Sex-Dependent Effects of 2,2',3,5',6-Pentachlorobiphenyl on Dendritic Arborization of Primary Mouse Neurons

Early life exposures to environmental contaminants are implicated in the pathogenesis of many neurodevelopmental disorders (NDDs). These disorders often display sex biases, but whether environmental neurotoxicants act in a sex-dependent manner to modify neurodevelopment is largely unknown. Since altered dendritic morphology is associated with many NDDs, we tested the hypothesis that male and female primary mouse neurons are differentially susceptible to the dendrite-promoting activity of 2,2',3,5',6-pentachlorobiphenyl (PCB 95). Hippocampal and cortical neuron-glia co-cultures were exposed to vehicle (0.1% dimethylsulfoxide) or PCB 95 (100 fM-1 μM) from day in vitro 7-9. As determined by Sholl analysis, PCB 95-enhanced dendritic growth in female but not male hippocampal and cortical neurons. In contrast, both male and female neurons responded to bicuculline with increased dendritic complexity. Detailed morphometric analyses confirmed that PCB 95 effects on the number and length of primary and nonprimary dendrites varied depending on sex, brain region and PCB concentration, and that female neurons responded more consistently with increased dendritic growth and at lower concentrations of PCB 95 than their male counterparts. Exposure to PCB 95 did not alter cell viability or the ratio of neurons to glia in cultures of either sex. These results demonstrate that cultured female mouse hippocampal and cortical neurons are more sensitive than male neurons to the dendrite-promoting activity of PCB 95, and suggest that mechanisms underlying PCB 95-induced dendritic growth are sex-dependent. These data highlight the importance of sex in neuronal responses to environmental neurotoxicants.