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

Background Cotinine - 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. Methods Pregnant C57 mice drank nicotine or cotinine-laced water for 6wks from conception (N PRE = 2% saccharin+100μg nicotine/ml; C PRE = 2% saccharin + 10μg cotinine/ml) or for 3wks after birth (C POST = 2% saccharin + 30μg cotinine/ml). Controls drank 2% saccharin (CTRL). At 17±1weeks male pups (CTRL n=6; C POST n=6; C PRE n=8; N PRE 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. Results Blood 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 (C PRE , p<0.0001) or reverse (C POST ; 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). N PRE pups also exhibited endothelium-mediated dysfunction. Conclusions Cotinine 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.