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bioRxiv · 10.1101/193003

Long-term cardiovascular re-programming by short-term perinatal exposure to nicotine‘s main metabolite cotinine

Bastianini, S.·Lo Martire, V.·Silvani, A.·Zoccoli, G.·Berteotti, C.·Lagercrantz, H.·Arner, A.·Cohen, G.
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Abstract

BackgroundCotinine - a nicotine by-product and biomarker of passive perinatal tobacco smoke exposure - is historically considered to lack significant health effects. We challenged this notion and sought \"proof-of-concept\" evidence of the adverse developmental potential of exposure to this substance at real-life levels.\n\nMethodsPregnant C57 mice drank nicotine or cotinine-laced water for 6wks from conception (NPRE = 2% saccharin+100g nicotine/ml; CPRE = 2% saccharin + 10g cotinine/ml) or for 3wks after birth (CPOST = 2% saccharin + 30g cotinine/ml). Controls drank 2% saccharin (CTRL). At 17{+/-}1weeks male pups (CTRL n=6; CPOST n=6; CPRE n=8; NPRE n=9) were instrumented for EEG and blood pressure (BP) telemetry. We evaluated (i) cardiovascular control during sleep (at rest / during stress); (ii) arterial reactivity ex vivo; (iii) expression of genes involved in arterial constriction/dilation.\n\nResultsBlood cotinine levels (ELISA) recapitulated passive smoker mothers-infants. Pups exposed only to cotinine exhibited (i) mild bradycardia - hypotension at rest (p<0.001); (ii) attenuated (CPRE, p<0.0001) or reverse (CPOST; p<0.0001) BP reactivity to asphyxia; (iii) pronounced adrenergic hypo-contractility (p<0.0003), low Protein Kinase C (p<0.001) and elevated adrenergic receptor mRNA (p<0.05) (all drug-treated arteries). NPRE pups also exhibited endothelium-mediated dysfunction.\n\nConclusionsCotinine has subtle, enduring developmental consequences. Some cardiovascular effects of nicotine can plausibly arise via conversion to cotinine. Low-level exposure to this metabolite may pose unrecognized perinatal risks. Adults must avoid inadvertently exposing a fetus or infant to cotinine as well as nicotine.

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Bastianini, S., Lo Martire, V., Silvani, A., Zoccoli, G., Berteotti, C., Lagercrantz, H., Arner, A., Cohen, G.. 2017-09-23. Long-term cardiovascular re-programming by short-term perinatal exposure to nicotine‘s main metabolite cotinine. https://doi.org/10.1101/193003

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