Harmful effects of nicotine


With the advent of nicotine replacement therapy, the consumption of the nicotine is on the rise. Nicotine is considered to be a safer alternative of tobacco. The IARC monograph has not included nicotine as a carcinogen. However there are various studies which show otherwise. We undertook this review to specifically evaluate the effects of nicotine on the various organ systems. A computer aided search of the Medline and PubMed database was done using a combination of the keywords. All the animal and human studies investigating only the role of nicotine were included. Nicotine poses several health hazards. There is an increased risk of cardiovascular, respiratory, gastrointestinal disorders. There is decreased immune response and it also poses ill impacts on the reproductive health. It affects the cell proliferation, oxidative stress, apoptosis, DNA mutation by various mechanisms which leads to cancer. It also affects the tumor proliferation and metastasis and causes resistance to chemo and radio therapeutic agents. The use of nicotine needs regulation. The sale of nicotine should be under supervision of trained medical personnel.
24 Indian Journal of Medical and Paediatric Oncology | Jan-Mar 2015 | Vol 36 | Issue 1
Harmful effects of nicotine
preparation that deliver around 1 mg and 3 mg nicotine to
the blood stream respectively. E-cigarette, a sophisticated
nicotine delivery device, delivers nicotine in a vapor form
and it closely mimics the act of smoking. Currently, these
products constitute approximately 1% of total nicotine
consumption and are showing an increasing trend in most
Nicotine is well known to have serious systemic side effects
in addition to being highly addictive. It adversely affects the
heart, reproductive system, lung, kidney etc. Many studies
have consistently demonstrated its carcinogenic potential.
[Table 1] The only other known use of nicotine has been
as an insecticide since 17th century.[4] After World War II,
its use has declined owing to the availability of cheaper,
more potent pesticides that are less harmful to mammals.
The environment Protection Agency of United States
has banned use of nicotine as a pesticide from 1st January
2014.[4] India, one of the largest producer and exporter
of nicotine sulphate, has progressively banned its use
as agricultural pesticide.[5] We undertook this review to
evaluate the systemic adverse effects of nicotine.
A computer aided search of the Medline and PubMed
databases was done using different combination of the
keywords “nicotine,” “chemical composition,” “history,”
“metabolism,” “addiction,” “cancer,” “toxic,” “endocrine
system,” “cardiovascular system,” “respiratory system,”
Access this article online
Quick Response Code:
Aseem Mishra,
Pankaj Chaturvedi,
Sourav Datta, Snita Sinukumar,
Poonam Joshi, Apurva Garg
Department of Surgical Oncology,
Head and Neck Services, Tata
Memorial Hospital, Parel, Mumbai,
Maharashtra, India
Address for correspondence:
Dr. Pankaj Chaturvedi,
Professor, Department of
Surgical Oncology, Head and
Neck Services, Tata Memorial
Hospital, Dr. E. Borges Road,
Parel, Mumbai - 400 012,
Maharashtra, India.
With the advent of nicotine replacement therapy, the consumption of the nicotine
is on the rise. Nicotine is considered to be a safer alternative of tobacco. The IARC
monograph has not included nicotine as a carcinogen. However there are various
studies which show otherwise. We undertook this review to specically evaluate the
effects of nicotine on the various organ systems. A computer aided search of the
Medline and PubMed database was done using a combination of the keywords. All
the animal and human studies investigating only the role of nicotine were included.
Nicotine poses several health hazards. There is an increased risk of cardiovascular,
respiratory, gastrointestinal disorders. There is decreased immune response and it also
poses ill impacts on the reproductive health. It affects the cell proliferation, oxidative
stress, apoptosis, DNA mutation by various mechanisms which leads to cancer. It also
affects the tumor proliferation and metastasis and causes resistance to chemo and radio
therapeutic agents. The use of nicotine needs regulation. The sale of nicotine should
be under supervision of trained medical personnel.
Key words: Addiction, cancer, cardiovascular, gastrointestinal, nicotine, respiratory
Tobacco is the leading cause of preventable cancers.
WHO estimated around 1.27 billion tobacco users world-
wide. Tobacco consumption alone accounts for nearly 5.4
million deaths per year and one billion people may die in
this century if global tobacco consumption remained at
the current levels.[1] An international treaty spearheaded
by WHO in 2003 and signed by 170 countries, aims to
encourage governments to reduce the production, sales,
distribution advertisement and promotion of tobacco
products. Despite strong opposition from the Industry,
the treaty has been making steady progress in achieving
its goal of comprehensive tobacco control around the
world.[2] As tobacco consumption is being curbed, there
is a growing demand for cessation. Pharmacological
treatment of nicotine addiction remains an active area of
research. There are many nicotine preparations (nicotine
gums, patches, e cigarettes and inhalational agents) that are
freely available in most parts of the world. These products
are being heavily promoted and marketed as magical
remedies. Nicotine gums are available in 2 mg and 4 mg
[Downloaded free from on Wednesday, September 16, 2015, IP:]
Mishra, et al.: Harmful effects of nicotine
Indian Journal of Medical and Paediatric Oncology | Jan-Mar 2015 | Vol 36 | Issue 1 25
“lung carcinogenesis, “gastrointestinal system,” “immune
system,” “ocular,” “ cataract,” “central nervous system,”
“renal system,” “ reproductive system,” “menstrual cycle,”
“oocytes,” “foetus,”. Initial search buildup was done using
“Nicotine/adverse effects” [Mesh], which showed 3436
articles. Articles were analyzed and 90 relevant articles were
included in the review. All the animal and human studies
that investigated the role of nicotine on organ systems
were analyzed. Studies that evaluated tobacco use and
smoking were excluded. All possible physiological effects
were considered for this review. We did not exclude studies
that reported benecial effects of nicotine. The objective
was to look at the effects of nicotine without confounding
effects of other toxins and carcinogens present in tobacco
or tobacco smoke.
Nicotine was rst extracted from tobacco by German
physicians Wilhelm Heinrich Posselt and Karl Ludwig
Reimann. Nicotine, a strong alkaloid, in its pure form is
a clear liquid with a characteristic odour. It turns brown
on exposure to air. It is water soluble and separates
preferentially from organic solvents. It is an amine
composed of pyridine and pyrrolidine rings.
Nicotine is a dibasic compound and the availability and
absorption in human body depends upon the pH of the
solution.[7] The absorption can occur through oral mucosa,
lungs, skin or gut.[6] The increase in pH of a solution causes
an increase in concentrations of uncharged lipophilic
nicotine, in this form it can actively pass through all
biological membranes.[7] The addition of slaked lime and
catechu to tobacco increases the absorption of nicotine
from the oral cavity.
Nicotine once ingested, is absorbed and metabolized
by the liver. The metabolic process can be categorized
into two phases. In phase I there is microsomal
oxidation of the nicotine via multiple pathways.[8] This
leads to formation of various metabolites like cotinine
and nornicotine, demethyl cotinine, trans-3-hydroxy-
cotinine and d-(3-pyridyl)-g-methylaminobutyric acid.[9,10]
Thereafter in phase II there is N’-and O’-glucuronidation
of the metabolites and excretion via urine, feces, bile,
saliva, sweat etc.[11,12] 5-10% of elimination is by renal
excretion of unchanged nicotine, however there is
reabsorption from the bladder when the urinary pH is
high.[14] There is evidence that nitrosation of nicotine
in vivo could lead to formation of N-nitrosonornicotine
(NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanone (NNK).[13] which are known to be highly
carcinogenic. Inammation in the oral cavity increases
risk of endogenous nitrosation.
Nicotine acts via 3 major mechanisms, producing
physiological and pathological effects on a variety of organ
1. Ganglionic transmission.
2. Nicotinic acetylcholine receptors (nAChRs) on
chromafn cells via catecholamines.
3. Central nervous system (CNS) stimulation of nAChRs.
Brain imaging studies demonstrate that nicotine acutely
increases activity in the prefrontal cortex and visual
systems. There is release of a variety of neurotransmitters
important in drug-induced reward. Nicotine also causes an
increased oxidative stress and neuronal apoptosis, DNA
damage, reactive oxygen species and lipid peroxide increase.
nAChRs were originally thought to be limited to neuronal
cells, however, studies have identied functional nAChRs
in tissues outside the nervous system. Actions on nicotinic
receptors produce a wide variety of acute and long-term
effects on organ systems, cell multiplication and apoptosis,
throughout the body.
Nicotine on direct application in humans causes irritation
and burning sensation in the mouth and throat, increased
salivation, nausea, abdominal pain, vomiting and diarrhea.[17]
Gastrointestinal effects are less severe but can occur even
after cutaneous and respiratory exposure.[18] Predominant
immediate effects as seen in animal studies and in humans
consist of increase in pulse rate and blood pressure.
Nicotine also causes an increase in plasma free fatty
acids, hyperglycemia, and an increase in the level of
catecholamines in the blood.[19,20] There is reduced coronary
blood ow but an increased skeletal muscle blood ow.[20,22]
The increased rate of respiration causes hypothermia, a
Table 1: Studies showing nicotine
as a carcinogen
Author Model System References
Jensen et al., 2012 Animal Gastrointestinal [50]
Schuller et al., 1995 Animal Lung cancer [45]
Nakada et al. 2012 Human Tumor promoter
in lung cancer
Al-Wadei et al., 2009 Mice Pancreatic cancer [56]
Treviño et al., 2012 Animal Pancreatic cancer [58]
Crowley-Weber et al.,
Human Pancreatc cancer [57]
Chen et al., 2011 Human Breast cancer [59]
Wassenaar et al., 2013 Human Lung [44]
[Downloaded free from on Wednesday, September 16, 2015, IP:]
Mishra, et al.: Harmful effects of nicotine
26 Indian Journal of Medical and Paediatric Oncology | Jan-Mar 2015 | Vol 36 | Issue 1
hypercoagulable state, decreases skin temperature, and
increases the blood viscosity.
Nicotine is one of the most toxic of all poisons and has a
rapid onset of action. Apart from local actions, the target
organs are the peripheral and central nervous systems. In
severe poisoning, there are tremors, prostration, cyanosis,
dypnoea, convulsion, progression to collapse and coma.
Even death may occur from paralysis of respiratory muscles
and/or central respiratory failure with a LD50 in adults
of around 30-60 mg of nicotine. In children the LD50 is
around 10 mg.[23]
This is an acute form of nicotine toxicity that is known
to occur due to handling of green tobacco leaves, with
symptoms lasting from 12 to 24 h. The acute symptoms
include headache, nausea, vomiting, giddiness, loss of
appetite, fatigue and tachyarrythmias.[24] No signicant
mortality has been reported due to green tobacco sickness
(GTS) but it signicantly affects the health of workers in
the tobacco industry.[25]
Nicotine is one of the most addicting agent. The US
surgeon general (2010) has concluded nicotine to be as
addictive as cocaine or heroin. Nicotine interacts with
the nicotinic acetyl choline receptors and stimulates the
dopaminergic transmission.[26] This in turn stimulates the
reward centre and is responsible for the mood elevation
and apparent improvement in cognitive function.[27] With
chronic stimulation by nicotine the GABAergic neurons
are desensitized and thus lose their inhibitory effect on
dopamine.[28] This in turn reinforces the addiction by
inducing craving. This effect has been shown to affect
the CYP2A6 gene and leads to heritable dependence to
nicotine. Studies have shown the nicotine dependence to be
transmitted maternally and grand maternally by epigenetic
Nicotine causes catecholamine release and stimulates the
autonomic system. There is increased glycogen synthesis
due to α-adrenoceptor stimulation. This leads to reduction
in the fasting blood glucose levels. It also causes lipolysis
thus decreasing body weight. Nicotine affects insulin
resistance and predisposes to metabolic syndrome. In an
animal study prenatal exposure was toxic to pancreatic
β-cell and leads to decreased B cell population, thus
increasing the risk of diabetes.[30,31]
The stimulation of nAChRs by nicotine has biologic
effects on cells important for initiation and progression of
cancer.[26] It activates signal transduction pathways directly
through receptor-mediated events, allowing the survival of
damaged epithelial cells. In addition, nicotine is a precursor
of tobacco specific nitrosamines (TSNAs), through
nitrosation in the oral cavity.[32,33] It is shown that nitrosation
of nicotine could lead to formation of NNN and NNK.
This effect of nicotine may be important because of its
high concentration in tobacco and nicotine replacement
products.[13] NNN and NNK are strongly carcinogenic.[34]
Nicotine forms arachidonic acid metabolites which cause
increased cell division. Binding to Bcl-2 and action on
vascular endothelial growth factor and cyclooxygenase-2
(COX-2) causes increased cancer proliferation and
survival.[35,36] Promotion of tumor angiogenesis accelerates
tumor growth which is mediated by β-adrenergic activation
and stimulation of nAChRs.[35,37-39] Nicotine also suppresses
apoptosis by phosphorylation mediated extracellular
signal regulated kinases of Bcl-2.[40,41] Recent studies show
that nicotine, activates nuclear factor kappa B (NF-kB)-
dependent survival of cancer cell and proliferation.[42]
In normal cells, nicotine can stimulate properties consistent
with cell transformation and the early stages of cancer
formation, such as increased cell proliferation, decreased
cellular dependence on the extracellular matrix for survival,
and decreased contact inhibition. Thus, the induced
activation of nAChRs in lung and other tissues by nicotine
can promote carcinogenesis by causing DNA mutations[26]
Through its tumor promoter effects, it acts synergistically
with other carcinogens from automobile exhausts or wood
burning and potentially shorten the induction period of
cancers[43] [Table 2].
A study relates lung carcinogenesis by nicotine due to
genetic variation in CYP2B6.[44] Its simultaneous exposure
with hyperoxia has been found to induce cancer in
hamsters.[45] Cotinine has been found to promote lung
tumorigenesis by inhibiting anti-apoptotic pathway.[46]
Nuclear translocation of ARB1 gene by nicotine has
found in proliferation and progression of nonsmall-cell
lung cancer. Several Studies have shown that nicotine
has signicant role in tumor progression and metastasis
via CXCR4 and increased angiogenesis.[36,47] Carriers of
the lung-cancer-susceptibility loci in their DNA extract
more nicotine. Smokers carrying the gene CHRNA3 and
CHRNA5 were found to extract more nicotine and cells
[Downloaded free from on Wednesday, September 16, 2015, IP:]
Mishra, et al.: Harmful effects of nicotine
Indian Journal of Medical and Paediatric Oncology | Jan-Mar 2015 | Vol 36 | Issue 1 27
were thus exposed to a higher internal dose of carcinogenic
nicotine-derived nitrosamines.[48] Additionally modulation
of the mitochondrial signaling pathway leads to resistance
to the chemotherapeutic agents.[49]
The carcinogenic role may be mediated by the MAPK/
COX-2 pathways, α-7 nAchR and β-adrenergic receptor
expression, and mi RNAs α-BTX anatagonist.[50]
Nicotine forms adducts with liver DNA which enhances
its mutagenic potential.[49,51,52] activation of cell-surface
receptors by nicotine stimulates downstream kinases that
can mediate resistance to chemotherapy. It has been shown
by the nding that smokers who continue to smoke during
chemotherapy have a worse prognosis. Moreover they
also have increased toxicity and lower efcacy of chemo
therapeutic drugs.[53] Nicotine affects the periostin gene,
α-7-nAChR and e-cadherin suppression which explains
the mechanism of gastric cancer growth, invasion and
metastasis.[54,55] Nicotine negatively impacts tumor biology
by promoting angiogenesis, tumor invasion and increased
risk of metastasis.[53]
Nicotine has been found to induce pancreatic
adenocarcinoma in mice model, by stimulating the stress
neurotransmitters.[56,57] In another study nicotine promoted
the growth of nonsmall cell lung cancer and pancreatic
cancer in a receptor dependent fashion. It also increased
tumor metastasis, and resistance to gemcitabine induced
apoptosis, causing chemoresistance.[58] The MUC-4
upregulation, NF-kB and GRP78 activation and Id1
expression by Src dependent manner are the probable
mechanism leading to tumor growth, metastasis and
chemotherapeutic drug resistance.[57,58]
Nicotine causes α9-nAChR-mediated cyclin D3
overexpression which might cause transformation of
normal breast epithelial cells and induce cancer. Nicotine
and cotinine has been found to be present in the breast
uid of lactating women.[59] Several studies have found
that α9-nAChR mediated mechanism leads to increased
tumor growth, metastasis and tumor cells resistant to
chemotherapeutic drugs in breast cancer.[59,60]
The acute hemodynamic effects of cigarette smoking
or smokeless tobacco are mediated primarily by
the sympathomimetic action. The intensity of its
hemodynamic effect is greater with rapid nicotine
delivery.[61] Nicotine causes catecholamine release both
locally and systemically leading to an increase in heart
rate, blood pressure and cardiac contractility. It reduces
blood ow in cutaneous and coronary vessels; and
increases blood ow in the skeletal muscles. Due to
restricted myocardial oxygen delivery there is reduced
cardiac work. In a study, chewing a low dose (4 mg)
of nicotine gum by healthy nonsmokers blunted the
increase in coronary blood flow that occurs with
increased heart rate produced by cardiac pacing.[21]
Thus, persistent stimulation by nicotine can contribute
to Coronary Vascular Disease by producing acute
myocardial ischemia. In the presence of coronary
disease, myocardial dysfunction can be worsened. In a
placebo-controlled experiment that produced transient
ischemia in anesthetized dogs myocardial dysfunction
was produced at doses, that did not alter heart rate,
blood pressure, or blood ow or myocyte necrosis.[62]
Nicotine alters the structural and functional characteristics of
vascular smooth muscle and endothelial cells.[63] It enhances
release of the basic broblast growth factor and inhibits
production of transforming growth factor-β1.[64] These
effects lead to increased DNA synthesis, mitogenic activity,
endothelial proliferation and increases atherosclerotic
plaque formation.[65] Neovascularization stimulated
by nicotine can help progression of atherosclerotic
plaques.[66] These effects lead to myointimal thickening and
atherogenic and ischemic changes, increasing the incidence
of hypertension and cardiovascular disorders. A study on
Table 2: Studies showing the role of nicotine
as tumor promoter
Author System References
Chu et al., 2013 Gastrointestinal
tumor growth
Improgo et al., 2013 Lung [47]
Heusch and Maneckjee, 1998 Lung [40]
Mai et al., 2003 Lung [41]
Shin et al., 2005 Gastric [36]
Heeschen et al., 2001 Tumor growth and
Zhu et al., 2003 Tumor angiogenesis
and growth
Heusch and Maneckjee, 1998 Lung [40]
Le Marchand et al., 2008 Lung [48]
Perez-Sayans et al., 2010 GIT [51]
Zhang et al., 2010 GIT [49]
Petros et al., 2012 Chemoresistance [53]
Trevino et al., 2012 Tumor growth and
GIT – Gastrointestinal tract
[Downloaded free from on Wednesday, September 16, 2015, IP:]
Mishra, et al.: Harmful effects of nicotine
28 Indian Journal of Medical and Paediatric Oncology | Jan-Mar 2015 | Vol 36 | Issue 1
dogs demonstrated the deleterious effects of nicotine on
the heart.[67]
Nicotinic acetylcholine receptor’s actions on vascular
smooth muscle proliferation and plaque neovascularization
increases the risk of peripheral arterial disorders. In a
murine model of hind limb ischemia, short-term exposure
to nicotine paradoxically increased capillary density and
improved regional blood ow in the ischemic hind limb.
[35] However, long-term exposure to nicotine for 16 weeks
(about one-third of the life span of a mouse) before
induction of ischemia obliterated angiogenic response to
The effects of nicotine on respiratory system are twofold.
One, directly by a local exposure of lungs to nicotine
through smoking or inhaled nicotine, and second via
a central nervous system mechanism. Nicotine plays a
role in the development of emphysema in smokers, by
decreasing elastin in the lung parenchyma and increasing
the alveolar volume. Nicotine stimulates vagal reex
and parasympathetic ganglia and causes an increased
airway resistance by causing bronchoconstriction.[69]
Nicotine alters respiration through its effects on the
CNS. The simultaneous effect of bronchoconstriction
and apnea increases the tracheal tension and causes
several respiratory disorders. In a study microinjection
of nicotine were administered to the prebotzinger
complex and adjacent nuclei in the brain. The ring
pattern of the brain signals and breathing pattern were
monitored. There was an increased frequency of bursts
and decreased amplitude and a shallow and rapid rhythm
of respiration.[70]
Nicotine use has been associated with Gastro Esophageal
Reux Disorder (GERD) and peptic ulcer disease (PUD).
[36,71] This effect is mediated by increased gastric acid,
pepsinogen secretion and stimulatory effects on vasopressin.
The action on the cyclo-oxygenase pathway also increases
the risk of GERD and PUD.[72] Nicotine causes smooth
muscle relaxation by action of endogenous nitric oxide
as a nonadrenergic noncholinergic neurotransmitter.[73]
The decrease in tone of the colon and gastric motility and
reduced lower esophageal sphincteric pressure might be
the reason of increased incidence of GERD.[74]
There is an increased incidence of treatment resistant
Helicobacter pylori infection in smokers. It potentiates the
effects of toxins of H. pylori by its action on the gastric
parietal cells.[75] This effect could be due to histamine
mediated response of nicotine.
Nicotine has been known to be immunosuppressive through
central and peripheral mechanisms. It impairs antigen and
receptor mediated signal transduction in the lymphoid
system leading to decreased immunological response. The
T-cell population is reduced due to arrest of cell cycle.
Even the macrophage response, which forms the rst
line defense against tuberculosis becomes dysfunctional
and causes increased incidence of tuberculosis.[76] The
migration of broblasts and inammatory cells to the
inamed site is reduced. There is decreased epithelialization
and cell adhesion and thus there is a delayed wound healing
as well as increased risk of infection in nicotine exposed
The action on the hypothalamo-pituitary adrenal axis and
autonomic nervous system stimulation via sympathetic and
parasympathetic pathways affects the immune system. The
adrenocorticotropic hormone (ACTH) secretion pathway
and corticotrophin release is affected and this causes
Nicotine promotes pathologic angiogenesis and retinal
neovascularization in murine models. It causes age-related
macular degeneration in mice.[78] In a clinical study, the
most virulent form of age-related maculopathy was
associated with retinal neovascularization that contributed
to visual deterioration. Tobacco smokers are known to be
at greater risk of age-related macular degeneration than
are nonsmokers.[79] In animal model, spraguely Dawley
rats with type 1 diabetes treated with nicotine, developed
cataract.[80] Thus the syngergistic relationship between
nicotine and glucose metabolism exaggerating diabetes
might cause accelerated cataract formation. There is
synergistic relationship between nicotine and glucose
metabolism which increases the risk of diabetes mellitus.
This might cause accelerated cataract formation.
Risk of chronic kidney disease in smokers is high. Cigarette
smoking has been found to increase albumin excretion in
urine, decrease glomerular ltration rate, causes increased
incidence of renal artery stenosis and is associated with an
increased mortality in patients with end-stage renal disease.
The pathogenesis of renal effects is due to the action
of nicotine via COX-2 isoform induction. The COX-2
[Downloaded free from on Wednesday, September 16, 2015, IP:]
Mishra, et al.: Harmful effects of nicotine
Indian Journal of Medical and Paediatric Oncology | Jan-Mar 2015 | Vol 36 | Issue 1 29
isoforms causes increased glomerular inammation, acute
glomerulonephritis and ureteral obstruction.[81] There is
impaired response of kidneys to the increased systemic
blood pressure in smokers. This loss of renoprotective
mechanism in smokers also leads to pathogenetic effects
of nicotine on the renal system.[82]
Nitrous oxide liberated from parasympathetico-nergic
nerves plays a pivotal role in generating immediate penile
vasodilatation and corpus cavernosum relaxation, and NO
derived from endothelial cells contributes to maintaining
penile erection. Nicotine causes impairment of NO
synthesis. This may lead to loss of penile erections and
erectile dysfunction.[83]
Various animal studies suggest that nicotine causes
seminiferous tubules degeneration, disrupts the
spermatogenesis and at cellular level, affect germ cell
structure and function in males.[84] It decreases testosterone
levels which is secondary to decreased production of
StAR.[85] StAR is the protein which plays an important role
in testosterone biosynthesis.
Menstrual cycle
Nicotine by inhibiting the 21 hydoxylase causes
hypoestrogenic state. It shunts the metabolites to
formation of androgen. This leads to chronic anovulation
and irregular menstrual cycles. Nicotine can predispose
the endometrium to inappropriate cytokine production
and irregular bleeding.[86] There is consistent evidence
that increase in follicle-stimulating hormone levels
and decreases in estrogen and progesterone that are
associated with cigarette smoking in women, is atleast in
part due to effects of nicotine on the endocrine system.[26]
Effect on oocytes
Nicotine affects the ovaries and alters the production of
oocytes in various animal studies. Nicotine-treated oocytes
appeared nonspherical with rough surface and torn and
irregular zona-pellucida. Nicotine also caused disturbed
oocyte maturation. There is a decreased blood ow to the
oviducts and thus impaired fertilization.[87]
Peri-natal effects
Maternal smoking has always been known to have
deleterious effects on the fetal outcome. There is an
increased incidence of intrauterine growth restriction,
still birth, miscarriages and mental retardation.[88] Various
animal studies show retarded fetal growth and lower birth
weight when treated perinatally with nicotine. The lower
levels of ACTH and cortisol due to nicotine are probable
reasons for the incidence of lower birth weight in the
Maternal as well as grand maternal smoking has been found
to increase risk of pediatric asthma. Another serious and
important effect is the transgenic transmission of the
addictive pattern.[29]
Nicotine is the fundamental cause of addiction among
tobacco users. Nicotine adversely affects many organs as
shown in human and animal studies. Its biological effects
are widespread and extend to all systems of the body
including cardiovascular, respiratory, renal and reproductive
systems. Nicotine has also been found to be carcinogenic
in several studies. It promotes tumorigenesis by affecting
cell proliferation, angiogenesis and apoptotic pathways. It
causes resistance to the chemotherapeutic agents. Nicotine
replacement therapy (NRT) is an effective adjunct in
management of withdrawal symptoms and improves the
success of cessation programs. Any substantive benecial
effect of nicotine on human body is yet to be proven.
Nicotine should be used only under supervision of trained
cessation personnel therefore its sale needs to be strictly
regulated. Needless to say, that research for safer alternative
to nicotine must be taken on priority.
1. WHO Data. Tobacco Fact Sheet; No. 339. Available from: [Last
accessed on 2015 Jan 29].
2. WHO Framework Convention on Tobacco Control. Available
from: [Last accessed on
2014 Sep 27].
3. Fagerström K. The nicotine market: An attempt to estimate
the nicotine intake from various sources and the total
nicotine consumption in some countries. Nicotine Tob Res
4. US Environmental Protection Agency. Nicotine: Product
cancellation order.Fed Regist 2009 Available from: http://
p12561.htm [Last accessed 2014 Nov 01].
5. APIB. Banned Pesticides. Available from: http://megapib.nic.
in/Int_pest_bannedPest.htm. [Last updated on 2002 Mar 25;
Last accessed on 2014 Sep 27].
6. Langone JJ, Gjika HB, Van Vunakis H. Nicotine and its
metabolites. Radioimmunoassays for nicotine and cotinine.
Biochemistry 1973;12:5025-30.
7. Schievelbein H, Eberhardt R, Löschenkohl K, Rahlfs V, Bedall FK.
Absorption of nicotine through the oral mucosa I. Measurement
of nicotine concentration in the blood after application of nicotine
and total particulate matter. Inamm Res 1973;3:254-8.
8. Armitage AK, Turner DM. Absorption of nicotine in
cigarette and cigar smoke through the oral mucosa. Nature
[Downloaded free from on Wednesday, September 16, 2015, IP:]
Mishra, et al.: Harmful effects of nicotine
30 Indian Journal of Medical and Paediatric Oncology | Jan-Mar 2015 | Vol 36 | Issue 1
9. Sobkowiak R, Lesicki A. Absorption, metabolism and excretion
of nicotine in humans. Postepy Biochem 2013;59:33-44.
10. Dempsey D, Tutka P, Jacob P 3rd, Allen F, Schoedel K,
Tyndale RF, et al. Nicotine metabolite ratio as an index of
cytochrome P450 2A6 metabolic activity. Clin Pharmacol
Ther 2004;76:64-72.
11. Nakajima M, Tanaka E, Kwon JT, Yokoi T. Characterization
of nicotine and cotinine N-glucuronidations in human liver
microsomes. Drug Metab Dispos 2002;30:1484-90.
12. Seaton MJ, Kyerematen GA, Vesell ES. Rates of excretion
of cotinine, nicotine glucuronide, and 3-hydroxycotinine
glucuronide in rat bile. Drug Metab Dispos 1993;21:927-32.
13. Stepanov I, Carmella SG, Briggs A, Hertsgaard L, Lindgren B,
Hatsukami D, et al. Presence of the carcinogen N’-
nitrosonornicotine in the urine of some users of oral nicotine
replacement therapy products. Cancer Res 2009;69: 8236-40.
14. Borzelleca JF. Drug movement from the isolated urinary
bladder of the rabbit. Arch Int Pharmacodyn Ther
15. Dani JA, Ji D, Zhou FM. Synaptic plasticity and nicotine
addiction. Neuron 2001;31:349-52.
16. Jones S, Sudweeks S, Yakel JL. Nicotinic receptors in the
brain: Correlating physiology with function. Trends Neurosci
17. Smith EW, Smith KA, Maibach HI, Andersson PO, Cleary G,
Wilson D. The local side effects of transdermally absorbed
nicotine. Skin Pharmacol 1992;5:69-76.
18. Sonnenberg A, Hüsmert N. Effect of nicotine on gastric
mucosal blood ow and acid secretion. Gut 1982;23:532-5.
19. Benowitz NL. Nicotine and smokeless tobacco. CA Cancer J
Clin 1988;38:244-7.
20. Dani JA, Heinemann S. Molecular and cellular aspects of
nicotine abuse. Neuron 1996;16:905-8.
21. Kaijser L, Berglund B. Effect of nicotine on coronary blood-
ow in man. Clin Physiol 1985;5:541-52.
22. Jolma CD, Samson RA, Klewer SE, Donnerstein RL,
Goldberg SJ. Acute cardiac effects of nicotine in healthy
young adults. Echocardiography 2002;19:443-8.
23. Centre for Disease Control and Prevention. Available from: [Last accessed
on 2014 Sep 27].
24. Parikh JR, Gokani VN, Doctor PB, Kulkarni PK, Shah AR, Saiyed
HN. Acute and chronic health effects due to green tobacco
exposure in agricultural workers. Am J Ind Med 2005;47:494-9.
25. Weizenecker R, Deal WB. Tobacco cropper’s sickness. J Fla
Med Assoc 1970;57:13-4.
26. US Department of Health and Human Services. Mental
Health. Available from:
MHUS2010/MHUS-2010.pdf. [Last accessed on 2014 Sep 27].
27. Mansvelder HD, McGehee DS. Cellular and synaptic mechanisms
of nicotine addiction. J Neurobiol 2002;53:606-17.
28. Vezina P, McGehee DS, Green WN. Exposure to nicotine
and sensitization of nicotine-induced behaviors. Prog
Neuropsychopharmacol Biol Psychiatry 2007;31:1625-38.
29. Leslie FM. Multigenerational epigenetic effects of nicotine on
lung function. BMC Med 2013;11:27.
30. Bruin JE, Kellenberger LD, Gerstein HC, Morrison KM,
Holloway AC. Fetal and neonatal nicotine exposure and
postnatal glucose homeostasis: Identifying critical windows
of exposure. J Endocrinol 2007;194:171-8.
31. Somm E, Schwitzgebel VM, Vauthay DM, Camm EJ,
Chen CY, Giacobino JP, et al. Prenatal nicotine exposure
alters early pancreatic islet and adipose tissue development
with consequences on the control of body weight and glucose
metabolism later in life. Endocrinology 2008;149:6289-99.
32. IARC Working Group on the Evaluation of Carcinogenic Risks
to Humans. Tobacco smoke and involuntary smoking. IARC
Monogr Eval Carcinog Risks Hum 2004;83:1-1438.
33. Hoffmann D, Adams JD. Carcinogenic tobacco-specic
N-nitrosamines in snuff and in the saliva of snuff dippers.
Cancer Res 1981;41(11 Pt 1):4305-8.
34. International Agency for Research on Cancer. Tobacco
smoke and involuntary smoking. IARC Monogr Eval Carcinog
Risk Hum 2007;89:455-7.
35. Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, et al.
Nicotine stimulates angiogenesis and promotes tumor growth
and atherosclerosis. Nat Med 2001;7:833-9.
36. Shin VY, Wu WK, Chu KM, Wong HP, Lam EK, Tai EK, et al.
Nicotine induces cyclooxygenase-2 and vascular endothelial
growth factor receptor-2 in association with tumor-associated
invasion and angiogenesis in gastric cancer. Mol Cancer Res
37. Natori T, Sata M, Washida M, Hirata Y, Nagai R, Makuuchi M.
Nicotine enhances neovascularization and promotes tumor
growth. Mol Cells 2003;16:143-6.
38. Wong HP, Yu L, Lam EK, Tai EK, Wu WK, Cho CH. Nicotine
promotes colon tumor growth and angiogenesis through
beta-adrenergic activation. Toxicol Sci 2007;97:279-87.
39. Zhu BQ, Heeschen C, Sievers RE, Karliner JS, Parmley WW,
Glantz SA, et al. Second hand smoke stimulates tumor
angiogenesis and growth. Cancer Cell 2003;4:191-6.
40. Heusch WL, Maneckjee R. Signalling pathways involved in
nicotine regulation of apoptosis of human lung cancer cells.
Carcinogenesis 1998;19:551-6.
41. Mai H, May WS, Gao F, Jin Z, Deng X. A functional role
for nicotine in Bcl2 phosphorylation and suppression of
apoptosis. J Biol Chem 2003;278:1886-91.
42. Tsurutani J, Castillo SS, Brognard J, Granville CA, Zhang C,
Gills JJ, et al. Tobacco components stimulate Akt-dependent
proliferation and NFkappaB-dependent survival in lung cancer
cells. Carcinogenesis 2005;26:1182-95.
43. Slotkin TA, Seidler FJ, Spindel ER. Prenatal nicotine exposure
in rhesus monkeys compromises development of brainstem
and cardiac monoamine pathways involved in perinatal
adaptation and sudden infant death syndrome: Amelioration
by vitamin C. Neurotoxicol Teratol 2011;33:431-4.
44. Wassenaar CA, Dong Q, Amos CI, Spitz MR, Tyndale RF. Pilot
study of CYP2B6 genetic variation to explore the contribution
of nitrosamine activation to lung carcinogenesis. Int J Mol Sci
45. Schuller HM, McGavin MD, Orloff M, Riechert A, Porter B.
Simultaneous exposure to nicotine and hyperoxia causes
tumors in hamsters. Lab Invest 1995;73:448-56.
46. Nakada T, Kiyotani K, Iwano S, Uno T, Yokohira M, Yamakawa K,
et al. Lung tumorigenesis promoted by anti-apoptotic effects
of cotinine, a nicotine metabolite through activation of PI3K/
Akt pathway. J Toxicol Sci 2012;37: 555-63.
47. Improgo MR, Soll LG, Tapper AR, Gardner PD. Nicotinic
acetylcholine receptors mediate lung cancer growth. Front
Physiol 2013;4:251.
48. Le Marchand L, Derby KS, Murphy SE, Hecht SS,
Hatsukami D, Carmella SG, et al. Smokers with the CHRNA
lung cancer-associated variants are exposed to higher levels
of nicotine equivalents and a carcinogenic tobacco-specic
nitrosamine. Cancer Res 2008;68:9137-40.
49. Zhang D, Ma QY, Hu HT, Zhang M. β2-adrenergic antagonists
suppress pancreatic cancer cell invasion by inhibiting CREB,
NFκB and AP-1. Cancer Biol Ther 2010;10:19-29.
50. Jensen K, Afroze S, Munshi MK, Guerrier M, Glaser SS.
Mechanisms for nicotine in the development and progression
of gastrointestinal cancers. Transl Gastrointest Cancer
51. Pérez-Sayáns M, Somoza-Martín JM, Barros-Angueira F,
Diz PG, Gándara Rey JM, García-García A. Beta-adrenergic
receptors in cancer: Therapeutic implications. Oncol Res
52. Majidi M, Al-Wadei HA, Takahashi T, Schuller HM.
Nongenomic beta estrogen receptors enhance beta1
adrenergic signaling induced by the nicotine-derived
carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
[Downloaded free from on Wednesday, September 16, 2015, IP:]
Mishra, et al.: Harmful effects of nicotine
Indian Journal of Medical and Paediatric Oncology | Jan-Mar 2015 | Vol 36 | Issue 1 31
in human small airway epithelial cells. Cancer Res
53. Petros WP, Younis IR, Ford JN, Weed SA. Effects of tobacco
smoking and nicotine on cancer treatment. Pharmacotherapy
54. Liu Y, Liu BA. Enhanced proliferation, invasion, and epithelial-
mesenchymal transition of nicotine-promoted gastric cancer
by periostin. World J Gastroenterol 2011;17:2674-80.
55. Lien YC, Wang W, Kuo LJ, Liu JJ, Wei PL, Ho YS, et al.
Nicotine promotes cell migration through alpha7 nicotinic
acetylcholine receptor in gastric cancer cells. Ann Surg Oncol
56. Al-Wadei HA, Plummer HK 3rd, Schuller HM. Nicotine
stimulates pancreatic cancer xenografts by systemic increase
in stress neurotransmitters and suppression of the inhibitory
neurotransmitter gamma-aminobutyric acid. Carcinogenesis
57. Crowley-Weber CL, Dvorakova K, Crowley C, Bernstein H,
Bernstein C, Garewal H, et al. Nicotine increases oxidative
stress, activates NF-κB and GRP78, induces apoptosis
and sensitizes cells to genotoxic/xenobiotic stresses by a
multiple stress inducer, deoxycholate: Relevance to colon
carcinogenesis. Chem Biol Interact 2003;145:53-66.
58. Treviño JG, Pillai S, Kunigal S, Singh S, Fulp WJ, Centeno BA,
et al. Nicotine induces inhibitor of differentiation-1 in a Src-
dependent pathway promoting metastasis and chemoresistance
in pancreatic adenocarcinoma. Neoplasia 2012;14:1102-14.
59. Chen CS, Lee CH, Hsieh CD, Ho CT, Pan MH, Huang CS,
et al. Nicotine-induced human breast cancer cell proliferation
attenuated by garcinol through down-regulation of the
nicotinic receptor and cyclin D3 proteins. Breast Cancer Res
Treat 2011;125:73-87.
60. Nishioka T, Kim HS, Luo LY, Huang Y, Guo J, Chen CY.
Sensitization of epithelial growth factor receptors by nicotine
exposure to promote breast cancer cell growth. Breast
Cancer Res 2011;13:R113.
61. Porchet HC, Benowitz NL, Sheiner LB, Copeland JR. Apparent
tolerance to the acute effect of nicotine results in part from
distribution kinetics. J Clin Invest 1987;80:1466-71.
62. Przyklenk K. Nicotine exacerbates postischemic contractile
dysfunction of ‘stunned’ myocardium in the canine model.
Possible role of free radicals. Circulation 1994;89:1272-81.
63. Csonka E, Somogyi A, Augustin J, Haberbosch W,
Schettler G, Jellinek H. The effect of nicotine on cultured cells
of vascular origin. Virchows Arch A Pathol Anat Histopathol
64. Villablanca AC. Nicotine stimulates DNA synthesis and
proliferation in vascular endothelial cells in vitro. J Appl
Physiol. 1998;84:2089-98.
65. Chalon S, Moreno H Jr, Benowitz NL, Hoffman BB, Blaschke TF.
Nicotine impairs endothelium-dependent dilatation in human
veins in vivo. Clin Pharmacol Ther 2000;67:391-7.
66. Lee J, Cooke JP. The role of nicotine in the pathogenesis of
atherosclerosis. Atherosclerosis 2011;215:281-3.
67. Sridharan MR, Flowers NC, Hand RC, Hand JW, Horan LG.
Effect of various regimens of chronic and acute nicotine
exposure on myocardial infarct size in the dog. Am J Cardiol
68. Konishi H, Wu J, Cooke JP. Chronic exposure to nicotine
impairs cholinergic angiogenesis. Vasc Med 2010;15:47-54.
69. Beck ER, Taylor RF, Lee LY, Frazier DT. Bronchoconstriction
and apnea induced by cigarette smoke: Nicotine dose
dependence. Lung 1986;164:293-301.
70. Jaiswal SJ, Pilarski JQ, Harrison CM, Fregosi RF. Developmental
nicotine exposure alters AMPA neurotransmission in the
hypoglossal motor nucleus and pre-Botzinger complex of
neonatal rats. J Neurosci 2013;33:2616-25.
71. Chu KM, Cho CH, Shin VY. Nicotine and gastrointestinal
disorders: Its role in ulceration and cancer development. Curr
Pharm Des 2013;19:5-10.
72. Ogle CW, Qiu BS, Cho CH. Nicotine and gastric ulcers in
stress. J Physiol Paris 1993;87:359-65.
73. Irie K, Muraki T, Furukawa K, Nomoto T. L-NG-nitro-arginine
inhibits nicotine-induced relaxation of isolated rat duodenum.
Eur J Pharmacol 1991;202:285-8.
74. Kadakia SC, De La Baume HR, Shaffer RT. Effects of
transdermal nicotine on lower esophageal sphincter and
esophageal motility. Dig Dis Sci 1996;41:2130-4.
75. Endoh K, Leung FW. Effects of smoking and nicotine on
the gastric mucosa: A review of clinical and experimental
evidence. Gastroenterology 1994;107:864-78.
76. Geng Y, Savage SM, Johnson LJ, Seagrave J, Sopori ML.
Effects of nicotine on the immune response. I. Chronic
exposure to nicotine impairs antigen receptor-mediated
signal transduction in lymphocytes. Toxicol Appl Pharmacol
77. Sopori ML, Kozak W, Savage SM, Geng Y, Soszynski D,
Kluger MJ, et al. Effect of nicotine on the immune system:
Possible regulation of immune responses by central and peripheral
mechanisms. Psychoneuroendocrinology 1998;23:189-204.
78. Suñer IJ, Espinosa-Heidmann DG, Marin-Castano ME,
Hernandez EP, Pereira-Simon S, Cousins SW. Nicotine increases
size and severity of experimental choroidal neovascularization.
Invest Ophthalmol Vis Sci 2004;45:311-7.
79. Seddon JM, Willett WC, Speizer FE, Hankinson SE. A
prospective study of cigarette smoking and age-related
macular degeneration in women. JAMA 1996;276:1141-6.
80. Tirgan N, Kulp GA, Gupta P, Boretsky A, Wiraszka TA,
Godley B, et al. Nicotine exposure exacerbates development
of cataracts in a type 1 diabetic rat model. Exp Diabetes Res
81. Jaimes EA, Tian RX, Joshi MS, Raij L. Nicotine augments
glomerular injury in a rat model of acute nephritis. Am J
Nephrol 2009;29:319-26.
82. Halimi JM, Philippon C, Mimran A. Contrasting renal effects
of nicotine in smokers and non-smokers. Nephrol Dial
Transplant 1998;13:940-4.
83. Xie Y, Garban H, Ng C, Rajfer J, Gonzalez-Cadavid NF. Effect
of long-term passive smoking on erectile function and penile
nitric oxide synthase in the rat. J Urol 1997;157:1121-6.
84. Jana K, Samanta PK, De DK. Nicotine diminishes testicular
gametogenesis, steroidogenesis, and steroidogenic acute
regulatory protein expression in adult albino rats: Possible
inuence on pituitary gonadotropins and alteration of
testicular antioxidant status. Toxicol Sci 2010;116:647-59.
85. Oyeyipo IP, Raji Y, Bolarinwa AF. Nicotine alters male
reproductive hormones in male albino rats: The role of
cessation. J Hum Reprod Sci 2013;6:40-4.
86. Jin Z, Roomans GM. Effects of nicotine on the uterine
epithelium studied by X-ray microanalysis. J Submicrosc
Cytol Pathol 1997;29:179-86.
87. Hammer RE, Mitchell JA, Goldman H. Effects of nicotine on
concept us cell proliferation and oviductal/uterine blood ow
in the rat. In: Cellular and Molecular Aspects of Implantation.
US: Springer; 1981. p. 439-42.
88. Chen M, Wang T, Liao ZX, Pan XL, Feng YH, Wang H.
Nicotine-induced prenatal overexposure to maternal
glucocorticoid and intrauterine growth retardation in rat. Exp
Toxicol Pathol 2007;59:245-51.
89. Liu L, Liu F, Kou H, Zhang BJ, Xu D, Chen B, et al. Prenatal
nicotine exposure induced a hypothalamic-pituitary-adrenal
axis-associated neuroendocrine metabolic programmed
alteration in intrauterine growth retardation offspring rats.
Toxicol Lett 2012;214:307-13.
How to cite this article: Mishra A, Chaturvedi P, Datta S,
Sinukumar S, Joshi P, Garg A. Harmful effects of nicotine. Indian J
Med Paediatr Oncol 2015;36:24-31.
Source of Support: Nil. Conict of Interest: None declared.
[Downloaded free from on Wednesday, September 16, 2015, IP:]
... In high doses, stimulation of the parasympathetic system and ganglionic and neuromuscular block may occur, resulting in reduced heart beating, gallbladder stimulation, and miosis. Nevertheless, the tobacco plant has shown anti-inflammatory and antiparasitic properties (Almeida et al., 2009;Mishra et al., 2015;Olson, 2014;Riba et al., 2003;Santos & Soares, 2015;Vechia, Gnoatto, & Gosmann, 2009). ...
... Regardless of the situation, nicotine is a molecule capable of promoting addiction (ANVISA, 1072;Olson, 2014). Most studies related toxic effects from tobacco considering smoking or cigarette exposition (Balbani & Montovani, 2005;Mishra et al., 2015;Moreno-Coutiño & Bello, 2012;Olson, 2014;Trilha, 2009), and there are no studies on tobacco exposition from shamanic snuff. ...
Full-text available
Snuff is a fine aromatic powder composed of dried and thin leaves combined with tobacco, roots, peels, and seeds. Its use for indigenous religious purposes has appeared since pre-Columbian period in various localities of American continent. Practice is considered sacred in indigenous culture and suffered from trivialization of consumption due to influence of colonizers, which triggered subsequent industrialization of this complex for commercial purposes. Commercial snuff is essentially made from industrialized tobacco without addition of other medicinal plants and without therapeutic or spiritual purposes beyond its indiscriminate and inappropriate use, causing health risks. Therefore, this study aimed to make a review on snuff in Brazilian culture and a tour of a local community. In shamanism, plants are used as access vehicles to other religions of cosmos and its inhabitants, from where experts dialogue, bring songs, news, omens, and acquire new knowledge. The plants used in shamanic composition of snuff vary with the locality of indigenous villages in America and are essential ingredients of this interaction between humans and non-humans, a special mediator of intersubjective interactions. Several studies show the use and meaning of Erythroxylum coca used in different communities of the Amazon, besides Chacrona and Mariri, popular names of plants used in manufacture of Ayahuasca drink by doctrine Santo Daime. Because of this, it is essential to establish differences between recreational snuff and shamanic and their effects on body as well as studies on use of shamanic snuff should be directed according to their applications and plants employed by communities.
... Nicotine can be rapidly absorbed from the oral mucosa and respiratory tract, inhaled into the lungs, and rapidly absorbed in the alveoli [8][9][10][11]. In addition, nicotine can also be absorbed through the skin and the gastrointestinal tract [12,13]. Of note, high levels of nicotine have been found in gastric juice, with nicotine concentrations of >800 ng/mL in gastric juice [13,14]. ...
... In addition, nicotine can also be absorbed through the skin and the gastrointestinal tract [12,13]. Of note, high levels of nicotine have been found in gastric juice, with nicotine concentrations of >800 ng/mL in gastric juice [13,14]. ...
Full-text available
Cigarette smoke exposure has a harmful impact on health and increases the risk of disease. However, studies on cigarette-smoke-induced adverse effects from the perspective of the gut–liver axis are lacking. In this study, we evaluated the adverse effects of cigarette smoke exposure on mice through physiological, biochemical, and histopathological analyses and explored cigarette-smoke-induced gut microbiota imbalance and changes in liver gene expression through a multiomics analysis. We demonstrated that cigarette smoke exposure caused abnormal physiological indices (including reduced body weight, blood lipids, and food intake) in mice, which also triggered liver injury and induced disorders of the gut microbiota and liver transcriptome (especially lipid metabolism). A significant correlation between intestinal bacterial abundance and the expression of lipid-metabolism-related genes was detected, suggesting the coordinated regulation of lipid metabolism by gut microbiota and liver metabolism. Specifically, Salmonella (harmful bacterium) was negatively and positively correlated with up- (such as Acsl3 and Me1) and downregulated genes (such as Angptl4, Cyp4a12a, and Plin5) involved in lipid metabolism, while Ligilactobacillus (beneficial bacterium) showed opposite trends with these genes. Our results clarified the key role of gut microbiota in liver damage and metabolism and improved the understanding of gut–liver interactions caused by cigarette smoke exposure.
... Gliserin akan bersifat toksik menghasilkan senyawa akrolein apabila dipanaskan pada suhu diatas 100ºC (Hajek et al., 2014). Pemberian nikotin dalam cairan RE akan memberikan sensasi rileks bagi pengguna (Mishra et al., 2019). ...
Rokok elektrik (RE) merupakan inovasi terbaru rokok yaitu tanpa proses pembakaran tar dan tembakau dan dianggap lebih aman dibandingkan rokok konvensional. Penelitian ini bertujuan mengetahui pengaruh paparan aerosol RE terhadap profil hematologis tikus putih (Rattus norvegicus) yang meliputi kadar hemoglobin, eritrosit, leukosit serta jenis leukosit. Dalam penelitian ini hewan uji Rattus norvegicus dibagi menjadi 4 kelompok dengan perlakuan yang berbeda yaitu diberi 0x paparan/hari (kontrol); 1x paparan/hari, 2x paparan/hari, dan 3x paparan/hari selama 14 hari. Setiap paparan dilakukan selama 5 menit (10 kali hembusan). Sampel darah diambil pada hari ke-0, hari ke-7 dan ke-14 melalui sinus orbitalis. Jumlah eritrosit dan leukosit dihitung dengan metode hitung bilik Neubauer. Kadar hemoglobin ditentukan menggunakan metode Sahli, dan persentase jenis leukosit dihitung dari preparat apus darah dengan pewarnaan Giemsa. Data yang diperoleh dianalisis secara deskriptif. Hasil penelitian menunjukkan terjadi peningkatan kadar hemoglobin dan jumlah eritrosit yang sejalan dengan peningkatan frekuensi dan durasi paparan RE sebagai kompensasi dari kondisi hipoksia. Jumlah leukosit juga cenderung meningkat, tetapi peningkatannya tidak linier dengan peningkatan frekuensi dan durasi paparan RE. Persentase limfosit, monosit dan eosinofil dibandingkan kontrol cenderung meningkat sedangkan persentase neutrofil cenderung menurun. Dengan demikian paparan RE dapat mempengaruhi profil hematologis hewan uji. E-cigarettes are the latest innovations of cigarettes without process of burning tar and tobacco. They are considered safer than conventional cigarettes. The purpose of this study was to determine the effect of e-cigarette aerosol exposure on the hematological profiles of Wistar rats (Rattus norvegicus). Rats were exposed to e-cigarette aerosol in different frequencies: 0x (control); once; twice; and 3x exposure/day. The experiment was ended on day 14th. Blood samples were taken through the orbital sinus on the day 0, 7th and 14th. Erythrocyte and leucocyte numbers were measured in Neubauer chamber count. Hemoglobin levels was determined by using Sahli method, and the percentage of leukocyte types was calculated based on Giemsa stained blood smear preparations. Data were analyzed descriptively. The results showed that hemoglobin levels and erythrocyte numbers tend to increase in line to the e-cigarette aerosol exposure as a compensation for hypoxic conditions. The leukocyte numbers also tends to increase, although the increase is not in line to the increase of exposure frequency and duration. The percentage of lymphocytes, monocytes and eosinophils tend to increase compared to the control group, while the percentage of neutrophils tends to decrease. Thus e-cigarette aerosol exposure affected the haematological profiles of rats
... Electronic cigarettes also deliver nicotine similar to cigarette smoking (4) and were suggested to cause cancer by affecting cell proliferation, periodontal cell migration, cytotoxicity, oxidative stress, apoptosis, and DNA maturation (5,6). In addition, smoking affects oral and pharyngeal tissues causing irritation, stimulation of microbial growth, reduced periodontal tissue immunity, enhanced alveolar bone resorption, and delayed healing (3,7). However, research is needed to identify differences between the use of regular and electronic cigarettes regarding determinants and effects. ...
Full-text available
The use of cigarettes among adolescents and young adults (AYA) is an important issue. This study assessed the association between regular and electronic-cigarettes use among AYA and factors of the Capability-Motivation-Opportunity-for-Behavior-change (COM-B) model. A multi-country survey was conducted between August-2020 and January-2021, Data was collected using the Global-Youth-Tobacco-Survey and Generalized-Anxiety-Disorder-7-item-scale. Multi-level logistic-regression-models were used. Use of regular and electronic-cigarettes were dependent variables. The explanatory variables were capability-factors (COVID-19 status, general anxiety), motivation-factors (attitude score) and opportunity-factors (country-level affordability scores, tobacco promotion-bans, and smoke free-zones) controlling for age and sex. Responses of 6,989-participants from 25-countries were used. Those who reported that they were infected with COVID-19 had significantly higher odds of electronic-cigarettes use (AOR = 1.81, P = 0.02). Normal or mild levels of general anxiety and negative attitudes toward smoking were associated with significantly lower odds of using regular-cigarettes (AOR = 0.34, 0.52, and 0.75, P < 0.001) and electronic-cigarettes (AOR = 0.28, 0.45, and 0.78, P < 0.001). Higher affordability-score was associated with lower odds of using electronic-cigarettes (AOR = 0.90, P = 0.004). Country-level-smoking-control policies and regulations need to focus on reducing cigarette affordability. Capability, motivation and opportunity factors of the COM-B model were associated with using regular or electronic cigarettes.
... Nicotine produces both immediate as well as remote effects. [6] Among the organs that nicotine effects, the urogenital organ system is the least explored and evaluated system. In males, the effects of nicotine on the reproductive system are erectile dysfunction, degeneration of seminiferous tubules, disruption of spermatogenesis, and affects germ cell structure and function at the cellular level. ...
Full-text available
Background and aim: The harmful effects of nicotine have been reported on the lungs and cardiovascular system in many studies, but the most unexplored profile of the effect of nicotine has been the genitourinary organs. In the current study, we planned to evaluate the effects of nicotine smoke on one of the important genitourinary organs, i.e., the testes and kidneys. Materials and methods: The study was conducted on 12 inbred adult Wistar albino rats; 6 animals acting as a control, and the remaining six acting as a test group. The control group animals were given only sterile water, whereas animals of the test group were exposed to smoke produced from the nicotine wrapped in cotton wool in the dose of 6mg/day three times a day for each session of 5 minutes each for five days. Each rat was exposed to the smoke produced due to nicotine separately in a closed inhalational chamber and not in groups. The rats were euthanized after experimentation, and testis and kidneys were removed and subjected further to tissue processing for histological examination. Results: The histological examination of tissue sections of the test group revealed marked distortion and degeneration of seminiferous tubules and germ cell lineage and distorted and widened interstitial spaces with loss of Leydig cells. On the other hand, the tissue sections of the control group showed normal histological architecture of testes with normal interstitial spaces and Leydig cells. Additionally, the renal sections of the test group showed dilation of urinary space, shrunken and distorted glomeruli. On the contrary, the renal specimens of the control group also demonstrated normal renal architectural patterns. Conclusion: the results of the present study concluded that even passive smoke exposure has drastic effects on the genitourinary organs, and hence, its use in public places should be checked.
... We selected phytochemicals from echinacea and ginger due to the recent increase in their consumption to strengthen the immune system as we face the COVID-19 pandemic [7,8]. On the other hand, we selected tobacco phytochemicals due to the well-known functions of its bioactive phytochemicals, such as nicotine [9] and cembranoids [10], which can have very different biological activities, yet are found within the same plant. In addition, we included in our analyses a well-known natural compound as theoretical control (ascorbic acid (vitamin C)) to compare and validate our methodology and GI absorption predictions for natural products. ...
Full-text available
The discovery of bioactive compounds for non-invasive therapy has been the goal of research groups focused on pharmacotherapy. Phytonutrients have always been attractive for researchers because they are a significant source of bioactive phytochemicals. Still, it is challenging to determine which components show high biomedical activity and bioavailability after administration. However, based on the chemical structure of these phytochemicals, their physicochemical properties can be calculated to predict the probability of gastrointestinal (GI) absorption after oral administration. Indeed, different researchers have proposed several rules (e.g., Lipinski’s, Veber’s, Ghose’s, and Muegge’s rules) to attain these predictions, but only for synthetic compounds. Most phytochemicals do not fully comply with these rules even though they show high bioactivity and high GI absorption experimentally. Here, we propose a detailed methodology using scientifically validated web-based platforms to determine the physicochemical properties of five phytochemicals found in ginger, echinacea, and tobacco. Furthermore, we analyzed the calculated data and established a protocol based on the integration of these classical rules, plus other extended parameters, that we called the Phytochemical Rule, to obtain a more reliable prediction of the GI absorption of natural compounds. This methodology can help evaluate bioactive phytochemicals as potential drug candidates and predict their oral bioavailability in patients.
... Nicotine was also detected as an alkaloid compound in bottled drinking water samples in Spain with an average concentration of 0.012 μg/L (Alonso et al. 2012). Nicotine is well-known as a highly addictive chemical that can cause adverse effects on the heart, reproductive system, lung, kidney, and multiple organs (Mishra et al. 2015). Nonylphenol (NP), octylphenols (OPs), triclosan (TCS), Aps, and BPA are endocrine-disrupting chemicals (EDCs) that have raised significant environmental and health concerns due to their estrogenic activity (Priac et al. 2017). ...
Full-text available
The aim of this study was to evaluate the levels of inorganic and organic substances as well as microbial contaminants in bottled drinking water on a global scale. The findings were compared to WHO guidelines, EPA standards, European Union (EU) directive, and standards drafted by International Bottled Water Association (IBWA). Our review showed that 46% of studies focused on the organic contaminants, 25% on physicochemical parameters, 12% on trace elements, 7% on the microbial quality, and 10% on microplastics (MPs) and radionuclides elements. Overall, from the 54 studies focusing on organic contaminants (OCs) compounds, 11% of studies had higher OCs concentrations than the standard permissible limit. According to the obtained results from this review, several OCs, inorganic contaminants (IOCs), including CHCl3, CHBrCl2, DEHP, benzene, styrene, Ba, As, Hg, pb, Ag, F, NO3, and SO4 in bottled drinking water of some countries were higher than the international guidelines values that may cause risks for human health in a long period of time. Furthermore, some problematic contaminants with known or unknown health effects such as EDCs, DBP, AA, MPs, and some radionuclides (40K and 222Rn) lack maximum permissible values in bottled drinking water as stipulated by international guidelines. The risk index (HI) for OCs and IOCs (CHBrCl2, Ba, As, and Hg) was higher than 1 in adults and children, and the value of HI for CHCl3 in children was more than 1. Thus, further studies are required to have a better understanding of all contaminants levels in bottled drinking water.
Full-text available
The use of tobacco products is a major global public health issue, as it is the leading cause of preventable death worldwide. In addition, nicotine (NIC) is a key component of electronic and conventional cigarettes. Although nicotine’s addictive potential is well known, its health effects are not entirely understood. Thus, the main objective of the present study was to evaluate its toxicological profile both in vitro, at the level of three healthy cell lines, and in ovo, at the level of the chorioallantoic membrane. Five different concentrations of nicotine were used in keratinocytes, cardiomyocytes, and hepatocytes for the purpose of evaluating cell viability, cell morphology, and its impact on nuclei. Additionally, the hen’s egg test on the chorioallantoic membrane (HET-CAM) method was used to assess the biocompatibility and irritant potential of the chorioallantoic membrane. Across all cell lines studied, nicotine was proven to be significantly damaging to cell viability, with the highest concentration tested resulting in less than 2% viable cells. Moreover, the morphology of cells changed dramatically, with alterations in their shape and confluence. Nicotine-induced cell death appears to be apoptotic, based on its impact on the nucleus. In addition, nicotine was also found to have a very strong irritating effect on the chorioallantoic membrane. In conclusion, nicotine has an extremely strong toxicological profile, as demonstrated by the drastic reduction of cell viability and the induction of morphological changes and nuclear alterations associated with cellular apoptosis. Additionally, the HET-CAM method led to the observation of a strong irritating effect associated with nicotine.
Understanding the genetic basis of a predisposition for nicotine and alcohol use across the lifespan is important for public health efforts because genetic contributions may change with age. However, parsing apart subtle genetic contributions to complex human behaviors is a challenge. Animal models provide the opportunity to study the effects of genetic background and age on drug-related phenotypes, while controlling important experimental variables such as amount and timing of drug exposure. Addiction research in inbred, or isogenic, mouse lines, has demonstrated genetic contributions to nicotine and alcohol abuse- and addiction-related behaviors. This review summarizes inbred mouse strain differences in alcohol and nicotine addiction-related phenotypes including voluntary consumption/self-administration, initial sensitivity to the drug as measured by sedative, hypothermic, and ataxic effects, locomotor effects, conditioned place preference or place aversion, drug metabolism and severity of withdrawal symptoms. This review also discusses how these alcohol and nicotine addiction-related phenotypes change from adolescence to adulthood.
Nicotine is one of several physiologically stable and active chemicals found in tobacco. The mechanism through which nicotine causes kidney damage is still obscure. As a result, the goal of this research was to investigate how oral nicotine intake can lead to kidney damage. Naturaly occurring superfood green algae are immense supplements help us using extra chemicals during cancer prevalence if the patient is exposed to nicotine. Hence, the mitigating role of Chlorella vulgaris extract (CVE) against nicotine-nephrotoxic impact in Ehrlich ascites carcinoma (EAC)-bearing mice was studied. For this purpose, four groups of Swiss female mice were assigned, nicotine group (NIC) (100 µg/ml/kg), CVE group (100 mg/kg), CVE+Nicotine, and a control group. Renal dysfunction was evaluated by estimating serum biomarkers of renal damage. The expression pattern of Nf-KB, MAPK, P53, and α7-nAchR, lipid peroxidation biomarker, and antioxidant enzyme activities were evaluated in kidney tissue. Also, micro-morphometric examination and apoptosis immunohistochemical reactivity of kidney tissue were applied. The obtained results indicated up-regulation of all estimated genes and oxidative stress. Moreover, a significant (P<0.05) increment in the apoptotic marker Caspase-3 and declined BCL-2 proteins were recorded. In serum, a significant (P<0.05) elevation of urea, creatinine, TNF-α, IL-1β, and Kim-1 were evident. Histological investigation reinforced the aforementioned data, revealing structural changes involving the tubules, glomeruli, and interstitium of mice kidneys. CVE may be a strong contender for protecting renal tissue damage since it reduces renal tissue injury and oxidative stress. Cancer patients who regularly use nicotine through direct smoking or second-hand exposure can benefit from CVE usage as a dietary supplement.
Full-text available
Ion channels modulate ion flux across cell membranes, activate signal transduction pathways, and influence cellular transport-vital biological functions that are inexorably linked to cellular processes that go awry during carcinogenesis. Indeed, deregulation of ion channel function has been implicated in cancer-related phenomena such as unrestrained cell proliferation and apoptotic evasion. As the prototype for ligand-gated ion channels, nicotinic acetylcholine receptors (nAChRs) have been extensively studied in the context of neuronal cells but accumulating evidence also indicate a role for nAChRs in carcinogenesis. Recently, variants in the nAChR genes CHRNA3, CHRNA5, and CHRNB4 have been implicated in nicotine dependence and lung cancer susceptibility. Here, we silenced the expression of these three genes to investigate their function in lung cancer. We show that these genes are necessary for the viability of small cell lung carcinomas (SCLC), the most aggressive type of lung cancer. Furthermore, we show that nicotine promotes SCLC cell viability whereas an α3β4-selective antagonist, α-conotoxin AuIB, inhibits it. Our findings posit a mechanism whereby signaling via α3/α5/β4-containing nAChRs promotes lung carcinogenesis.
Full-text available
The use of nicotine through smoking remains a serious health problem. It has been associated with reduced fertility, although the mechanism responsible is still unclear. The present study was designed to investigate whether nicotine-induced infertility is associated with altered male reproductive hormones in male albino rats. Forty male rats were divided equally into five groups and treated orally for thirty days. Group I, which served as the control received 0.2 ml/kg normal saline, Group II and III received 0.5 mg/kg (low dose) and 1.0 mg/kg (high dose) body weight of nicotine, respectively. The fourth and fifth groups were gavaged with 0.5 mg/kg and 1.0 mg/kg body weight of nicotine but were left untreated for another 30 days. These groups served as the recovery groups. Serum was analyzed for testosterone, luteinizing hormone (LH), follicle stimulating hormones (FSH), and prolactin using radioimmunoassay. Results showed that nicotine administration significantly decreased (P < 0.05) testosterone in the low and high treated groups and FSH in the high dose treated group when compared with the control group. There was a significant increase (P < 0.05) in mean LH and prolactin level in the high dose treated group when compared with the control. However, the values of the recovery groups were comparable with the control. The findings in this study suggest that nicotine administration is associated with distorted reproductive hormones in male rats although ameliorated by nicotine cessation. It is plausible that the decreased testosterone level is associated with testicular dysfunction rather than a pituitary disorder.
Full-text available
Nicotine is an alkaloid present in many plants of Solanaceae family. The levorotatory enantiomer (S) is a naturally occurring form. Nicotine enters the human body as a component of tobacco smoke. In alkaline environment the rate of nicotine permeation through biological membranes is increased. Almost 90% of nicotine absorbed by the body is metabolized in the liver. Nicotine may also be metabolized in the kidneys, lungs, brain, and respiratory epithelium membranes. The nicotine undergoes many transformations. Key role in the metabolism of nicotine is played by cytochrome P450 oxidases (mainly CYP2A6). Apart from them, UDP-glucuronosyltransferases, cytosolic aldehyde oxidase, amine N-methyltransferase, and flavin-containing monooxygenase 3 are involved in the decomposition of nicotine. Six major metabolites of nicotine have been identified. One of the most important metabolite is cotinine, from which is formed of trans-3'-hydroxycotinine--the compound which is excreted in the largest amount within the urine. The rate of nicotine metabolism is affected by diversified activity of polymorphic enzymes involved in this process, diet, gender and physiological condition of the organism.
Full-text available
We explored the contribution of nitrosamine metabolism to lung cancer in a pilot investigation of genetic variation in CYP2B6, a high-affinity enzymatic activator of tobacco-specific nitrosamines with a negligible role in nicotine metabolism. Previously we found that variation in CYP2A6 and CHRNA5-CHRNA3-CHRNB4 combined to increase lung cancer risk in a case-control study in European American ever-smokers (n = 860). However, these genes are involved in the pharmacology of both nicotine, through which they alter smoking behaviours, and carcinogenic nitrosamines. Herein, we separated participants by CYP2B6 genotype into a high- vs. low-risk group (*1/*1 + *1/*6 vs. *6/*6). Odds ratios estimated through logistic regression modeling were 1.25 (95% CI 0.68-2.30), 1.27 (95% CI 0.89-1.79) and 1.56 (95% CI 1.04-2.31) for CYP2B6, CYP2A6 and CHRNA5-CHRNA3-CHRNB4, respectively, with negligible differences when all genes were evaluated concurrently. Modeling the combined impact of high-risk genotypes yielded odds ratios that rose from 2.05 (95% CI 0.39-10.9) to 2.43 (95% CI 0.47-12.7) to 3.94 (95% CI 0.72-21.5) for those with 1, 2 and 3 vs. 0 high-risk genotypes, respectively. Findings from this pilot point to genetic variation in CYP2B6 as a lung cancer risk factor supporting a role for nitrosamine metabolic activation in the molecular mechanism of lung carcinogenesis.
Full-text available
Developmental nicotine exposure (DNE) impacts central respiratory control in neonates born to smoking mothers. We previously showed that DNE enhances the respiratory motor response to bath application of AMPA to the brainstem, although it was unclear which brainstem respiratory neurons mediated these effects (Pilarski and Fregosi, 2009). Here we examine how DNE influences AMPA-type glutamatergic neurotransmission in the pre-Bötzinger complex (pre-BötC) and the hypoglossal motor nucleus (XIIMN), which are neuronal populations located in the medulla that are necessary for normal breathing. Using rhythmic brainstem slices from neonatal rats, we microinjected AMPA into the pre-BötC or the XIIMN while recording from XII nerve rootlets (XIIn) as an index of respiratory motor output. DNE increased the duration of tonic activity and reduced rhythmic burst amplitude after AMPA microinjection into the XIIMN. Also, DNE led to an increase in respiratory burst frequency after AMPA injection into the pre-BötC. Whole-cell patch-clamp recordings of XII motoneurons showed that DNE increased motoneuron excitability but did not change inward currents. Immunohistochemical studies indicate that DNE reduced the expression of glutamate receptor subunits 2 and 3 (GluR2/3) in the XIIMN and the pre-BötC. Our data show that DNE alters AMPAergic synaptic transmission in both the XIIMN and pre-BötC, although the mechanism by which this occurs is unclear. We suggest that the DNE-induced reduction in GluR2/3 may represent an attempt to compensate for increased cell excitability, consistent with mechanisms underlying homeostatic plasticity.
Full-text available
A recent preclinical study has shown that not only maternal smoking but also grandmaternal smoking is associated with elevated pediatric asthma risk. Using a well-established rat model of in utero nicotine exposure, Rehan et al. have now demonstrated multigenerational effects of nicotine that could explain this 'grandmother effect'. F1 offspring of nicotine-treated pregnant rats exhibited asthma-like changes to lung function and associated epigenetic changes to DNA and histones in both lungs and gonads. These alterations were blocked by co-administration of the peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, implicating downregulation of this receptor in the nicotine effects. F2 offspring of F1 mated animals exhibited similar changes in lung function to that of their parents, even though they had never been exposed to nicotine. Thus epigenetic mechanisms appear to underlie the multigenerational transmission of a nicotine-induced asthma-like phenotype. These findings emphasize the need for more effective smoking cessation strategies during pregnancy, and cast further doubt on the safety of using nicotine replacement therapy to reduce tobacco use in pregnant women. Please see related article:
Full-text available
Smoking is a significant risk factor for pancreatic cancer, but the molecular mechanisms by which tobacco smoke components promote the growth and progression of these cancers are not fully understood. While nicotine, the addictive component of tobacco smoke, is not a carcinogen, it has been shown to promote the growth of non-small cell lung and pancreatic cancers in a receptor-dependent fashion. Here, we show that stimulation of pancreatic cancer cells with nicotine concentrations that are within the range of human exposure results in activation of Src kinase, which facilitated the induction of the inhibitor of differentiation-1 (Id1) transcription factor. Depletion of Id1 prevented nicotine-mediated induction of proliferation and invasion of pancreatic cancer cells, indicating that it is a major mediator of nicotine function. Nicotine could promote the growth and metastasis of pancreatic cancers orthotopically implanted into SCID mice; in addition, cells stably expressing a short hairpin RNA for Id1 did not grow or metastasize in response to nicotine. Nicotine could also confer resistance to apoptosis induced by gemcitabine in pancreatic cancer cells in vitro and depletion of Src or Id1 rendered the cells sensitive to gemcitabine. Further, nicotine could effectively inhibit the chemotherapeutic effects of gemcitabine on pancreatic tumors xenografted into mice. Clinical analyses of resected pancreatic cancer specimens demonstrated a statistically significant correlation between Id1 expression and phospho-Src, tumor grade/differentiation, and worsening overall patient survival. These results demonstrate that exposure to tobacco smoke components might promote pancreatic cancer progression, metastasis, and chemoresistance and highlight the role of Id1 in these processes.
Full-text available
Diabetes and smoking are known risk factors for cataract development. In this study, we evaluated the effect of nicotine on the progression of cataracts in a type 1 diabetic rat model. Diabetes was induced in Sprague-Dawley rats by a single injection of 65 mg/kg streptozotocin. Daily nicotine injections were administered subcutaneously. Forty-five rats were divided into groups of diabetics with and without nicotine treatment and controls with and without nicotine treatment. Progression of lens opacity was monitored using a slit lamp biomicroscope and scores were assigned. To assess whether systemic inflammation played a role in mediating cataractogenesis, we studied serum levels of eotaxin, IL-6, and IL-4. The levels of the measured cytokines increased significantly in nicotine-treated and untreated diabetic animals versus controls and demonstrated a positive trend in the nicotine-treated diabetic rats. Our data suggest the presence of a synergistic relationship between nicotine and diabetes that accelerated cataract formation via inflammatory mediators.
Daily administration of nicotine to rats during Days 0–5 of pregnancy delays loss of the zona pellucida, obliteration of the blastocyst cavity, and implantation (Card and Mitchell, 1979). Prior to implantation the unattached conceptus depends on oxygen and other essential metabolic substrates available within the lumen of the reproductive tract to sustain its continued growth and development. The availability of oxygen within the uterine lumen of the rat increases prior to implantation (Yochim and Mitchell, 1968) and declines rapidly upon vasoconstriction of the uterine vasculature (Mitchell and Yochim, 1968). Because conceptus development requires optimal oxygen tension (Brinster, 1972) and nicotine is a potent vasoactive substance, it was suggested that the nicotine-induced alterations in conceptus development and implantation may result, in part, from changes in reproductive tract blood flow (Hammer and Mitchell, 1979). The following study was undertaken to establish whether nicotine alters cell proliferation in embryos prior to implantation and if so whether such alterations are associated with reduced oviductal and/or uterine blood flow.