Hexabromocyclododecane (HBCD) exposure induced premature testicular aging via NCOA4/Fe2+/ROS mediation.

ABSTRACT

Hexabromocyclododecane (HBCD) has been detected in animals and humans blood. As an environment contamination, HBCD damages tissues and organs in animals and humans and produces cytotoxicity. In current study, we explored the effect of HBCD on premature testicular aging in vivo and in vitro. In vivo, C57 mice (8-week-old) were used as model to estimate the effect of HBCD on premature testicular aging. The results showed that testes were premature aging through measuring several aging-related markers (such as p16INK4a, hereafter p16; p21CIP, hereafter p21) in response to HBCD exposure for 20 weeks. In addition, HBCD exposure can cause oxidative stress and inflammation. Further, mouse spermatogonial cells (GC-1spg cells) were premature senescence after HBCD exposure by the evaluation of cellular senescence marker molecules. Hence, GC-1spg cell line was applied for cell model to investigate the molecule mechanism by which HBCD cause premature testicular aging., Through eliminating Fe2+ in senescent GC-1spg cells, cellular senescence was greatly alleviated. Thus, Fe2+ was identified as the key driver molecule in HBCD-induced premature cellular senescence. Next, we found that elevated iron levels in HBCD-triggered senescent GC-1spg cells were due to Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Furthermore, our results revealed that HBCD-induced senescence was caused by Fe2+ mediated oxidative stress. In summary, HBCD-induced premature testicular aging is dependent on NCOA4/Fe2+/ROS signaling molecule. The current study lays the foundation for further exploration of the effects of HBCD on reproductive toxicology.