Mimicking maternal smoking and pharmacotherapy of preterm labor: Fetal nicotine exposure enhances the effect of late gestational dexamethasone treatment on noradrenergic circuits

Abstract

Smoking during pregnancy increases the risk of preterm delivery, which in turn necessitates the common use of glucocorticoids to prevent respiratory distress syndrome. Accordingly, there is a substantial population exposed conjointly to fetal nicotine and glucocorticoids (typically dexamethasone). We administered nicotine to pregnant rats throughout gestation, using a regimen (3 mg/kg/day by osmotic minipump) that maintains plasma nicotine levels within the range seen in smokers; on gestational days 17, 18 and 19, we gave 0.2 mg/kg of dexamethasone. We assessed norepinephrine levels in three brain regions (frontal/parietal cortex, brainstem, cerebellum) throughout adolescence, young adulthood and later adulthood, and contrasted the persistent effects with comparable measures in peripheral tissues (heart, liver). In adolescence, males showed initial deficits in the frontal/parietal cortex with either dexamethasone alone or the combined treatment, with resolution to normal by young adulthood; the group exposed to both nicotine + dexamethasone showed subsequent elevations that emerged in full adulthood and persisted through five months of age, an effect not seen with either agent separately. In females, the combined exposure produced an initial deficit that resolved by young adulthood, without any late-emerging changes. We did not see comparable effects in the other brain regions or peripheral tissues. This indicates that nicotine exposure sensitizes the developing brain to the adverse effects of dexamethasone treatment, producing sex-selective changes in innervation and/or activity of specific noradrenergic circuits. The fact that the combined treatment produced greater effects points to potentially worsened neurobehavioral outcomes after pharmacotherapy of preterm labor in the offspring of smokers.

Prenatal nicotine alters the developmental neurotoxicity of postnatal chlorpyrifos directed toward cholinergic systems: Better, worse, or just “different?”

“…As has been shown in prior studies of the developmental neurotoxicity of nicotine and chlorpyrifos individually (Aldridge et al, 2004; Levin et al, 2001, 2002; Rauh et al, 2012; Slotkin, 2005; Slotkin et al, 2001, 2013, 2014a; Slotkin and Seidler, 2011), we found a high degree of sex-selectivity of the effects of each agent and of the combination treatment. As presented in those earlier reports, this does not likely represent a difference in the initial effects of the toxicants but rather the sex-dependence of adaptive mechanisms, such as neural cell replacement.…”

“…We minimized stress contributions by including control pump implants, followed by either postnatal vehicle or chlorpyrifos administration, thus permitting comparison of the doubly-exposed group to those receiving only the prenatal stressor. Furthermore, the surgery was carried out on the fourth day of gestation, two days prior to the implantation of the embryo in the uterine wall, so that there was no communication between maternal and fetal circulation at the time of surgery; indeed, any anomalies at that stage typically lead to failure of the embryo to implant or to spontaneous abortion, neither of which were noted here or in earlier studies with the same design (Slotkin et al, 2010; Slotkin and Seidler, 2010, 2011). Nevertheless, we cannot absolutely rule out a stress × drug interaction.…”

Neurobehavioral effects of choninergic drugs in prenatal period

“…Существуют данные, что различные реакции на пренатальное воздействие никотина связаны с по-лом [109,160,173]. Особая чувствительность жен-ского пола к никотину может быть обусловлена центральными эффектами половых стероидных гор-монов, прежде всего опосредованной ими половой дифференцировкой мозга и глубоким организую-щим эффектом половых гормонов на нейрональные структуры, функции и нейрохимию мозга [30,151].…”

“…Однако известно, что НА-ергические нейроны в раз-вивающемся мозге особо чувствительны к прена-тальному воздействию никотина [173,193] в связи с ранней активацией этой нейромедиаторной си-стемы [105] в мозге развивающегося организма. Хотя однократное воздействие никотина на самку значительно увеличивает НА-ергическую актив-ность [173], более значимые эффекты наблюдаются после хронического воздействия [143,173]. Поэто-му было выдвинуто предложение, что стимулирую-щие эффекты никотина связаны с гипоксией [170].…”

“…Таким образом, в зависимости от того, когда применяется никотин, эффект на развивающуюся нейронную схе-му будет отличаться. Например, есть ранняя иннер-вация многих мозговых областей терминалами LC, и развивающиеся нейроны НА особенно чувстви-тельны к пренатальной экспозиции никотина [173]. Для развития мозга такая чувствительность являет-ся критической, потому что НА оказывает значитель-ное воздействие на клеточное развитие [105].…”