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ScienceWeek
MEDICAL BIOLOGY: CHROMOSOME DAMAGE AND MOTHERS WHO SMOKE
The following points are made by R.A. de la Chica et al (J. Am. Med. Assoc. 2005 293:1212):
1) The long-term public health consequences of regular tobacco consumption include an increased risk of coagulation problems, cancer, cardiovascular disease, chronic obstructive pulmonary disease, and adverse effects on pregnancy. Maternal smoking during pregnancy has many consequences both during and after pregnancy, such as infertility, coagulation problems, obstetric accidents such as extrauterine pregnancy or placenta previa, and intrauterine growth retardation.[1] A relationship between postnatal exposure to tobacco and childhood cancer, especially leukemia and lymphomas, has also been suggested.[2]
2) Tobacco contains a high number of mutagenic compounds.[3] Recently, the presence of tobacco-specific metabolites has been described in fetal blood and cell-free amniotic fluid (transferred from the mother via placenta) and in newborns from women who smoke,[4,5] suggesting a possible genotoxic effect of smoking during pregnancy. However, although many cytogenetic studies have demonstrated the existence of an increased incidence of chromosomal aberrations, sister chromatid exchanges (SCEs), micronuclei, and fragile-site expression in peripheral blood lymphocytes of adult smokers, no data regarding a possible genotoxic effect of tobacco on the embryo and fetus are available. Only indirect data using chorionic villi have been published[1].
3) The authors assessed the possible genotoxic effect of maternal smoking on amniotic fluid cells, based on the presence of an increased chromosomal instability expressed as chromosomal lesions (gaps and breaks) and structural chromosomal abnormalities. The authors also analyze whether any chromosomal regions are especially affected by exposure to tobacco in the fetus. Amniocytes were obtained by routine amniocentesis for prenatal diagnosis from 25 controls and 25 women who smoke (10 cigarettes per day for 10 years). Chromosomal instability was analyzed in blinded fashion by two independent observers in routine chromosome spreads.
4) The authors conclude their findings demonstrate that smoking 10 or more cigarettes per day for at least 10 years and during pregnancy is associated with increased chromosomal instability in amniocytes. Band 11q23, known to be involved in leukemogenesis, seems especially sensitive to genotoxic compounds contained in tobacco.
References (abridged):
1. Vogler GP, Kozlowski LT. Differential influence of maternal smoking on infant birth weight: gene-environment interaction and targeted intervention. JAMA. 2002;287:241-242
2. Ji BT, Shu XO, Linet MS, et al. Paternal cigarette smoking and the risk of childhood cancer among offspring of nonsmoking mothers. J Natl Cancer Inst. 1997;89:238-244
3. Jalili T, Murthy GG, Schiestl RH. Cigarette smoke induces DNA deletions in the mouse embryo. Cancer Res. 1998;58:2633-2638
4. Lackmann GM, Salzberger U, Tollner U, et al. Metabolites of a tobacco-specific carcinogen in urine from newborns. J Natl Cancer Inst. 1999;91:459-465
5. Jauniaux E, Gulbis B, Acharya G, et al. Maternal tobacco exposure and cotinine levels in fetal fluids in the first half of pregnancy. Obstet Gynecol. 1999;93:25-29
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Related Material:
EFFECTS OF MATERNAL CIGARETTE SMOKING
The following points are made by X. Wang et al (J. Am. Med. Assoc. 2002 287:195):
1) In the US, 65 percent of all infant deaths occur among low-birth-weight infants (less than 2500 grams), with such infants accounting for 7.6 percent of all live-born infants. The etiology of low birth weight is largely unknown, but both environmental and genetic factors may play a role. Numerous studies have demonstrated that maternal cigarette smoking during pregnancy is associated with reduced birth weight or increased risk of low birth weight.
2) In 1997, 13.2 percent of US women reported smoking cigarettes during pregnancy. Maternal cigarette smoking is identified as the single largest modifiable risk factor for intrauterine growth restriction in developed countries. However, not all women who smoke cigarettes during pregnancy have low-birth-weight infants. The reason for this variability is largely unknown, but may be related to maternal genetic susceptibility.
3) Tobacco smoke contains approximately 4000 compounds. The most important carcinogens in tobacco smoke are polycyclic aromatic hydrocarbons, arylamines, and N-nitrosamines. The ability of an individual to convert toxic metabolites of cigarette smoke to less harmful moieties is important for minimizing the adverse health effects of these compounds. Using polycyclic aromatic hydrocarbons (PAHs) as an example, the metabolic processing of these compounds in humans involves 2 phases: a) an activation process, in which the inhaled hydrophobic PAHs are converted mainly via aryl hydrocarbon hydroxylase activity into hydrophilic reactive electrophilic intermediates that can bind covalently to macromolecules, especially to DNA. These intermediates may be more toxic than the original form; b) a detoxification process, in which these metabolic intermediates are detoxified by enzymes via transformation into conjugate forms sufficiently polar to be excreted from the body.
4) The authors investigated the correlation between polymorphisms of 2 metabolic genes (CYP1A1 and GSTT1) and the relation between maternal cigarette smoking and infant birth weight. 741 human mothers were involved in the study. The authors report that maternal CYP1A1 and GSTT1 genotypes modified the association between maternal cigarette smoking and infant birth weight, indicating an interaction between metabolic genes and cigarette smoking.
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Related Material:
ON THE TOBACCO INDUSTRY AND NICOTINE AS AN ADDICTIVE DRUG
Notes by ScienceWeek:
In 1994 the state of Minnesota filed suit against the tobacco industry, and although this trial is now history, there are many people who feel the legacy of the trial will carry on into the 21st century because of the revelations contained in the millions of pages of previously secret internal tobacco industry documents made public in the trial.
The following points are made by R.D. Hurt and C.R. Robertson (J. Am. Med. Assoc. 1998 280:1173):
1) The litigation tobacco industry documents reveal that for decades the tobacco industry knew and internally acknowledged that *nicotine is an addictive drug and that cigarettes are the ultimate nicotine delivery device. The following statements by executives, for example, are found in tobacco industry documents: "Very few consumers are aware of the effects of nicotine, i.e., its addictive nature and that nicotine is a poison." (H.D. Steele, Brown and Williamson Tobacco Company, 1978). And in another Brown and Williamson memo: "Nicotine is the addicting agent in cigarettes." (A.J. Mellman, Brown and Williamson Tobacco Company, 1983). Concerning cigarettes as a drug delivery device, the litigation documents reveal that C.E. Teague Jr., assistant director of research at R.J. Reynolds Tobacco Company, wrote in 1972 in an internal memorandum: "In a sense, the tobacco industry may be thought of as being a specialized, highly ritualized and stylized segment of the pharmaceutical industry. Tobacco products, uniquely, contain and deliver nicotine, a potent drug with a variety of physiological effects... Thus a tobacco product is, in essence, a vehicle for delivery of nicotine."
2) The authors report that perhaps their most surprising finding in the document review was the evidence of tobacco industry efforts spanning 3 decades to alter the chemical form of nicotine to increase the percentage of freebase nicotine delivered to smokers. Depending on pH, nicotine exists as a diprotonated salt, a monoprotonated salt, or an uncharged neutral species. The salt forms are called the "bound" forms, and the neutral species is called the "freebase" form. Nicotine favors the salt form at low values of pH (e.g., pH = 3) and the freebase form at high values of pH (e.g., pH = 8). Freebase nicotine apparently crosses biological membranes more easily than the charged counterparts, and this affects the physiological response to the drug.
3) The tobacco industry was apparently well aware of these properties of nicotine as far back as 1966, and for 3 decades the tobacco industry had a focus on developing high pH delivery of nicotine to increase its physiological effects. The authors conclude: "When the breadth and depth of tobacco industry actions are understood, it becomes evident that allowing a tobacco settlement that honors the industry demands for legal and financial immunity would be a public health disaster of epic proportions and would allow the industry to continue to promote its deadly product throughout the 21st century. Congress must use its power to stop the carnage of more than 400,000 Americans dying each year of cigarette-related diseases."
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Notes by ScienceWeek:
nicotine: The alkaloid nicotine [3-(1-methyl-pyrrolidyl)pyridine] is a tertiary amine composed of pyridine and pyrrolidine rings. The current consensus among neuropharmacologists is that nicotine is the psychoactive drug primarily responsible for the addictive nature of tobacco use. Nicotine is highly selective for so-called "nicotinic receptors" for *acetylcholine in the peripheral and central nervous systems, and activation of these receptors is the likely source of the psychoactive effects of the drug. The nicotinic-acetylcholine receptor is a molecularly well-characterized receptor, and its activation evidently leads to conformation changes in its 5 subunits that result in a transient increase of permeability of the neuron membrane to the sodium ion. The nicotinic-acetylcholine receptor is therefore characterized as a neurotransmitter-gated ion channel. Concentrations of nicotine in blood rise quickly during cigarette smoking and peak at its completion.
Nicotine is also deposited in the lungs, spleen, liver, and brain, where concentrations are typically twice those of measurable blood concentrations. Nicotine readily crosses the *blood-brain barrier, leading to the release of acetylcholine, *norepinephrine, *dopamine, *serotonin, *vasopressin, *growth hormone, *cortisol, *prolactin, *neurophysin 1, and *adrenocorticotropic hormone, and release of these substances causes various neuropharmacological effects. Apart from the neuropharmacological effects of nicotine, nicotine and other constituents in cigarette smoke elevate blood pressure, cause *tachycardia, *arrhythmia, and *vasoconstriction in *cutaneous tissue and skin; lower body temperature; inhibit *diuresis; increase *gastrointestinal tonus; antagonize ulcer healing; and decrease pain threshold.
acetylcholine: A prevalent *neurotransmitter substance, both in the brain and in the peripheral nervous system, where it controls the actions of skeletal and smooth muscle.
neurotransmitter substance: Neurotransmitters are chemical substances released at the terminals of nerve axons in response to the propagation of an impulse to the end of that axon. The neurotransmitter substance diffuses into the synapse, the junction between the presynaptic nerve ending and the postsynaptic neuron, and at the membrane of the postsynaptic neuron the transmitter substance interacts with a receptor. Depending on the type of receptor, the result may be an excitatory or an inhibitory effect on the postsynaptic nerve cell.
blood-brain barrier: A selective mechanism opposing the passage of most ions and large molecular-weight compounds from the blood to brain tissue, the mechanism operating in a continuous layer of endothelial cells connected by tight junctions between cells. (Endothelial cells are flat cells forming a layer lining blood vessels, lymphatic vessels, the heart, etc.)
norepinephrine: The principal neurotransmitter substance released from nerve endings of the sympathetic nervous system. (The sympathetic nervous system is a part of the autonomic nervous system involved in the mobilization of energy resources during stress and arousal.
dopamine: A neurotransmitter substance.
serotonin: A neurotransmitter substance involved in nearly everything occurring in the brain, including psychological states such as anxiety and depression, and dysfunctions producing migraine and epilepsy.
vasopressin: A peptide hormone important in the regulation of *diuresis.
growth hormone: A vertebrate polypeptide hormone that regulates growth. In general, hormones are signaling molecules secreted into the blood stream by endocrine cells and acting on target cells that possess receptors for the hormone.
cortisol: A corticosteroid hormone secreted by the adrenal gland.
prolactin: A polypeptide hormone synthesized and released by the pituitary gland.
neurophysin 1: Neurophysins are a family of proteins synthesized in the hypothalamus, and function as carriers in the transport and storage of a number of hypothalamic-pituitary hormones.
adrenocorticotropic hormone: (ACTH) A pituitary hormone.
tachycardia: Rapid beating of the heart, conventionally applied to rates over 100 per minute.
arrhythmia: Irregularity of the heartbeat.
vasoconstriction: Narrowing of the blood vessels.
cutaneous tissue: In general, tissue associated with skin.
diuresis: Excretion of large volumes of urine.
gastrointestinal tonus: In general, contraction of gastrointestinal muscle.
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