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Connexin-43 is a promising target for lycopene preventing phthalate-induced spermatogenic disorders
Journal of Advanced Research ( IF 10.7 ) Pub Date : 2022-09-08 , DOI: 10.1016/j.jare.2022.09.001
Yi Zhao 1 , Ming-Shan Chen 1 , Jia-Xin Wang 1 , Jia-Gen Cui 1 , Hao Zhang 1 , Xue-Nan Li 2 , Jin-Long Li 2
Affiliation  

Introduction

Male infertility is a multifactorial pathological condition and may be a harbinger of future health. Phthalates are ubiquitous environmental contaminants that have been implicated in the global decline in male fertility. Among them, di-(2-ethylhexyl) phthalate (DEHP) is the most prevalently used. Lycopene (LYC) is a possible preventive and therapeutic agent for male infertility owing to its antioxidant properties. The blood-testis barrier (BTB) is formed between Sertoli cells where it creates a unique microenvironment for spermatogenesis.

Objectives

We hypothesize that phthalate caused male infertility and LYC plays an important role in phthalate-induced male fertility disorders.

Methods

Hematoxylin-eosin (H&E) staining, ultrastructure observation, and fluorescence microscopy were used to examine the morphological changes. RNA-Seq, and western blotting were conducted to detect gene and protein levels. Routine testing for sperm morphology and sperm-egg binding assay were conducted to examine the morphological structure and function of sperm. Cell scratch assay and transepithelial electrical resistance (TER) were used to detect cell migration capacity and barrier integrity.

Results

In vivo experiments, we showed that LYC prevented DEHP-induced impairment of BTB integrity, which provided a guarantee for the smooth progress of spermatogenesis. LYC improved DEHP-induced change in sperm parameters and fertilization ability. Subsequent in vitro experiments, LYC alleviated MEHP-induced disruption of intercellular junctions in mouse Spermatogonia cells (GC-1 cells) and mouse Sertoli cells (TM4 cells). In MEHP-induced BTB impairment models of Sertoli cells, treatment with LYC or overexpressing connexin-43 (Cx43) promoted cell migration capacity and normalized BTB integrity. Cx43 knockdown inhibited cell migration capacity and perturbed BTB reassembly in LYC preventing DEHP-induced BTB impairment.

Conclusion

Our study provides evidence for the role of LYC in phthalates-induced spermatogenic disorders and points to Cx43 as a potential target for male fertility.



中文翻译:

Connexin-43 是番茄红素预防邻苯二甲酸盐诱发的生精障碍的一个有前景的靶标

介绍

男性不育症是一种多因素病理状况,可能是未来健康的先兆。邻苯二甲酸盐是普遍存在的环境污染物,与全球男性生育能力下降有关。其中,邻苯二甲酸二(2-乙基己基)酯(DEHP)是最常用的。番茄红素(LYC)由于其抗氧化特性,可能成为男性不育症的预防和治疗剂。血睾屏障 (BTB) 在支持细胞之间形成,为精子发生创造了独特的微环境。

目标

我们假设邻苯二甲酸盐导致男性不育,LYC 在邻苯二甲酸盐引起的男性生育障碍中发挥重要作用。

方法

采用苏木精-伊红(H&E)染色、超微结构观察和荧光显微镜检查形态变化。进行RNA-Seq和蛋白质印迹来检测基因和蛋白质水平。常规进行精子形态学检测和精卵结合实验,检查精子的形态结构和功能。细胞划痕实验和跨上皮电阻(TER)用于检测细胞迁移能力和屏障完整性。

结果

体内实验表明,LYC可以防止DEHP引起的BTB完整性受损,为精子发生的顺利进行提供了保证。LYC 改善了 DEHP 引起的精子参数和受精能力的变化。随后的体外实验中,LYC 减轻了 MEHP 诱导的小鼠精原细胞(GC-1 细胞)和小鼠支持细胞(TM4 细胞)细胞间连接的破坏。在 MEHP 诱导的支持细胞 BTB 损伤模型中,LYC 或过表达 connexin-43 (Cx43) 治疗可促进细胞迁移能力并使 BTB 完整性正常化。Cx43 敲低抑制细胞迁移能力并扰乱 LYC 中的 BTB 重组,从而防止 DEHP 诱导的 BTB 损伤。

结论

我们的研究为 LYC 在邻苯二甲酸盐引起的生精障碍中的作用提供了证据,并指出 Cx43 作为男性生育力的潜在靶点。

更新日期:2022-09-08
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