Abstract
Zearalenone (ZEA), a common mycotoxin in grains and animal feeds, has been associated with male reproductive disorders. However, the potential toxicity mechanism of ZEA is not fully understood. In this study, in vivo and in vitro models were used to explore the effects of ZEA on the blood–testis barrier (BTB) and related molecular mechanisms. First, male BALB/C mice were administered ZEA orally (40 mg/kg·bw) for 5–7 d. Sperm motility, testicular morphology, and expressions of BTB junction proteins and autophagy-related proteins were evaluated. In addition, TM4 cells (mouse Sertoli cells line) were used to delineate the molecular mechanisms that mediate the effects of ZEA on BTB. Our results demonstrated that ZEA exposure induced severe testicular damage in histomorphology and an ultrastructural, time-dependent decrease in the expression of blood–testis barrier junction-related proteins, accompanied by an increase in the expression of autophagy-related proteins. Additionally, similar to the in vitro results, the dose-dependent treatment of ZEA increased the level of cytoplasmic Ca2+ and the levels of the autophagy markers LC3-II and p62, in conjunction with a decrease in the BTB junction proteins occludin, claudin-11, and Cx43, with the dislocation of the gap junction protein Cx43. Meanwhile, inhibition of autophagy by CQ and 3-MA or inhibition of cytoplasmic Ca2+ by BAPTA-AM was sufficient to reduce the effects of ZEA on the TM4 cell BTB. To summarize, this study emphasizes the role of Ca2+-mediated autophagy in ZEA-induced BTB destruction, which deepens our understanding of the molecular mechanism of ZEA-induced male reproductive disorders.
Highlights
Zearalenone (ZEA), known as the F-2 or RAL mycotoxin, is produced by fungi belonging to the Fusarium family, which show strong estrogenic activity [1,2]
We investigated how calcium-induced autophagy is involved in the regulation of testicular toxicity and blood–testis barrier (BTB) damage induced by ZEA
These findings demonstrate that Cato autophagy bewithout involved (D) Localization for LC3 punctate staining and connexin 43 (Cx43) in BTB for TM4 cells exposed to 20 μmol/L ZEA for 24 h with or
Summary
Zearalenone (ZEA), known as the F-2 or RAL mycotoxin, is produced by fungi belonging to the Fusarium family, which show strong estrogenic activity [1,2]. A previous study illustrated that the presence of ZEA in the diet of piglets caused significant increases in vulva size, the genital organ coefficient, and the level of certain immunoglobulins or hormones [6]. A study conducted by Pang et al [7,8] showed that long-term exposure to low concentrations of ZEA can cause disturbances in the reproductive capacity of male mice. The blood–testis barrier (BTB) formed by Sertoli cells is a target of environmental toxicants [9]. It has been found that disorders of the intracellular environment and damage to Sertoli cell junction complex-related proteins (such as claudin-5, claudin-11, occludin, connexin-43, and ZO-1) are the main reasons for the destruction of BTB, which affects spermatogenesis and eventually leads to infertility [10]. Previous studies have shown that acute exposure to ZEA can reduce sperm motility and significantly reduce testosterone and estradiol levels. The activity of testicular marker enzymes and related
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