Perinatal environmental tobacco smoke exposure in rhesus monkeys: critical periods and regional selectivity for effects on brain cell development and lipid peroxidation

Abstract

Perinatal environmental tobacco smoke (ETS) exposure in humans elicits neurobehavioral deficits. We exposed rhesus monkeys to ETS during gestation and through 13 months postnatally, or postnatally only (6-13 months). At the conclusion of exposure, we examined cerebrocortical regions and the midbrain for cell damage markers and lipid peroxidation. For perinatal ETS, two archetypal patterns were seen in the various regions, one characterized by cell loss (reduced DNA concentration) and corresponding increases in cell size (increased protein/DNA ratio), and a second pattern suggesting replacement of larger neuronal cells with smaller and more numerous glia (increased DNA concentration, decreased protein/DNA ratio). The membrane/total protein ratio, a biomarker of neurite formation, also indicated potential damage to neuronal projections, accompanied by reactive sprouting. When ETS exposure was restricted to the postnatal period, the effects were similar in regional selectivity, direction, and magnitude. These patterns resemble the effects of prenatal nicotine exposure in rodent and primate models. Surprisingly, perinatal ETS exposure reduced the level of lipid peroxidation as assessed by the concentration of thiobarbituric acid reactive species, whereas postnatal ETS did not. The heart, a tissue that, like the brain, has high oxygen demand, displayed a similar but earlier decrease (2-3 months) in lipid peroxidation in the perinatal exposure model, whereas values were reduced at 13 months with the postnatal exposure paradigm. Our results provide a mechanistic connection between perinatal ETS exposure and neurobehavioral anomalies, reinforce the role of nicotine in these effects, and buttress the importance of restricting or eliminating ETS exposure in young children.

Figure 1

Effects of ETS exposure on biomarkers of neural cell development: (A) DNA concentration (ANOVA: treatment, p < 0.01; treatment × region, p < 0.0001). (B) Total protein/DNA ratio (ANOVA: treatment × region, p < 0.004). (C) Membrane/total protein ratio (ANOVA: treatment, p < 0.008; there was no treatment × region interaction); the main effect of each ETS treatment in (C) is as follows: continuous ETS, p < 0.005; ETS 6–13 months, p < 0.008. *Individual values for which the ETS groups differ from the corresponding control. These were not evaluated in (C) because of the absense of a treatment × region interaction.

Figure 2

Effects of ETS exposure on TBARS in brain regions and heart (note different scales). ANOVA across all treatments and tissues: treatment, p < 0.0001; treatment × tissue, p < 0.004. Lower order ANOVAs for each tissue are shown within the figure. *Individual values for which the ETS groups differ from the corresponding control.

Figure 3

Effects of ETS exposure on cardiac βAR and m₂AChR binding (note different scales); ANOVA: treatment, p < 0.004. There was no interaction of treatment × receptor type; the only main treatment effect is ETS 6–13 months (p < 0.003). There were no significant differences in the concentration of membrane proteins.