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Effects of nicotine exposure in utero on brain cell death

Institution: University of California, San Diego
Investigator(s): Jerold Chun, M.D., Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6IT-0239 Award: $74,499
Subject Area: General Biomedical Science
Award Type: Inno Dev & Exp Awards (IDEAS)
Abstracts

Initial Award Abstract
The major addictive component of cigarettes is nicotine. When pregnant mothers smoke cigarettes, they expose not only themselves but also their unborn child to nicotine. Studies on the effects of nicotine exposure during prenatal life have demonstrated both physical changes in the brain as well as behavioral changes in the affected individual after birth. Recent, controlled data from human studies have demonstrated a behavioral association between maternal cigarette smoking, and a high probability that the resultant children would become addicted to cigarette smoking as well. How this form of nicotine addiction comes about is unknown; however, it is likely related to some of the clear changes in the developing brain - both cellular and molecular changes - that have been demonstrated in animal studies where prenatal exposure to nicotine has been followed by anatomical and biochemical analyses.

One of the most striking changes following fetal nicotine exposure in rats is a pronounced reduction in brain weight that corresponds to a reduction in the number of cells in the cerebral cortex. Especially intriguing is the observation of "a large number of electron dense cells" that likely corresponds to dying neurons. Another set of studies has similarly documented decreases in the production of brain cells following prenatal exposure to nicotine.

The vast majority of neurons of the cerebral cortex, and indeed the rest of the brain, are generated before birth. Thus, changes in brain size should be due, at least in part, to alterations in the production of young neurons. The only previously known mechanism for controlling the production of cerebral cortical neurons during embryonic life was cell proliferation. However, our laboratory discovered that, in addition to cell proliferation, programmed cell death or "apoptosis" plays a very significant role in the development of the embryonic brain.

In this proposal, I will test the hypothesis that prenatal nicotine exposure alters the production of neurons by increasing neuronal apoptosis. Another analysis is defining the relationship of apoptosis to the 2 other primary parameters of brain growth: cell proliferation and differentiation. A mouse model will be used, and nicotine at biologically relevant doses will be delivered during gestation. We will initially focus our attention on the cerebral cortex, since that is where quantitative changes have been well documented and where behavior is most likely to arise, and we will examine each day of gestation for cell death, cell proliferation, and cell differentiation. From these analyses, the role of nicotine on the production of central nervous system neurons will be determined, and the result of nicotine exposure on cell death, cell proliferation, and differentiation established towards explaining the phenomenon of nicotine addiction in children exposed to nicotine during prenatal life.

Final Report
The major addictive component of cigarettes is nicotine. When pregnant mothers smoke cigarettes, they expose not only themselves but also their unborn child to nicotine. Studies on the effects of nicotine exposure during prenatal life have demonstrated both physical changes in the brain as well as behavioral changes in the affected individual after birth. Recent, controlled data from human studies have demonstrated a behavioral association between maternal cigarette smoking, and a high probability that the resultant children would become addicted to cigarette smoking as well. How this form of nicotine addiction comes about is unknown; however, it is likely related to some of the clear changes in the developing brain - both cellular and molecular changes - that have been demonstrated in animal studies where prenatal exposure to nicotine has been followed by anatomical and biochemical analyses. One of the most striking changes following fetal nicotine exposure in rats is a pronounced reduction in brain weight that corresponds to a reduction in the number of cells in the cerebral cortex. Especially intriguing is the observation of "a large number of electron dense cells" that likely corresponds to dying neurons. Another set of studies has similarly documented decreases in the production of brain cells following prenatal exposure to nicotine. The vast majority of neurons of the cerebral cortex, and indeed the rest of the brain, are generated before birth. Thus, changes in brain size should be due, at least in part, to alterations in the production of young neurons. The only previously known mechanism for controlling the production of cerebral cortical neurons during embryonic life was cell proliferation. However, our laboratory discovered that, in addition to cell proliferation, programmed cell death or "apoptosis" plays a very significant role in the development of the embryonic brain. In this proposal, I will test the hypothesis that prenatal nicotine exposure alters the production of neurons by increasing neuronal apoptosis. Another analysis is defining the relationship of apoptosis to the 2 other primary parameters of brain growth: cell proliferation and differentiation. A mouse model will be used, and nicotine at biologically relevant doses will be delivered during gestation. We will initially focus our attention on the cerebral cortex, since that is where quantitative changes have been well documented and where behavior is most likely to arise, and we will examine each day of gestation for cell death, cell proliferation, and cell differentiation. From these analyses, the role of nicotine on the production of central nervous system neurons will be determined, and the result of nicotine exposure on cell death, cell proliferation, and differentiation established towards explaining the phenomenon of nicotine addiction in children exposed to nicotine during prenatal life.
Publications

Programmed cell death is a universal feature of neuroproliferative regions throughout the developing CNS
Periodical: Journal of Comparative Neurology Index Medicus:
Authors: Blaschke AJ, Weiner JA, Chun J ART
Yr: 1998 Vol: 396 Nbr: Abs: Pg: 39-50

Onset of apoptotic DNA fragmentation can precede cell elimination by days in the small intestinal villus
Periodical: Cell Death and Differentiation Index Medicus:
Authors: Pompeiano M, Hvala M, Chun J ART
Yr: 1998 Vol: 5 Nbr: Abs: Pg: 702-709