Prenatal nicotine exposure in rhesus monkeys compromises development of brainstem and cardiac monoamine pathways involved in perinatal adaptation and sudden infant death syndrome: Amelioration by Vitamin C
Open accessAbstract
Maternal smoking during pregnancy greatly enhances perinatal morbidity/mortality and is the major risk factor for Sudden Infant Death Syndrome (SIDS). Studies in developing rodents indicate that nicotine is a neuroteratogen that targets monoamine pathways involved in the responses to hypoxia that are in turn, hypothesized to contribute to these adverse events. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers; we examined neurochemical parameters immediately after Cesarean delivery at the end of the exposure period. Nicotine evoked elevations in brainstem serotonin levels and serotonin turnover, indicating hyperactivity of these pathways. The same treatment evoked a deficit in cardiac norepinephrine levels. Both effects were offset by coadministration of the antioxidant, Vitamin C. Brainstem serotonin hyperinnervation is a hallmark of SIDS, and the hyperactivity seen here can also account for the downregulation of serotonin receptors noted in this disorder. Deficient cardiac sympathetic innervation is also consistent with increased vulnerability to hypoxia during delivery or in the agonal event in SIDS. Our results thus indicate that nicotine exposure in a primate model produces brainstem and autonomic abnormalities of the key monoamine systems that govern the response to hypoxia, indicate an important role of oxidative stress in the adverse effects, and point to potential amelioration strategies that could offset these particular effects of nicotine.
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Prenatal nicotine exposure from the start of pregnancy in Rhesus macaque monkeys causes significant serotonergic hyperinnervation of brainstem, a hallmark of SIDS, that was reversed with Vitamin C cotreatment.
“Prenatal nicotine exposure from the start of pregnancy in Rhesus macaque monkeys causes significant serotonergic hyperinnervation of brainstem, a hallmark of SIDS, that was reversed with Vitamin C cotreatment [37].”
From Nicotine on the developing brain. (2023) · cites this paper as [37]
The Methods say nicotine exposure began on gestational day 30, the earliest pregnancy could be reliably detected—not literally at conception. The Results report significant increases in brainstem serotonin, and the Discussion links serotonin hyperinnervation to SIDS. But the Discussion explicitly says Vitamin C prevented the increase in serotonin turnover while brainstem serotonin remained elevated and innervation was still augmented; it did not reverse the hyperinnervation. (LLM, conf=0.90)
Experimental — accuracy not yet measuredNicotine is a key cause of the neurodevelopmental harm from tobacco smoke exposure.
“and these studies show that nicotine itself is a critical contributor to the harmful neurodevelopmental effects of tobacco smoke exposure.(307-310)”
From Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products (2017) · cites this paper as [307]
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- Authors
- Slotkin, T. A., Seidler, F. J., & Spindel, E. R.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- Oregon National Primate Research Center (US)
- Corresponding author
- Slotkin, Theodore A.
- Venue
- Neurotoxicology and Teratology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 33
- Issue
- 3
- Pages
- 431-434
- ISSN
- 0892-0362 (ISSN-L)
- PMC
- PMC3109087
- OpenAlex
- W2086413968
- Cited by
- 60
- References
- 41
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 9 · 2012: 5
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurotoxicology and Teratology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL087710, R01HL087710)
- National Institute of Environmental Health Sciences (ES10356, P42ES010356)
- National Center for Research Resources (P51RR000163, K01RR000163, RR-00163.)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Keywords
- prenatal nicotine exposure, maternal smoking, sudden infant death syndrome, rhesus monkeys, serotonin turnover, cardiac norepinephrine, hypoxia response, oxidative stress, vitamin C, perinatal adaptation, cardiac sympathetic innervation
- MeSH terms
- Adaptation, Physiological, Animals, Antioxidants, Ascorbic Acid, Brain Stem, Disease Models, Animal, Female, Fetal Hypoxia, Fetal Heart, Humans, Infant, Newborn, Macaca mulatta, Nicotine, Pregnancy, Prenatal Exposure Delayed Effects, Serotonin, Smoking, Sudden Infant Death, Biogenic Monoamines, Oxidative Stress, Fetal Development
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