Abstract
BackgroundMale fertility impaired by exogenous toxins is a serious worldwide issue threatening the health of the new-born and causing infertility. However, the metabolic connection between toxic exposures and testicular dysfunction remains unclear.ResultsIn the present study, the metabolic disorder of testicular dysfunction was investigated using triptolide-induced testicular injury in mice. We found that triptolide induced spermine deficiency resulting from disruption of polyamine biosynthesis and uptake in testis, and perturbation of the gut microbiota. Supplementation with exogenous spermine reversed triptolide-induced testicular dysfunction through increasing the expression of genes related to early and late spermatogenic events, as well as increasing the reduced number of offspring. Loss of gut microbiota by antibiotic treatment resulted in depletion of spermine levels in the intestine and potentiation of testicular injury. Testicular dysfunction in triptolide-treated mice was reversed by gut microbial transplantation from untreated mice and supplementation with polyamine-producing Parabacteroides distasonis. The protective effect of spermine during testicular injury was largely dependent on upregulation of heat shock protein 70s (HSP70s) both in vivo and in vitro.ConclusionsThe present study linked alterations in the gut microbiota to testicular dysfunction through disruption of polyamine metabolism. The diversity and dynamics of the gut microbiota may be considered as a therapeutic option to prevent male infertility.1i44qFJDRbDet-fJN3JiqxVideo
Highlights
Male fertility impaired by exogenous toxins is a serious worldwide issue threatening the health of the newborn and causing infertility
IHC showed that spermatogonial stem cell (marked by inhibitor of differentiation 4 (Id4)) decreased mildly, the marks of spermatogonical stem cell Id4 mRNA and B lymphoma Mo-MLV insertion region 1 (Bmi1) mRNA levels were decreased (Fig. 1d and Supplementary Fig. 2)
TP reduced the expression of mRNAs involved in late spermatogenic events including bromodomain testisspecific factor (Brdt, involved in the generation of male gametes in post-meiotic cells), tudor domaincontaining 7 (Tdrd7, involved in dynamic ribonucleoprotein remodeling of chromatoid bodies during spermatogenesis), a disintegrin and metallopeptidase domain 3 (Adam3, involved in sperm assembly and sperm-zona pellucida binding), transition protein 2 (Tnp2, involved in histone displacement), and spermatogenesis associated 19 (Spata19, involved in mitochondria adhesion of the sheath during spermatogenesis) mRNAs (Fig. 1d)
Summary
Male fertility impaired by exogenous toxins is a serious worldwide issue threatening the health of the newborn and causing infertility. The metabolic connection between toxic exposures and testicular dysfunction remains unclear. Infertility is a worldwide clinical issue affecting approximately 12% of the reproductive-aged couples, among which males contribute to nearly 50% of all cases [1]. Continuous administration of TP significantly suppresses the marker-enzymes of spermatogenesis and testosterone levels, reduces sperm counts, diminishes the testis indices (testis weight/body weight × 100%), and damages the microstructure of testis in mice [7]. The severe testicular toxicity induced by TP largely limited its clinical use in humans despite its notable therapeutic effects on inflammatory, autoimmune diseases, and cancers [8, 9]. Uncovering the testicular toxicity of TP was helpful to explore the process of male infertility
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