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. 2018 Dec;596(23):5977-5991.
doi: 10.1113/JP275885. Epub 2018 Jul 15.

Pre- and early postnatal nicotine exposure exacerbates autoresuscitation failure in serotonin-deficient rat neonates

Stella Y Lee  1 , Chrystelle M Sirieix  1 , Eugene Nattie  1 , Aihua Li  1   2
Affiliations

Pre- and early postnatal nicotine exposure exacerbates autoresuscitation failure in serotonin-deficient rat neonates

Stella Y Lee et al. J Physiol. 2018 Dec.

Abstract

Key points: Sudden infant death syndrome (SIDS) is one of the leading causes of death during the first year of life and abnormalities linked to serotonin (5-HT) have been identified in many SIDS cases. Cigarette smoking and associated exogenous stressors, e.g. developmental nicotine exposure, may compound these serotonergic defects and any associated defects in cardiorespiratory function. Using neonatal rodent pups subjected to medullary 5-HT deficiency and perinatal nicotine exposure, we examined the impact of this interplay of factors on the neonates' ability to autoresuscitate at specific ages. In perinatal nicotine-exposed 5-HT deficient pups, impaired autoresuscitation along with significantly delayed post-anoxic recovery of normal breathing and heart rate was observed at postnatal day 10 (P10). We found that the interaction between 5-HT deficiency and perinatal nicotine exposure can significantly increase pups' vulnerability to environmental stressors and exacerbate defects in cardiorespiratory protective reflexes to repetitive anoxia during the development period.

Abstract: Cigarette smoking during pregnancy increases the risk of sudden infant death syndrome (SIDS), and nicotine replacements, a key ingredient of cigarettes, have been recently prescribed to women who wish to quit smoking during their pregnancy. Serotonin (5-HT) abnormalities have been consistently identified in many SIDS cases. Here we investigated the effects of perinatal nicotine exposure in mild 5-HT deficiency rat neonates on autoresuscitation, a protective cardiorespiratory reflex. The mild 5-HT deficiency was induced by a maternal tryptophan-deficient diet, and nicotine was delivered from embryonic day (E) 4 to postnatal day (P) 10 at 6 mg kg-1 day-1 through an osmotic pump. In P10 rats, nicotine exposure exacerbates autoresuscitation failure (mortality) in mildly 5-HT-deficient rats to a greater extent than in controls (P = 0.029). The recovery of eupnoea and heart rate to baseline values following repetitive anoxic events (which elicit an apnoea accompanied by a bradycardia) is significantly delayed in 5-HT-deficient rats treated with nicotine, making them more susceptible to failure of autoresuscitation (eupnoea recovery: P = 0.0053; heart rate recovery: P = < 0.0001). Neither 5-HT deficiency nor nicotine exposure alone appears to affect the ability to autoresuscitate significantly when compared among the four treatments. The increased vulnerability to environmental stressors, e.g. severe hypoxia, asphyxia, or anoxia, in these nicotine-exposed 5-HT-deficient neonates during postnatal developmental period is evident.

Keywords: Developmental nicotine exposure; Serotonin deficiency; Triple Risk hypothesis.

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Figures

Figure 1
Figure 1. The effect of tryptophan‐deficient (TD) on medullary monoamine levels
A–C, the total 5‐HT (5‐HT + 5‐HIAA) (A), ratio of 5‐HIAA to 5‐HT (5‐HIAA/5‐HT) (C), and 5‐HT and 5‐HT metabolite (5‐HIAA) levels (B) in the medulla were significantly lower in TD diet pups than control (Ctr) diet pups at P10, P15 and P25 (* P < 0.05). Although 5‐HT levels were lower in TD diet pups than Ctr diet pups at all three ages, they were only significant at P15 and P25 (* P < 0.05). D, there were no significant differences with other monoamines and their metabolite levels between Ctr and TD diet groups at all three ages (P > 0.05). Data are presented as means ± SEM, and each circle represents an individual animal. Two‐way ANOVA followed by the Holm‐Sidak post hoc test were used for all comparisons. Black bar: Ctr diet; grey bar: TD diet. NAd, noradrenaline; Adr adrenaline; DA, dopamine; DOP, DOPAC or dihydroxyphenylacetic acid; HVA, homovanillic acid.
Figure 2
Figure 2. The effects of diet and nicotine on body weights in P5, 8, 10 and 12 neonates
Body weight was significantly affected by age (P ≤ 0.001), diet (P ≤ 0.001) and treatment (P = 0.005), and the significant interactions were found between age and diet (P ≤ 0.001), diet and treatment (P = 0.003) (three‐way ANOVA with Holm‐Sidak post hoc test; **significant interaction between age and diet). At P8, P10 and P12, the TD diet/nicotine (TD/Nic)‐treated pups (black bars) were significantly smaller than pups from other treatment groups at P8, P10 and P12 (*statistical significance; P ≤ 005). At P12, TD diet/vehicle (TD/Veh) pups (grey hatched bars) were significantly smaller than the Ctr/Veh (white bars) and Ctr/Nic (white hatched bar) pups (P = 0.011). Data presented as means ± SEM and each circle represents an individual animal.
Figure 3
Figure 3. Percentage survival across 15 bouts of anoxia in P10 neonates
At P10, there is a statistically significant difference between survival curves (P = 0.029, Kaplan‐Meier survival (Gehan‐Breslow) analysis), with 69% of Ctr diet/vehicle‐treated pups (11 of 16), 50% of TD diet/vehicle pups (8 of 16), 40% of Ctr diet/nicotine pups (6 of 15), and only 27% of the TD diet/nicotine‐exposed pups (4 of 15) surviving all 15 episodes. All pairwise comparisons showed that TD diet/nicotine‐treated pups had significant lower surviving rates than Ctr diet and saline (Ctr diet/vehicle)‐treated pups (* P = 0.0425, Survival Gehan‐Breslow–Holm‐Sidak all pairwise analysis).
Figure 4
Figure 4. Mean number of anoxic bouts survived in P10 neonates
The mean number of anoxic episodes survived (filled circles) was significantly less in TD diet/nicotine‐exposed P10 rats (12 episodes; far right column) than saline vehicle‐treated Ctr and TD diet pups (* P = 0.025). Neither tryptophan deficiency nor nicotine exposure alone significantly altered the mean number of anoxic episodes survived. Data presented as means ± SEM and each circle represents an individual animal.
Figure 5
Figure 5. Gasp latency, eupnoea and HR recovery at anoxic episodes 1, 5, 10 and the last survived episode in P10 neonates
A, no significant differences in gasp latency (duration of primary apnoea) were observed amongst the four treatment groups (no treatment effect) across the repeated bouts of anoxia (no episode effect). B, recovery to eupnoea was delayed with progressive anoxic bouts (episode effect: P < 0.0001,) in all treatment groups, with the longest recovery period observed during the last survived anoxic episode. Eupnoea recovery was significantly delayed in TD diet/nicotine‐treated pups at P10 (grey inverted triangles, dashed line; treatment effect: * P = 0.0053) compared to all other treatment groups during the last survived anoxic episode. C, HR recovery was delayed with progressive anoxic bouts in all treatment groups. The pups treated with TD diet had longer HR recovery periods during the last anoxia episode than the pups treated with Ctr diet (* P ≤ 0.05). TD diet/nicotine pups had the slowest HR recovery compared to all other treatment groups (grey inverted triangles, dashed line; # P < 0.0001). Two‐way RM ANOVA with Holm‐Sidak post hoc analysis. Data presented as means ± SEM.
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