PCB 37 (3,4, 4'-trichlorobiphenyl) increased apoptosis and modulated neuronal morphogenesis in primary rat cortical neuron-glia cocultures in a concentration-, sex-, age-, and CREB-dependent manner.

Higher-chlorinated (HC) polychlorinated biphenyls (PCBs) are known developmental neurotoxicants. In contrast, there are limited data regarding the developmental neurotoxicity of lower-chlorinated (LC) PCBs despite the increasing environmental prevalence and detection of LC-PCBs in contemporary human tissues, including the perinatal brain. This study characterized the neurotoxic effects of the LC-PCB congener PCB 37 in primary male and female rat cortical neuron-glia co-cultures. Cultures were exposed to varying concentrations of PCB 37 for 48 h beginning on day in vitro 0 or 7. Cell viability was assessed by measuring lactate dehydrogenase release into the culture medium and the percentage of live cells identified using Calcein-AM and Hoechst staining. Apoptosis was measured using fluorometric assays of caspase 3/7 activity and Annexin V binding. Axonal and dendritic growth were quantified in neurons immunostained for Tau-1 or transfected with MAP2B-red fluorescent protein, respectively, using automated image analysis protocols. At environmentally relevant concentrations (0.0001, 0.1, and 100 nM) that did not affect cell viability, PCB 37 caused sex-, age-, and concentration-dependent increases in apoptosis, axonal, and dendritic growth. Pretreatment with the CREB inhibitor 666-15 (500 nM) blocked the effects of PCB 37 on apoptosis and dendritic morphology but not axonal growth. These findings suggest that the pro-apoptotic and dendrite-promoting effects of PCB 37 are mediated by CREB signaling, but that CREB-independent mechanisms underlie PCB 37 effects on axonal growth. Overall, these findings identify PCB 37 as a potential developmental neurotoxicant and further support increasing evidence identifying CREB as a convergent mechanism of developmental neurotoxicity.