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Histopathological examination and transcriptomic profiling reveal gossypol toxicity-responsive genes related to
Teame Gereziher Mehari1, Maorong Jiang2, Dandan Gu2
1School of Life Sciences, Nantong University, Nantong, China.
Introduction:
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.
Methods:
The mice were divided into four groups: a control group receiving pure dimethyl sulfoxide (DMSO) and three treatment groups receiving 20, 40, or 80 mg/kg gossypol dissolved in DMSO. The mice were treated daily via oral gavage for 14 days and subjected to clinical observation. At study completion, physical, hematological, and histopathological (ovary, testis, liver, lung, kidney, and spleen) evaluations were performed.
Results:
Compared with the control treatment, gossypol treatment adversely affected routine blood parameters and histopathology (p < 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 mg/kg gossypol was performed to investigate the molecular mechanisms of reproductive damage. Eighteen cDNA libraries were constructed and yielded 113.6 Gb of raw reads, which were filtered to obtain 112.4 Gb 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 ENSMUSG00000048138 (Dmrt2) and mouse blood test results. Dmrt2 gene expression was confirmed by RT-qPCR and GFP expression analysis. Lentivirus-mediated DMRT2 silencing (shRNA-Sh-a, Sh-b, and Sh-c) resulted in low DMRT2 expression, whereas overexpression (OE-DMRT2) resulted in high DMRT2 expression relative to that of the controls. Gossypol stress significantly upregulated Dmrt2 expression in ovarian tissue.
Conclusion:
Gossypol powder from cotton is toxic to mice, affecting their pathology, histology, and hematology. This study strongly links the Dmrt2 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.
Insights
Gossypol from cottonseed is toxic to mice, causing reproductive damage and affecting blood and tissue health. The Dmrt2 gene in reproductive tissues is linked to gossypol resistance, offering potential protective insights.
Area of Science:
- Toxicology
- Reproductive Biology
- Genetics
Background:
- Gossypol, derived from cottonseed, is known to impair reproductive functions in both sexes.
- It induces mitochondrial dysfunction, irregular estrous cycles, and reduced ovarian follicle counts, ultimately decreasing fertility rates.
Purpose of the Study:
- To investigate the toxicological effects of (+)-gossypol powder on mouse reproduction.
- To explore the molecular mechanisms underlying gossypol-induced reproductive damage and identify potential genetic factors involved.
Main Methods:
- Mice were administered varying doses of gossypol (20, 40, 80 mg/kg) or a control (DMSO) daily for 14 days.
- Evaluations included clinical observations, physical examinations, hematology, histopathology of reproductive organs and major tissues, and transcriptome sequencing.
Main Results:
- Gossypol significantly altered blood parameters (increased neutrophils and monocytes, decreased lymphocytes) and caused adverse histopathological changes in ovaries, testes, liver, kidneys, lungs, and spleen.
- Transcriptome analysis revealed 639 differentially expressed genes (DEGs), with the gene Dmrt2 strongly correlating with blood test results and upregulated in ovarian tissue under gossypol stress.
- Dmrt2 manipulation (silencing or overexpression) confirmed its role in gossypol response.
Conclusions:
- Gossypol powder exhibits toxicity in mice, impacting hematology, histology, and reproductive health.
- The Dmrt2 gene is identified as a key factor in reproductive tissues related to gossypol resistance, suggesting a potential protective role and advancing understanding of gene regulation in mouse fertility.
