In vitro investigations for the QSAR mechanism of lymphocytes apoptosis induced by substituted aromatic toxicants

The objective of this study was to assess the chemicals-induced apoptosis effects on fish lymphocytes and to use the QSAR model to interpret the relationships between apoptotic effects and chemical structures to identify the immune toxicology mechanism. By the use of a simple in vitro toxicological assay, the measured apoptotic parameter (EC50) is used in a QSAR to interpret the apoptotic effects of 25 substituted benzenes at low exposure levels. The apoptotic effects of all tested substituted aromatic chemicals with Carassius auratus lymphocytes were confirmed by DNA ladder and nucleus condensation. For both chlorobenzenes and PCBs, the EC50 values increase with increasing Cl number in the molecule, a result reflecting probably the increased p–π conjugation of the C–Cl bonds that lowers the molecular reactivity. Furthermore, the apoptotic EC50 data were best correlated with the dipole moment (μ) and the energy of the lowest unoccupied molecular orbital (ELUMO) such that: log ( 1 / EC 50 ) = 0.325 + 0.222 μ − 0.163 ( ELUMO ) (with R2 = 0.879). The dependence on the electronic ELUMO factor of the established correlation suggests that during the apoptotic process the ROS (reactive oxygen substance) produced by cells acts as a Lewis base in substituted nucleophilic reactions with toxic chemicals behaving as an electron acceptor. On the basis of the test results, the present toxicological assay offers a rapid tool for assessing the toxic effects of chemicals at low exposure levels.