jats:italic>DMRT2<\/jats:italic> silencing (shRNA-Sh-a, Sh-b, and Sh-c) resulted in low <jats:italic>DMRT2<\/jats:italic> expression, whereas overexpression (OE-<jats:italic>DMRT2<\/jats:italic>) resulted in high <jats:italic>DMRT2<\/jats:italic> expression relative to that of the controls. Gossypol stress significantly upregulated <jats:italic>Dmrt2<\/jats:italic> expression in ovarian tissue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Gossypol powder from cotton is toxic to mice, affecting their pathology, histology, and hematology. This study strongly links the <jats:italic>Dmrt2<\/jats:italic> gene in reproductive tissues to gossypol resistance, highlighting its potential protective role and advancing the understanding of gene regulation in mouse fertility. Further research and food safety considerations are therefore crucial.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1654299","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T05:44:10Z","timestamp":1756446250000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Histopathological examination and transcriptomic profiling reveal gossypol toxicity-responsive genes related to fertility in mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Teame Gereziher","family":"Mehari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maorong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxi","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungfeng","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashenafi Kiros","family":"Wubshet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deng-Bing","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baohua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"B74","article-title":"Tukey's honestly significant difference (HSD) test. 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