Oral Nicotine Alters Uterine Histo-Morphology but Does Not Disrupt the Estrous Cycle in Female Rats.

INTRODUCTION: The primary goal of nicotine replacement therapy (NRT) is to reduce smoking related harms by introducing low nicotine products. In spite of being a potential mode of NRT, there is lack of information on the risks and safety of long term oral nicotine usage on the female reproductive system. METHODS: We evaluated the effects of 30 µg/mL oral nicotine consumption on the estrous cycle, circulating estradiol levels, and uterine and ovarian morphology after 2 or 7 weeks of intake by female Sprague-Dawley rats. RESULTS: Estrous phase frequencies were similar between nicotine treated and control groups throughout the study, no changes were detected in nicotine-treated animals before and during the nicotine exposure period, and circulating estradiol levels were comparable between animals in both groups after 2 weeks of nicotine consumption. Histological examination of uteri from the nicotine group revealed a significant decrease in the height of uterine surface epithelium and an increase in the height of glandular epithelium compared to control animals; yet, the ovaries did not show attrition or changes in follicular appearance due to nicotine. CONCLUSIONS: These preclinical studies suggest that nicotine intake results in structural changes in uterine tissues without disrupting estrous cyclicity or estradiol hormone levels. Though oral nicotine may not be totally risk-free, continuing research on this mode of nicotine administration is worthwhile to determine optimal dosing and duration of consumption for its potential use as an NRT.

The multiple bottle effect is overridden in male and female rats by simultaneous presentation of two oral nicotine solutions.

BACKGROUND: Studies on the oral route of nicotine administration in rodents make important contributions to our understanding of human nicotine use, and alternative approaches to smoking cessation. While environmental availability of oral nicotine contributes to voluntary intake and appears to drive consumption initially, solution concentration may exert more control over intake with continued exposure. Further, it is believed that female rodents consume more nicotine and show greater motivation to obtain it than males. OBJECTIVES: The purpose of our study was to determine voluntary oral nicotine intake patterns following continuous exposure to relatively high concentrations in male and female rats, employing a multiple bottle approach, and to describe the relationship between oral nicotine consumption and sera cotinine. METHODS: Using five bottles, adult Sprague-Dawley rats were given continuous access to water and 15 µg/ml nicotine solutions or water and 15 and 30 µg/ml nicotine solutions for 2 weeks; blood serum was analyzed for cotinine. RESULTS: Rats consistently consumed oral nicotine and female rats ingested more nicotine than males, even at relatively high concentrations. Yet, when both concentrations were presented simultaneously, oral nicotine intake did not exceed that of water, thus overriding an environmental, or multiple-bottle, effect. Cotinine was systemically circulated following first-pass hepatic metabolism of nicotine at early, but not at later stages of nicotine exposure. CONCLUSIONS: Our findings suggest rats will readily and voluntarily ingest considerably higher doses of nicotine than previously reported resulting in initial systemic cotinine, and trends toward sex differences are mitigated by solution concentration.