Abstract
Sertoli cells, by creating an immune-privileged and nutrition supporting environment, maintain mammalian spermatogenesis and thereby holds the heart of male fertility. Olaquindox, an effective feed additive in livestock industry, could potentially expose human into the risk of biological hazards due to its genotoxicity and cytotoxicity, highlighting the significance of determining its bio-safety regarding human reproduction. Herein, we deciphered the detrimental effects of olaquindox on male fertility by mechanistically unraveling how olaquindox intervenes blood-testis barrier in mouse. Olaquindox (400 μg/ml) exposure significantly compromised tight junction permeability function, decreased or dislocated the junction proteins (e.g., ZO-1, occludin and N-cadherin) and attenuated mTORC2 signaling pathway in primary Sertoli cells. Furthermore, olaquindox disrupted F-actin architecture through interfering with the expression of actin branching protein complex (CDC42-N-WASP-Arp3) and actin bunding protein palladin. Olaquindox also triggered severely DNA damage and apoptosis while inhibiting autophagic flux in Sertoli cell presumably due to the exacerbated generation of reactive oxygen species (ROS). Pre-treatment with antioxidant N-acetylcysteine effectively ameliorated olaquindox-induced exhaustion of ZO-1 and N-Cadherin proteins, DNA damage and apoptosis. More significantly, olaquindox disrupted the epigenetic status in Sertoli cells with hypermethylation and concomitantly hypoacetylation of H3K9 and H3K27. Overall, our study determines olaquindox targets Sertoli cells to affect BTB function through tight junction proteins and F-actin orgnization, which might disrupt the process of spermatogenesis.
Highlights
During spermatogenesis, Sertoli cells offer nutritional and physical support to the developing germ cells, and creates an immuno-privileged microenvironment by blood-testis barrier (BTB) spatially sequestering germ cells from autoimmunity and ectogenesis stimulus and thereby, fostering the completion of meiosis [1, 2]
We for the first time deciphered that OLA has deleterious effects on male reproduction by interfering with the BTB integrity, cytoskeleton architecture, DNA damage and even histone epigenetic status in Sertoli cells
tight junction (TJ) proteins (e.g., zonula occludens 1 (ZO-1) and occludin), basal basal ectoplasmic specializations (ES) protein (e.g., N-Cadherin) and gap junction (GJ) protein are important structural components in Sertoli cells, which are essential for the regulation of BTB function [3]
Summary
Sertoli cells offer nutritional and physical support to the developing germ cells, and creates an immuno-privileged microenvironment by blood-testis barrier (BTB) spatially sequestering germ cells from autoimmunity and ectogenesis stimulus and thereby, fostering the completion of meiosis [1, 2]. Olaquindox (OLA, 2-(N-2-hydroxyethyl-carba monyl)-3-methyl-quinoxaline-N1, N4-dioxide), a common medicinal feed additive in livestock husbandry for growth promoting and antibacterial purpose to prevent dysentery and bacterial enteritis, has been banned for using by the European Commission of the European Community and Canada since 1998 due to its potential risks such as genotoxic, mutagenic and photoallergenic effects [14,15,16]. It is still being widely used in China due to its beneficial effects, which potentially exposes our human, if consume those animal products with residual OLA due to its illogical usage, into the risks of its biological hazards. Despite OLA could be categorized as mutagenic and carcinogenic with developmental and reproductive toxicities [24] whether OLA has deleterious effects on mammalian spermatogenesis, or the BTB dynamic and if so, what the underlying mechanisms might be involved in still remain to be explored
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