1,3-Dinitrobenzene neurotoxicity – Passage effect in immortalized astrocytes
2016
Abstract Age-related disturbances in astrocytic mitochondrial function are linked to loss of neuroprotection and decrements in neurological function. The immortalized rat neocortical astrocyte-derived cell line, DI-TNC 1 , provides a convenient model for the examination of cellular aging processes that are difficult to study in primary cell isolates from aged brain. Successive passages in culture may serve as a surrogate of aging in which time-dependent adaptation to culture conditions may result in altered responses to xenobiotic challenge. To investigate the hypothesis that astrocytic mitochondrial homeostatic function is decreased with time in culture, low passage DI-TNC 1 astrocytes (LP; #2–8) and high passage DI-TNC 1 astrocytes (HP; #17–28) were exposed to the mitochondrial neurotoxicant 1,3-dinitrobenzene (DNB). Cells were exposed in either monoculture or in co-culture with primary cortical neurons. Astrocyte mitochondrial membrane potential, morphology, ATP production and proliferation were monitored in monoculture, and the ability of DI-TNC 1 cells to buffer K + -induced neuronal depolarization was examined in co-cultures. In HP DI-TNC 1 cells, DNB exposure decreased proliferation, reduced mitochondrial membrane potential and significantly decreased mitochondrial form factor. Low passage DI-TNC 1 cells effectively attenuated K + -induced neuronal depolarization in the presence of DNB whereas HP counterparts were unable to buffer K + in DNB challenge. Following DNB challenge, LP DI-TNC 1 cells exhibited greater viability in co-culture than HP. The data provide compelling evidence that there is an abrupt phenotypic change in DI-TNC 1 cells between passage #9–16 that significantly diminishes the ability of DI-TNC 1 cells to compensate for neurotoxic challenge and provide neuroprotective spatial buffering. Whether or not these functional changes have an in vivo analog in aging brain remains to be determined.
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