Normal zinc and iron concentrations in mice after early exposure to phenobarbital

Zinc and iron levels were studied in mice with early (pre/neonatal) exposure to phenobarbital, as the levels of these trace metals are known to be correlated with specific behaviors shown in our previous and present experiment to be affected by early phenobarbital administration. Mice were exposed to phenobarbital prenatally or neonatally. At adulthood they showed marked reduction from control in all parameters of eight-arm maze performance (P < 0.001). Since zinc is known to be correlated with this behavior, it was subsequently studied in barbiturate exposed animals. The differences between barbiturate exposed and control offspring for zinc levels in plasma, brain and hippocampus did not reach statistical significance. Our previous studies have shown that the number of dopamine receptors and the resulting apomorphine-induced climbing behavior is altered after early exposure to phenobarbital. The effect of iron level on dopamine receptors is now well established. Subsequently, a group of mice were tested for iron levels in their brain and liver. No significant differences were found.

It is suggested that deficits in the hippocampal behaviors, mainly eight-arm maze, after early exposure to phenobarbital are not related to changes in zinc levels. Similarly, early phenobarbital-induced alternation in dopamine receptors and the resulting dopaminergic behaviors are not related to changes in iron levels.     

Prenatal and postnatal exposure to bisphenol a induces anxiolytic behaviors and cognitive deficits in mice

Bisphenol A (BPA), an environmental endocrine‐disrupting chemical, has been extensively evaluated for reproductive toxicity and carcinogenicity. However, little is known about the behavioral and neurochemical effects of BPA exposure. This study examined whether chronic daily exposure to an environmental endocrine‐disrupting chemical, bisphenol A [(BPA); 100 μg/kg/day or 500 μg/kg/day, p.o.], from prenatal Day 7 to postnatal Day 36 would lead to changes in anxiety and memory in mice. First, we observed the behavioral alterations of BPA‐treated mice using two anxiety‐related models, the open field test and elevated plus maze (EPM) test. In the open field test, BPA treatment (100 μg/kg/day) increased movement in the central zone. BPA treatment (500 μg/kg/day) also increased the time spent in the open arms in the EPM test. Second, we measured cognitive ability in the Y‐maze test and novel object test. BPA‐treated mice showed decreased alternation behavior in the Y‐maze at both of doses, indicating working memory impairment. BPA‐treated mice (100 μg/kg/day) also showed decreased novel object recognition as expressed by central locomotion and frequency in the central zone, showing recognition memory impairment. Finally, to measure changes in the dopaminergic and NMDAergic systems in the brain, we performed autoradiographic receptor binding assays for dopamine D₁ and D₂ receptors, the NMDA receptor, and the dopamine transporter. BPA treatment increased D₂ receptor binding in the caudate putamen (CPu) but decreased DAT binding. BPA treatment also decreased NMDA receptor binding in the frontal cortex and CA1, CA3, and DG of the hippocampus. Taken together, our results suggest that long‐term BPA exposure in mice can induce anxiolytic behaviors, cognitive deficits and changes in the dopaminergic and NMDAergic systems. Synapse 64:432–439, 2010. © 2010 Wiley‐Liss, Inc.     

In utero nicotine exposure causes persistent, gender-dependant changes in locomotor activity and sensitivity to nicotine in C57Bl/6 mice

Maternal cigarette smoking during pregnancy can result in a wide variety of adverse fetal outcomes, ranging from preterm delivery and low birth weight, to sudden infant death syndrome. In addition, in utero tobacco smoke exposure is associated with delayed or impaired neuropsychological development. Although the causative agent in tobacco smoke that leads to these aberrations is not known, some studies have concluded that nicotine may play an important role. Many studies using animal models of prenatal nicotine exposure have supported the hypothesis that nicotine may directly and/or indirectly cause impairments in fetal and neonatal development. However, in many of the animal studies nicotine has been administered acutely to naive dams, which could lead to significant fetal hypoxia; some routes of drug administration are also very stressful to pregnant dams, and changes in stress hormones could also create an unfavorable fetal environment. In this study, pregnant mice were exposed to chronic nicotine via the drinking solution; locomotor activity and sensitivity to nicotine were evaluated in the offspring. We have previously shown that oral nicotine administration produces behavioral and physiological changes that resemble those seen following other routes of nicotine administration. Although oral nicotine exposure did not significantly alter any aspect of the pregnancy, dams drinking a nicotine-containing solution consumed approximately 20% less volume, compared to saccharin controls. All animals were cross fostered to nicotine na?ve lactating dams, immediately after birth. On PN40 and PN60, male mice exposed to in utero nicotine demonstrated significant locomotor hyperactivity in an open filed arena. Although female animals did not show any signs of hyperactivity, they did have a significant attenuation of their hypothermic response to acute nicotine challenge. These results suggest that oral nicotine delivery to pregnant mice causes persistent, gender-dependant changes in behavior and sensitivity to nicotine. This model may be very useful for future studies that try to more accurately define the windows of sensitivity for nicotine exposure and the possible underlying neurochemical mechanisms involved.     

Prenatal exposure to organomercury,thimerosal, persistently impairs the serotonergic and dopaminergic systems in the rat brain: Implications for association with developmental disorders

Thimerosal, an organomercury compound, has been widely used as a preservative. Therefore, concerns have been raised about its neurotoxicity. We recently demonstrated perturbation of early serotonergic development by prenatal exposure to thimerosal (Ida-Eto et al. (2011) [11]). Here, we investigated whether prenatal thimerosal exposure causes persistent impairment after birth. Analysis on postnatal day 50 showed significant increase in hippocampal serotonin following thimerosal administration on embryonic day 9. Furthermore, not only serotonin, striatal dopamine was significantly increased. These results indicate that embryonic exposure to thimerosal produces lasting impairment of brain monoaminergic system, and thus every effort should be made to avoid the use of thimerosal.     

Exposure to nicotine during a defined period in neonatal life induces permanent changes in brain nicotinic receptors and in behaviour of adult mice

Neonatal exposure to low doses of nicotine has been shown to prevent the development of low-affinity nicotine-binding sites, and to elicit a different behaviour response to nicotine in the mice as adults. This study has identified a defined period during the development of neonatal mouse brain for the induction of these permanent changes. Neonatal mice, aged either 3, 10, or 19 days were exposed to nicotine, 66 micrograms nicotine-base/kg b.wt., s.c. twice daily, on 5 consecutive days. In the cerebral cortex, high- and low-affinity (HA and LA) nicotine-binding sites were assayed (3H-nicotine/nicotine) in neonatal male mice aged 8, 15, and 24 days and in adult mice aged 4 months. Spontaneous behaviour and nicotine-induced behaviour were observed in 4-month-old male mice. The spontaneous behaviour test did not indicate any difference between saline- and nicotine-treated mice, whereas the nicotine-induced behaviour test revealed a hypoactive response to nicotine, though only in mice given nicotine on days 10-14. The response of controls and the other age categories to nicotine was an increased activity. At no time during the neonatal period could LA nicotine-binding sites be found following nicotine treatment, but the persistence of this effect was evident only in adult mice exposed on days 10-14.