Effects of Tributyltin Chloride on Human Neuronal Differentiation and Mice Brain Development

According to the developmental origins of health and disease hypothesis, perinatal exposure to an environmental toxicant during the development of the nervous system could cause a permanent cellular modification that may promote the appearance of neurodegenerative diseases at an older age. Tributyltin chloride is an environmental pollutant that, among other effects, provokes a dysfunction of the oxidative phosphorylation system and has adverse effects on the nervous system. We studied neuronal differentiation of human neuroblastoma cells and neural stem cells in the presence of tributyltin chloride concentrations found in human blood (≤ 100 nM), and brain development in two-year-old mice after perinatal exposure to tributyltin chloride (≤ 1000 nM). Pregnant mice (8-9 weeks old) were exposed to TBTC (0, 100, 500, or 1000 nM) via drinking water throughout gestation and lactation and ended upon weaning of the pups. Genetic-molecular, biochemical and cellular studies were performed on human SH-SY5Y neuroblastoma cells and on neural stem cells differentiating into neurons. In addition to these studies, histological studies of the brain and functional tests were performed in two-year-old mice. A decrease in the oxidative phosphorylation activity, essential for the proper function of the nervous system, affected neuronal differentiation of human neural stem cells and neuroblastoma cells in vitro. Exposure to this compound during pregnancy and lactation resulted in a modification of global deoxyribonucleic acid methylation levels in 2-year-old mice. Additionally, various histological changes were detected in the brains of these mice. Therefore, the alteration of brain development with long-term consequences may be one of the manifestations of early exposure to tributyltin.