Tributyltin chloride induced testicular toxicity by JNK and p38 activation, redox imbalance and cell death in sertoli-germ cell co-culture

• Tributyltin chloride induces cytosolic Ca 2+ mediated oxidative damage and cell death in sertoli-germ cell co-culture. • TBTC induces both apoptotic (low dose) and necrotic (high dose) cell death. • TBTC primarily affects sertoli cells which may lead to germ cell damage. • p38 and JNK signaling pathways instigate downstream pathways via mitochondria. • TBTC disrupts blood–testicular barrier (BTB) and spermatogenesis in-vivo upon a single oral dose. The widespread use of tributyltin (TBT) as biocides in antifouling paints and agricultural chemicals has led to environmental and marine pollution. Human exposure occurs mainly through TBT contaminated seafood and drinking water. It is a well known endocrine disruptor in mammals, but its molecular mechanism in testicular damage is largely unexplored. This study was therefore, designed to ascertain effects of tributyltin chloride (TBTC) on sertoli-germ cell co-culture in ex-vivo and in the testicular tissue in-vivo conditions. An initial Ca 2+ rise followed by ROS generation and glutathione depletion resulted in oxidative damage and cell death. We observed p38 and JNK phosphorylation, stress proteins (Nrf2, MT and GST) induction and mitochondrial depolarization leading to caspase-3 activation. Prevention of TBTC reduced cell survival and cell death by Ca 2+ inhibitors and free radical scavengers specify definitive role of Ca 2+ and ROS. Sertoli cells were found to be more severely affected which in turn can hamper germ cells functionality. TBTC exposure in-vivo resulted in increased tin content in the testis with enhanced Evans blue leakage into the testicular tissue indicating blood–testis barrier disruption. Tesmin levels were significantly diminished and histopathological studies revealed marked tissue damage. Our data collectively indicates the toxic manifestations of TBTC on the male reproductive system and the mechanisms involved.