Dose-dependent Effects of Adolescent Nicotine Exposure on Cognition in the Adult Female Rat

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NBTS 2011 Abstracts

NBTS P3 Dose-dependent Effects of Adolescent Nicotine Exposure on Cognition in the Adult Female Rat Laura Pickens1, James Rowan2, Rick Bevins3, Stephen Fountain1 Kent State University, Kent, OH, USA 2 Wesleyan College, Macon, GA, USA 3 University of Nebraska Lincoln, Lincoln, NE, USA

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Adolescent nicotine exposure produces impairments in adult sequential learning in male rats (Fountain et al., 2008). Motivated by reports of sex differences in neurophysiology following adolescent nicotine exposure (Trauth et al., 1999) and cognitive function (Trauth et al., 2000; Cheeta, et al., 2001; Slawecki, et al., 2003; Rezvani & Levin, 2004; Smith, et al., 2006; Iniquez, et al., 2009), the current study examined whether similar cognitive impairments would be seen in females. The study included a) females rather than males, b) an additional higher dose, and c) behavioral testing beginning at an earlier age and for a longer period of acquisition. Female Long Evans rats (n = 51; 12-14/group) were exposed to once- or twice-daily i. p. injections of either vehicle or 1.0 mg/kg nicotine on postnatal days 25–59 (P25-P59), but not thereafter. Beginning on P65, adult rats learned a 24-element serial pattern of responses, 123-234-345-456567-678-781-818, for water reinforcement, where digits indicate clockwise positions of correct nosepoke receptacles in an 8-position circular array on successive trials. The sequence was composed of eight 3-element chunks, as in Fountain et al. (2008), but with the addition of an element ending the sequence that violated the otherwise simple pattern structure. For the first element of chunks, twice-daily injection nicotine rats showed impaired learning compared to once-daily injections. For the second two elements of each chunk, twice-daily injection nicotine rats showed a transient impairment in learning compared to once-daily injections and controls. At the last “violation element” of the pattern, both onceand twice-daily nicotine rats showed impaired learning, with twicedaily injection rats performing worse than once-daily injections rats. Taken together, these results demonstrate that adolescent nicotine exposure caused learning impairments and that it impaired different aspects of serial pattern learning differentially. Further, the results demonstrate a dose-dependent impairment for all aspects of the pattern, with rats receiving twice-daily injections (2 mg/kg/day) learning slower than those receiving once-daily injections (1 mg/kg/ day). The results add to evidence that adolescent nicotine exposure is a threat to adult cognitive capacity, demonstrating a new dosedependent effect and suggesting sex differences in comparison to prior work with male rats. doi:10.1016/j.ntt.2011.05.057

NBTS P4 EPA Research on Health Effects of Biofuels: Studies with inhaled ethanol in rats Philip Bushnell, Tracey Beasley, William Boyes, Hisham El-Masri, Paul Evansky, Jermaine Ford, Mary Gilbert, David Herr, William LeFew, Sheppard Martin, Kathy McDaniel, Eva McLanahan, Denise MacMillan, Ginger Moser, Wendy Oshiro U.S. Environmental Protection Agency, Research Triangle Park, NC, USA The Energy Independence and Security Act of 2007 mandates increased use of alternative fuels in the American automobile fleet. Currently, the primary alternative to petroleum fuels is ethanol, and the public health risk associated with adding ethanol to gasoline at concentrations above 10% is uncertain. This research project will

address the potential for neurological and immunological effects from developmental exposure to evaporative emissions from ethanol-gasoline blends. It combines computational modeling and animal experimentation with a goal of estimating the developmental toxicity of inhaled vapors from gasoline blended with any concentration of ethanol. Modeling approaches include PBPK models parameterized for pregnant rats inhaling ethanol and complex mixtures of volatile components of gasoline. The experimental approach involves exposing pregnant female rats to vapors of ethanol and gasoline-ethanol blends from gestational day 9 through 20; quantifying target-tissue doses (concentrations ethanol in blood and brain); and determining relationships between internal dose and effect in their offspring using behavioral, neurophysiological, and immunological assessments. Pilot studies demonstrated that pregnant female Long-Evans rats (N= 8/group) tolerated a high concentration of inhaled ethanol (20,000 ppm, 6 hr/day for 12 days) without apparent distress and delivered viable litters. No significant differences in maternal weight gain, litter size, or offspring brain weight were observed, nor was fear conditioning affected in the pups at postnatal day (PND) 60. However, exposed pups grew more slowly and performed a choice reaction time test less accurately than controls. In a larger study, pregnant rats were exposed under the same scenario to ethanol vapor at concentrations of 0, 5,000, 10,000, and 21,000 ppm (N= 18/group) and successfully delivered litters that did not differ significantly in size or weight. Assessment of offspring from this study is underway. Future studies will compare dose-effect relationships from this exposure to neat ethanol to those from exposure to vapor condensates of gasoline:ethanol blend ratios of 100:0, 85:15 and 15:85. This abstract does not reflect EPA policy. doi:10.1016/j.ntt.2011.05.058

NBTS P5 Latent Effects of In Utero Methanol Exposure on Gonadal and Gamete Morphometrics Function of Adult Macaca fascicularis Eliza Curnow1, Eric Hayes1, Kimberly Grant2, 3, Noelle Liberato1, Thomas Burbacher1, 2 1 Washington National Primate Research Center, University of Washington, Seattle, WA, USA 2 Center on Human Development and Disability, University of Washington, Seattle, WA, USA 3 Department of Environmental and Occupational Health Sciences, School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA The use of methanol (MeOH) as a fuel source for the reduction of hydrocarbon emissions has the potential to result in widespread public exposure to MeOH vapors. The effects of chronic MeOH inhalation on the reproductive and birth outcome of dams and the consequences of fetal methanol exposure (FME) on the post-natal neurodevelopment of M. fascicularis have previously been studied. However, the latent effects of chronic FME (0, 200, 600 and 1800 ppm MeOH) on the subsequent reproductive function of primates are not known. Here we describe preliminary findings on the latent effects of MeOH on gross gonadal morphology and in-vitro gamete function in both male (n = 2-5/group) and female (n = 4-5/group) M. fascicularis. Reproductive tissues (testis, ovaries and uterus) collected at necropsy were weighed prior to retrieval of gametes. For males, sperm concentration, motility, morphology and oocyte activation were assessed. For females, immature oocytes retrieved from ovarian antral follicles were subject to in-vitro maturation (IVM) and assessed for maturity. Serum anti-müllerian hormone (AMH) levels were also used as a surrogate measure of ovarian reserve. There was no significant difference in testis weight between