The exposure of the fetus to nicotine during development has several effects. The most well known result of smoking is low birth weight of the infant. There are also some studies that reveal nicotine as a drug that can affect the brain of the developing fetus. Nicotine also has direct effects on the neurotransmitter systems in the CNS and may cause a decrease in cell growth which could result in mental impairment.
The correlation between maternal smoking and low birth weight has been strongly established. Nicotine affects the placental function by inducing the release of norepinephrine and epinephrine into the maternal blood, which causes decreased blood flow to the placenta (1). The decreased blood flow causes a decrease in delivery of oxygen and nutrients to the fetus. This may have an effect on cell growth and development. High levels of carboxyhemoglobin are present in the blood of the mother and the fetus. This may decrease the capacity of the blood to transport oxygen and fetal hypoxia is the result (2). Fetal hypoxia and ischemia are major contributors to developmental defects, but nicotine has been implicated, in various studies, to have a direct affect on fetal development (3).
Several studies suggest that nicotine interferes with cell acquisition and development in various brain regions. The developing nervous system seems to be more vulnerable to nicotine exposure than the rest of the body (4). This is important since nicotine readily crosses the placental barrier and fetal blood concentrations are equal to or above that of the mother (1). DNA can be used as a index for measuring cell acquisition. An experiment on rats by Lichtensteiger et. al. reported that DNA was reduced in the lower brain and midbrain, but levels were restored by postnatal day 14. However, in the same study, the DNA was still reduced by day 14 in both the cerebral cortex and the cerebellum (1). This indicates that cell acquisition in the cortex and the cerebellum may be impaired by exposure to nicotine.
There is another indicator that may be used to measure the affects of nicotine. The activity of the enzyme ornithine decarboxylase was used by Navarro et. al. to assess the perturbation of cellular development in the fetus exposed to nicotine. Navarro et. al. reported that there were widespread delays in cell maturation expressed as suppressed enzyme activity in the fetus with an increase after birth to compensate (4). Navarro et. al. also suggest that low doses of nicotine may not result in growth retardation, but could still affect neural cell development. Infusion of nicotine was found to cause impairment of cellular development and neurotransmitter systems throughout the central nervous system (4).
In the cholinergic neurotransmitter system, nicotine has been implicated in altering cellular development. The area of the cortex that is sensitive to nicotine has also been shown to be the area where endogenous cholinergic input controls cellular development (3). Nicotine can incoordinate cellular development through the actions it exerts on the nicotinic cholinergic receptors, even at levels that are not usually considered toxic (4). There are several sites in the brain that have nicotinic receptors. The nicotinic receptors are especially abundant in the brainstem during early fetal development (1). Nicotine exposure during fetal life may have various affects on the cholinergic system. In general, the constant levels of nicotine typically cause an up regulation of the nicotinic cholinergic receptors, which increases the number of binding sites (1,4).
Another neurotransmitter system that nicotine affects is the catecholaminergic system. Nicotine can cause blunting of neural activity in catecholaminergic areas in both the central and peripheral nervous system (3). The interactions between nicotine and catecholamine are varied depending upon the stage of development: l) in the early fetus, the brainstem is involved; 2)in the mid-fetal period, the forebrain is involved and; 3)in the later developmental stages the neocortical areas are involved, including the striatum (1). The two main neurotransmitters that are associated with nicotine are norepinephrine and dopamine. Lichtensteiger et. al. found that increased dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid were more prominent in male fetal rats exposed to nicotine. This same study also revealed that increased norepinephrine and 3-methoxy-4-hydrophenylethylene glycol was the result of nicotine exposure in both male and female fetuses (1). These results suggest that catecholaminergic systems have an acute responsiveness to nicotine. The increased levels of both dopamine and norepinephrine could be the result of altering the number of nerve terminals and catecholamine synthesizing enzymes (1).
Since there is a correlation between the cholino-aminergic system and nicotine, nicotine receptors must be present in these areas. Lichtensteiger et. al. demonstrated that nicotine binding sites are detected in the deep neocortex at gestational day 18 in rats; this is two days after the appearance of catecholamine fibers and receptors in this area (1). These results indicate that the nicotine is indeed intimately associated with catecholamine systems. Nicotine binding receptors are found in regions of catecholaminergic nerve cells. The area of the brain known as the substantia nigra has an abundant store of the neurotransmitter dopamine. The substantia nigra has been shown to have catecholamine nerve cell areas which overlap with areas of high density nicotine binding sites (1). The postulate has be made that dopaminergic neurons actually have a receptor site for nicotine, but actual proof is not yet available.
The result of nicotine on the catecholaminergic system in the brain may be associated with minimal brain dysfunction. The brain dysfunction encountered in exposed fetuses is similar in nature to that of attention deficit disorder (ADD). This behavioral abnormality is seen in children whose mothers smoked during pregnancy. One experiment with rats indicated that males were more likely to have increased motor activity and decreased performance when lesions of dopaminergic systems occurred (1). This would be similar to ADD with hyperactivity. Selective lesions of norepinephrine systems resulted in learning deficits without activity changes in both males and females (1). This case would be similar to ADD without hyperactivity. These lesion studies in catecholaminergic systems with outcomes similar to those seen in nicotine studies, indicate that there is a relationship between catecholamines and nicotine.
The effects of maternal smoking on the fetus are still unclear, but the evidence suggests that nicotine is associated with adverse outcomes. These include hypoxia, decreased cell development in the CNS, and alterations in neurotransmitter systems in the brain. The exposure of the fetus to nicotine may also be a factor in increased behavioral abnormalities and spontaneous abortions seen in cases of maternal cigarette smoking. Therefore, pregnant women should be discouraged to smoke since there is some risk to the fetus.
REFERENCES:
1. Lichtensteiger W., U. Ribary, M. Schlumpf, B. Odermatt, H. R. Widmer. (1988) Prenatal adverse effects of nicotine on the developing brain. Progress in Brain Research. 73:137-157.
2. Moore, K. L. The Developing Human: Clinically oriented embryology, 4th edition. Philadelphia PA: W.B. Saunders Co., 1988, p.146.
3.Navarro, H. A., F. J. Seidler, J. P. Eylers, F. E. Baker, S. S. Dobbins, S. E. Lappi, T. A. Slotkin. (1989) Effects of Prenatal Nicotine Exposure on Development of Central and Peripheral Cholinergic Neurotransmitter Systems. Evidence for Cholinergic Trophic Influences in Developing Brain. The Journal of Pharmacology and Experimental Therapeutics, 251(3):894-900.
4. Navarro, H. A., F. J. Seidler, R. D. Schwartz, F. E. Baker, S. S. Dobbins, T. A. Slotkin. (1989) Prenatal Exposure to Nicotine Impairs Nervous System Development at a Dose Which Does Not Affect Viability or Growth. Brain Research Bulletin. 23:187-192.
*Note: there were no new journal articles on this subject. Both the 1991 and 1992 Medline catalogs were searched.