Theranostics 2020; 10(7):3308-3324. doi:10.7150/thno.43189

Research Paper

Alginate oligosaccharides improve germ cell development and testicular microenvironment to rescue busulfan disrupted spermatogenesis

Yong Zhao1,2, Pengfei Zhang1, Wei Ge1, Yanni Feng3, Lan Li1, Zhongyi Sun4, Hongfu Zhang2✉, Wei Shen1✉

1. College of Life Sciences, Qingdao Agricultural University, Qingdao 266109, P. R. China.
2. State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, P. R. China
3. College of Veterinary Sciences, Qingdao Agricultural University, Qingdao 266109, P. R. China.
4. Center for Reproductive Medicine, Urology Department, Peking University Shenzhen Hospital, Shenzhen 518036, P. R. China.

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Citation:
Zhao Y, Zhang P, Ge W, Feng Y, Li L, Sun Z, Zhang H, Shen W. Alginate oligosaccharides improve germ cell development and testicular microenvironment to rescue busulfan disrupted spermatogenesis. Theranostics 2020; 10(7):3308-3324. doi:10.7150/thno.43189. Available from http://www.thno.org/v10p3308.htm

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Abstract

Rationale: Busulfan is currently an indispensable anti-cancer drug, particularly for children, but the side effects on male reproduction are so serious that critical drug management is needed to minimize any negative impact. Meanwhile, alginate oligosaccharides (AOS) are natural products with many consequent advantages, that have attracted a great deal of pharmaceutical attention. In the current investigation, we performed single-cell RNA sequencing on murine testes treated with busulfan and/or AOS to define the mitigating effects of AOS on spermatogenesis at the single cell level.

Methods: Testicular cells (in vivo) were examined by single cell RNA sequencing analysis, histopathological analysis, immunofluorescence staining, and Western blotting. Testes samples (ex vivo) underwent RNA sequencing analysis. Blood and testicular metabolomes were determined by liquid chromatography-mass spectrometry (LC/MS).

Results: We found that AOS increased murine sperm concentration and motility, and rescued busulfan disrupted spermatogenesis through improving (i) the proportion of germ cells, (ii) gene expression important for spermatogenesis, and (iii) transcriptional factors in vivo. Furthermore, AOS promoted the ex vivo expression of genes important for spermatogenesis. Finally, our results showed that AOS improved blood and testis metabolomes as well as the gut microbiota to support the recovery of spermatogenesis.

Conclusions: AOS could be used to improve fertility in patients undergoing chemotherapy and to combat other factors that induce infertility in humans.

Keywords: AOS, Single cell RNA sequencing, Spermatogenesis, Metabolome, Microbiota