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Long‐term cardiovascular reprogramming by short‐term perinatal exposure to nicotine's main metabolite cotinine
Author(s) -
Bastianini Stefano,
Lo Martire Viviana,
Silvani Alessandro,
Zoccoli Giovanna,
Berteotti Chiara,
Lagercrantz Hugo,
Arner Anders,
Cohen Gary
Publication year - 2018
Publication title -
acta paediatrica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.772
H-Index - 115
eISSN - 1651-2227
pISSN - 0803-5253
DOI - 10.1111/apa.14181
Subject(s) - cotinine , nicotine , medicine , metabolite , endocrinology , gestation , pregnancy , physiology , anesthesia , biology , genetics
Aim Gather ‘proof‐of‐concept’ evidence of the adverse developmental potential of cotinine (a seemingly benign biomarker of recent nicotine/tobacco smoke exposure). Methods Pregnant C57 mice drank nicotine‐ or cotinine‐laced water for 6 wks from conception ( N PRE = 2% saccharin + 100 μ g nicotine/mL; C PRE = 2% saccharin + 10 μ g cotinine/mL) or 3 wks after birth ( C POST = 2% saccharin + 30 μ g cotinine/mL). Controls drank 2% saccharin ( CTRL ). At 17 ± 1 weeks (male pups; CTRL n = 6; C POST n = 6; C PRE n = 8; N PRE n = 9), we assessed (i) cardiovascular control during sleep; (ii) arterial reactivity ex vivo ; and (iii) expression of genes involved in arterial constriction/dilation. Results Blood cotinine levels recapitulated those of passive smoker mothers’ infants. Pups exposed to cotinine exhibited (i) mild bradycardia – hypotension at rest (p < 0.001); (ii) attenuated ( C PRE , p < 0.0001) or reverse ( C POST ; p < 0.0001) BP stress reactivity; (iii) adrenergic hypocontractility (p < 0.0003), low protein kinase C (p < 0.001) and elevated adrenergic receptor mRNA (p < 0.05; all drug‐treated arteries); and (iv) endothelial dysfunction ( N PRE only). Conclusion Cotinine has subtle, enduring developmental consequences. Some cardiovascular effects of nicotine can plausibly arise via conversion into cotinine. Low‐level exposure to this metabolite may pose unrecognised perinatal risks. Adults must avoid inadvertently exposing a foetus or infant to cotinine as well as nicotine.