Abstract

BACKGROUND

Cigarette smoking is associated with lower fecundity rates, adverse reproductive outcomes and a higher risk of IVF failures. Over the last few decades, prevalence of smoking among women of reproductive age has increased. This review focuses on current knowledge of the potential effects of smoke toxicants on all reproductive stages and the consequences of smoke exposure on reproductive functions.

METHODS

We conducted a systematic review of the scientific literature on the impact of cigarette smoking and smoke constituents on the different stages of reproductive function, including epidemiological, clinical and experimental studies. We attempted to create hypotheses and find explanations for the deleterious effects of cigarette smoke observed in experimental studies.

RESULTS

Cigarette smoke contains several thousand components (e.g. nicotine, polycyclic aromatic hydrocarbons and cadmium) with diverse effects. Each stage of reproductive function, folliculogenesis, steroidogenesis, embryo transport, endometrial receptivity, endometrial angiogenesis, uterine blood flow and uterine myometrium is a target for cigarette smoke components. The effects of cigarette smoke are dose-dependent and are influenced by the presence of other toxic substances and hormonal status. Individual sensitivity, dose, time and type of exposure also play a role in the impact of smoke constituents on human fertility.

CONCLUSIONS

All stages of reproductive functions are targets of cigarette smoke toxicants. Further studies are necessary to better understand the deleterious effects of cigarette smoke compounds on the reproductive system in order to improve health care, help to reduce cigarette smoking and provide a better knowledge of the molecular mechanisms involved in reproductive toxicology.

Introduction

In Europe, smoking prevalence among women of reproductive age has increased over the last decades and reached 33% in 2006 (Huisman et al., 2005). In the USA, during the same period, the prevalence rate was 28% (CDC, 2008).

The relationship between decreased fertility and smoking is not well known. In a study involving infertile and pregnant smokers, Hughes et al. (2000) observed that only 47% of infertile patients and 14% of pregnant patients believed that smoking significantly impaired fertility. Moreover, only 30% of infertile patients were informed by their physicians about the risks of smoking. Poor understanding of the deleterious effects of smoking on fertility highlights the necessity for physicians to encourage patients of childbearing age to quit smoking.

Cigarette smoking is associated with reproductive life impairment such as an earlier onset of menopause (Jick and Porter, 1977), higher infertility risk (Augood et al., 1998; de Mouzon and Belaisch-Allart, 2005), lower fecundity rate (Baird and Wilcox, 1985; Tzonou et al., 1993; Bolumar et al., 1996; Hull et al., 2000) and lower IVF success rates (Hughes and Brennan, 1996; Feichtinger et al., 1997; Augood et al., 1998; Klonoff-Cohen et al., 2001; Neal et al., 2005; Wright et al., 2006). In a recent meta-analysis involving 21 studies that investigated the effects of smoking on IVF results, smoking was associated with a lower chance of clinical pregnancy [odds ratio (OR) = 0.56, 95 confidence interval (CI) 0.43–0.73], higher risk of miscarriage and ectopic pregnancy, and a lower chance of live birth per cycle (OR = 0.54, 95 CI 0.30–0.99) (Waylen et al., 2009). Despite controversial results, studies involving IVF procedures demonstrated that cigarette smoke had deleterious effects on all steps: ovarian sensitivity (Elenbogen et al., 1991; Hughes et al., 1994; El-Nemr et al., 1998), number of oocytes (Van Voorhis et al., 1996; El-Nemr et al., 1998; Klonoff-Cohen et al., 2001; Wright et al., 2006; Fuentes et al., 2010), fertilization (Elenbogen et al., 1991; Gruber et al., 2008), implantation and early placentation (Winter et al., 2002; Soares et al., 2007).

Cigarette smoke contains about 4000 compounds belonging to a variety of chemical classes known to be toxic, including polycyclic aromatic hydrocarbons (PAH) [e.g. benzo(a)pyrene (BaP), acenapthelene, phenanthrene, pyrene and chrysene], nitrosamines, heavy metals [e.g. cadmium (Cd), lead and cobalt], alkaloids (nicotine), aromatic amines and so forth (Kaiserman and Rickert, 1992; Ding et al., 2005). These compounds have different properties and probably different targets on the human reproductive system. The aim of this review was to focus on current knowledge of tobacco smoke effects on the reproduction process and analyse for each reproductive stage the deleterious effects of smoke components.

Methods

For this systematic review, Pubmed, EMBASE and Web of Science databases were used to collect all human epidemiological and clinical studies, as well as experimental studies with animal or cell culture models, by means of the following keywords: ‘smoke’, ‘cigarettes’, ‘tobacco’, ‘fertility’, ‘fecundity’, ‘assisted reproductive techniques’, ‘in vitro fertilization’, ‘folliculogenesis’, ‘oocyte’, ‘steroidogenesis’, ‘Fallopian tubes’, ‘embryo’, ‘embryo implantation’, ‘endometrium’, ‘trophoblast’, ‘myometrium’, ‘uterine Doppler’, ‘uterine blood flow’, ‘passive smoking’, ‘active smoking’, ‘mainstream smoke’, ‘sidestream smoke’, ‘environmental tobacco exposure’, ‘antenatal exposure’ and ‘childhood exposure’. In addition, references cited in the selected articles and reviews were searched. Four hundred and forty-eight publications were found. Only clinical and experimental studies were included. We excluded studies analysing cigarette smoke effects on male fertility and publications about other types of smoke (i.e. Marijuana). As we focused on reproductive functions from folliculogenesis to implantation, we excluded publications about the effects of cigarette smoke on pregnancy, the fetus and placenta. Only publications written in English and French were considered. One hundred and eighty-one publications were selected and analysed. Our review was conducted according to different reproductive functions which were classified as follows: folliculogenesis, steroidogenesis, preimplantation embryo development, Fallopian tube function, embryo implantation, uterine flow velocity and myometrial activity. For each reproductive function, we collected observations from human epidemiological or clinical studies about cigarette smoke effects. Then, we attempted to find hypotheses and explanations for the deleterious effects of cigarette smoke observed in experimental studies. Thereafter, factors influencing the negative effects of cigarette smoke on reproductive function were studied.

Results

Cigarette smoking and folliculogenesis

Effects of cigarette smoke on folliculogenesis

Cigarette smoking is associated with a risk of an earlier onset of menopause, which is advanced by 2 years (Jick and Porter, 1977). Cooper et al. (1995) demonstrated a higher FSH level in smokers. Ovarian reserve seems to be lower in smokers: Freour et al. (2008) evaluated anti-Mullerian hormone (AMH) in patients with comparable FSH and estradiol (E2) levels on Day 3 of the menstrual cycle and found that AMH was significantly lower in smokers (3.06 versus 3.81 µg/l).

Experimental studies confirmed the deleterious effect of cigarette smoke (Table I). In a mouse model exposed to BaP, Mattison et al. (1989) found ovarian weight to be decreased. When different types of animal models were exposed to cigarette smoke metabolites, such as Cd, nicotine or BaP, regardless of the administration route (i.p., intra-ovarian or oral), follicle loss was reported at all stages of folliculogenesis (Shiromizu and Mattison, 1984; Mattison et al., 1989; Miller et al., 1992; Lienesch et al., 2000; Barbieri et al., 2005). Primordial follicles appeared to be especially sensitive to cigarette smoke (Mulligan Tuttle et al., 2009). Moreover, follicle growth was also shown to be inhibited, with smaller-sized follicles after nicotine (Bordel et al., 2006) or BaP exposure (Neal et al., 2007). Follicle growth in an isolated rat follicle culture decreased by 35% when exposed to 1.5 ng/ml of BaP, a concentration representative of levels found in the follicular fluid of women who smoked an average of 15 cigarettes/day (Neal et al., 2007).

Table I

Effects of cigarette smoke compounds on folliculogenesis.

Reference Model Exposure Toxicants Dose Effects 
Neal et al. (2007Rat follicle Culture medium BaP 1.5, 5, 45 and 135 ng/ml Inhibition of follicle growth 
     Inhibition by 35% at 1.5 ng/ml (equivalent follicular concentration of 15 daily cigarettes) 
     Dose-dependent decreased growth 
Bordel et al. (2006Hamster dorsal skin chamber with transplanted follicles Daily s.c. injection Nicotine 0.2 and 1 mg/kg Inhibition of follicle growth 
     Increased cells apoptosis with increased caspase-3 levels 
     No effect on follicular angiogenesis 
Vrsanska et al. (2003Porcine COC Culture medium Nicotine 2 × 10−4 to 10−6Decreased COC expansion 
   Anabasine 10−4 to 10−6Decreased hyaluronic acid synthesis 
   Cotinine 10−4 to 10−6Decreased progesterone synthesis 
Neal et al. (2007Human COC Mainstream smoke BaP Smokers follicular fluid BaP = 1.32 ng/ml Inhibition of follicle growth 
     Decreased E2 synthesis 
Lienesch et al. (2000Xenopus laevis Dorsal lymph injection Cadmium 3.0 and 5.0 mg/kg Decreased follicle growth 
     Increased number of atretic oocytes 
Barbieri et al. (2005Human COC Cigarette smoke Cigarette smoke Not mentioned Decreased number of retrieved oocytes 
Miller et al. (1992Mouse i.p. injection BaP 0–500 mg/kg Decreased ovarian volume 
     Decreased corpus luteum volume 
     Decreased corpus luteum number 
Mattison et al. (1989Mouse Intraovarian injection BaP and metabolites: Not mentioned Decreased ovary weight and volume 
   7,8-oxide (7,8-O)  Decreased number of follicles at all stages of development 
   7,8-dihydrodiol   
   7,8-dihydrodiol-9,10-epoxide   
Mulligan Tuttle et al. (2009Mouse Exposure chambers Mainstream smoke 1 puff/52 s Decreased ovarian volume 
  Culture medium BaP 1–1 × 10−5g/ml Decreased number of follicles 
     Decreased Bcl-2 expression 
Liu et al. (2008a, bBovine COC Culture medium Nicotine 0.05, 1.0, 2.5, 5.0 and 10.0 mmol Decreased COC expansion 
     Decreased perivitelline space formation 
Paksy et al. (1997Human granulosa cells Culture medium Cadmium 6–16–32–64 × 10−6Cytoplasmic retractions 
     Cells detachment 
Sanders et al. (2002Bovine granulosa and thecal cells Culture medium Nicotine 0.3, 3, 30 and 10−6Decreased cell viability 
Gieseke and Talbot (2005Hamster COC Culture medium Smoke solution from 60 puffs of cigarette Not mentioned Decreased COC sizeLoss of cumulus cellIncreased matrix degradation 
Nampoothiri et al. (2007Rats In vivo Cadmium i.p. injection of cadmium 0.05 mg/kg Inhibition of SOD activity 
  In vitro with granulosa cells  Culture medium Increased catalase activity 
Reference Model Exposure Toxicants Dose Effects 
Neal et al. (2007Rat follicle Culture medium BaP 1.5, 5, 45 and 135 ng/ml Inhibition of follicle growth 
     Inhibition by 35% at 1.5 ng/ml (equivalent follicular concentration of 15 daily cigarettes) 
     Dose-dependent decreased growth 
Bordel et al. (2006Hamster dorsal skin chamber with transplanted follicles Daily s.c. injection Nicotine 0.2 and 1 mg/kg Inhibition of follicle growth 
     Increased cells apoptosis with increased caspase-3 levels 
     No effect on follicular angiogenesis 
Vrsanska et al. (2003Porcine COC Culture medium Nicotine 2 × 10−4 to 10−6Decreased COC expansion 
   Anabasine 10−4 to 10−6Decreased hyaluronic acid synthesis 
   Cotinine 10−4 to 10−6Decreased progesterone synthesis 
Neal et al. (2007Human COC Mainstream smoke BaP Smokers follicular fluid BaP = 1.32 ng/ml Inhibition of follicle growth 
     Decreased E2 synthesis 
Lienesch et al. (2000Xenopus laevis Dorsal lymph injection Cadmium 3.0 and 5.0 mg/kg Decreased follicle growth 
     Increased number of atretic oocytes 
Barbieri et al. (2005Human COC Cigarette smoke Cigarette smoke Not mentioned Decreased number of retrieved oocytes 
Miller et al. (1992Mouse i.p. injection BaP 0–500 mg/kg Decreased ovarian volume 
     Decreased corpus luteum volume 
     Decreased corpus luteum number 
Mattison et al. (1989Mouse Intraovarian injection BaP and metabolites: Not mentioned Decreased ovary weight and volume 
   7,8-oxide (7,8-O)  Decreased number of follicles at all stages of development 
   7,8-dihydrodiol   
   7,8-dihydrodiol-9,10-epoxide   
Mulligan Tuttle et al. (2009Mouse Exposure chambers Mainstream smoke 1 puff/52 s Decreased ovarian volume 
  Culture medium BaP 1–1 × 10−5g/ml Decreased number of follicles 
     Decreased Bcl-2 expression 
Liu et al. (2008a, bBovine COC Culture medium Nicotine 0.05, 1.0, 2.5, 5.0 and 10.0 mmol Decreased COC expansion 
     Decreased perivitelline space formation 
Paksy et al. (1997Human granulosa cells Culture medium Cadmium 6–16–32–64 × 10−6Cytoplasmic retractions 
     Cells detachment 
Sanders et al. (2002Bovine granulosa and thecal cells Culture medium Nicotine 0.3, 3, 30 and 10−6Decreased cell viability 
Gieseke and Talbot (2005Hamster COC Culture medium Smoke solution from 60 puffs of cigarette Not mentioned Decreased COC sizeLoss of cumulus cellIncreased matrix degradation 
Nampoothiri et al. (2007Rats In vivo Cadmium i.p. injection of cadmium 0.05 mg/kg Inhibition of SOD activity 
  In vitro with granulosa cells  Culture medium Increased catalase activity 

COC, cumulus–oocyte complex; BaP, benzo(a)pyrene; E2, estradiol; SOD, superoxide dismutase.

Impairment in follicle growth could be explained by morphological alterations of the cumulus–oocyte complex (COC). When cultures of porcine COC were exposed to cigarette smoke compounds, such as cotinine, anabasine, nicotine and Cd, Vrsanska et al. found an inhibitory effect on cumulus expansion, with abnormal extracellular matrix. Hyaluronic acid synthesis was diminished in the presence of Cd and nicotine (Vrsanska et al., 2003). Liu et al. (2008a) demonstrated a dose-dependent negative effect of nicotine on bovine COC expansion as well as an impairment of perivitelline space formation, suggesting that smoke components induced impairment of the mucification process. Paksy et al. (1997) studied the effects of smoke metabolites on human granulosa cell culture: at high doses of Cd or low doses with longer exposure times, granulosa cells began to separate, cellular extensions retracted and nuclear abnormalities were observed. In addition, high doses of Cd led to granulosa cell necrosis (Leoni et al., 2002).

Zenzes et al. investigated the effect of cigarette smoking on oocyte maturation in IVF patients: in patients younger than 35 years, a positive correlation between the number of cigarettes smoked and follicular cotinine was observed. Surprisingly, a positive correlation was also seen between follicular cotinine level and the rate of oocyte maturation (Zenzes et al., 1997b). In contrast, in a frog model exposed to Cd, Lienesch et al. (2000) observed an accumulation of Cd in ovaries as well as delayed oocyte development and maturation. Different results regarding oocyte maturation in these two studies could be accounted for by differences in the toxicants studied and models used. In a mouse model exposed to nicotine, Mailhes et al. studied the rate of chromosomal abnormalities in metaphase II oocytes. In non-exposed mice, the rates of premature chromatid separation and premature anaphase were, respectively, 4.6 and 0.3%, whereas in the group exposed to high levels of nicotine, the rates were 9.2 and 5.4%, respectively (Mailhes et al., 2000). Higher rates of morphological oocyte abnormalities and aneuploidies were observed after nicotine exposure, suggestive of deleterious effects of smoke metabolites on COC and nuclear maturation.

Presence of cigarette smoke metabolites in ovarian tissue

Many cigarette smoke compounds have thus far been identified in ovarian tissue (Table II). Nicotine and cotinine were found in the follicular fluid (Weiss and Eckert, 1989; Zenzes et al., 1996) (mean cotinine levels of 710.4, 76.3 and 4.2 ng/ml, respectively, in active, passive and non-smokers), with a positive correlation between follicular cotinine levels and the rate of cigarette consumption (Zenzes et al., 1996). Cotinine was also detected in both the nucleus and the cytoplasm of the granulosa cells (Zenzes et al., 1997a). BaP was also identified in granulosa cells (Zenzes et al., 1998). Neal et al. (2007,, 2008) investigated follicular PAH levels in IVF patients and found that BaP levels were positively correlated with female cigarette consumption (mean BaP levels of 1.32, 0.05 and 0.03 ng/ml, respectively, in active, passive and non-smokers). This may suggest that the follicular fluid that bathes the growing follicle acts as a sink for toxicants such as BaP. Thus, they established that 1.5 ng/ml of BaP corresponded to a human follicular fluid BaP concentration resulting from consuming 15 cigarettes/day. Cd was also detected in human ovarian tissue and the follicular fluid, with higher levels in smokers than non-smokers (Zenzes et al., 1995a). All these studies allow us to conclude that follicular fluid and ovarian cells retain toxic compounds and create a toxic environment for follicle growth and oocyte maturation, to differing degrees depending on the number of cigarettes smoked per day.

Table II

Cigarette smoke metabolite concentrations (ng/ml) in human serum and follicular fluid in smokers and non-smokers.

 Serum
 
Follicular fluid
 
Reference
 
 NS NS 
Cotinine   3.8 340 Zenzes et al. (1998
PAH 
 BaP 0.22 0.40 0.03 1.32 Neal et al. (2007
 Acenaphtelene 0.44 0.99 1.44 1.71 Neal et al. (2008
 Phenantrene 5.9 5.45 3.20 3.56 Neal et al. (2008
 Pyrene 0.27 0.30 0.25 0.22 Neal et al. (2008
 Chrysene 0.40 0.20 0.15 0.15 Neal et al. (2008
Cadmium 0.85 0.97 7.93 6.73 Shaham et al. (1996
 Serum
 
Follicular fluid
 
Reference
 
 NS NS 
Cotinine   3.8 340 Zenzes et al. (1998
PAH 
 BaP 0.22 0.40 0.03 1.32 Neal et al. (2007
 Acenaphtelene 0.44 0.99 1.44 1.71 Neal et al. (2008
 Phenantrene 5.9 5.45 3.20 3.56 Neal et al. (2008
 Pyrene 0.27 0.30 0.25 0.22 Neal et al. (2008
 Chrysene 0.40 0.20 0.15 0.15 Neal et al. (2008
Cadmium 0.85 0.97 7.93 6.73 Shaham et al. (1996

NS, non-smokers; S, smokers; PAH, polycyclic aromatic hydrocarbons.

Mechanisms involved in folliculogenesis impairment

Some mechanisms explaining folliculogenesis impairment have been described: abnormal oxidative stress, increased cellular apoptosis, abnormal cross-talk between oocyte and granulosa cells, and impairment of oocyte nuclear function.

Paszkowski et al. measured follicular oxidative activity in smokers: lipid peroxidation product was 0.49, 0.50 and 1.07 µmol/l and the total antioxidative capacity was 440.0, 385.4 and 362.3 µmol/l, respectively, in non-, passive and active smokers. Moreover, they found a positive correlation between the rate of lipid peroxidation and the level of patient exposure to cigarette smoke (Paszkowski et al., 2002). The effects of cigarette smoke on oxidative stress are well known as are the effects of smoke on cellular apoptosis and aneuploidy (Lee et al., 1989; Van der Vaart et al., 2004; Kim et al., 2008). Cd was shown to increase ovarian oxidative stress: Nampoothiri et al. evaluated the effects of Cd on mouse ovarian oxidative stress by using granulosa cells exposed in vitro to Cd and granulosa cells isolated from mice exposed for 15-day periods. Increased lipid peroxidation, reduced glutathione contents, increased catalase activity and decreased superoxide dismutase activity were observed in ovaries exposed to Cd (Nampoothiri et al., 2007).

Cigarette smoking was shown to be associated with follicle loss, involving complex mechanisms and cell death pathways. Higher expression and synthesis of Bax, a pro-apoptotic molecule, were observed in mouse ovaries after exposure to BaP (Matikainen et al., 2001). The action of BaP is mediated through the aryl hydrocarbon receptor (AhR), a cytoplasmic receptor identified in granulosa cells (Bussmann and Baranao, 2006) and implicated in follicle growth (Benedict et al., 2000; Pocar et al., 2005). The identification of an AhR-response element in Bax promoters suggested that AhR and Bax were implicated in cell death signalling pathways of granulosa cells exposed to smoke components (Matikainen et al., 2001). Mulligan Tuttle et al. (2009) studied apoptosis markers in ovaries of mice exposed to mainstream smoke (MS) and found lower levels of Bcl-2, an anti-apoptotic protein. Using human ovarian tissue transplanted subcutaneously in mice exposed to PAH, Jurisicova et al. (2007) observed an up-regulation of harakiri, a Bcl-2 interacting protein involved in cell death pathways, in the granulosa and stromal cells.

Paksy et al. (1997) demonstrated that human granulosa cells exposed to Cd were characterized by cytoplasmic retractions and fewer intercellular junctions. In vitro, BaP was shown to inhibit gap junction formation (Sharovskaya et al., 2006), junctions being indispensable for oocyte–granulosa cell cross-talk. In Sertoli cells exposed to Cd, lower levels of connexin 43, a molecule involved in gap junction structure were observed (Fiorini et al., 2004; Gershon et al., 2008). Furthermore, smoke components are associated with damage to DNA. Using comet assay, Sinko et al. (2005) studied nuclear consequences in granulosa cells from IVF patients: higher rates of DNA strand breaks in smokers were observed. Moreover, high levels of BaP–DNA adducts in human luteal cells were also detected (Shamsuddin and Gan, 1988).

Cigarette smoking was associated with an increased risk of oocyte aneuploidy (Zenzes et al., 1995b). In mouse models exposed to nicotine, higher rates of both chromosomal abnormalities and premature separation of sister chromatids during meiosis were observed (Mailhes et al., 2000). In rat germinal cells exposed to increasing BaP doses, inhibition and blockage of meiosis were shown (Georgellis et al., 1990), implying that smoke components may induce meiotic spindle disturbances. With bovine oocytes exposed to nicotine, Liu et al. (2007,, 2008a) observed a dose-dependent increased rate of aneuploidy during meiosis with irregular, malformed and multipolar spindles, abnormal chromosomal alignment and disorganized microfilaments. It was suggested that actin filaments were targets for nicotine, resulting in disorganized microfilaments and chromosomal segregation (Liu et al., 2007). Liu et al. (2008b) studied the effects of nicotine on meiotic spindles in bovine oocytes at different meiotic stages and found that the second meiotic spindles were far more sensitive to nicotine. Most constituents of cigarette smoke, such as PAH, have carcinogenic properties with the ability to link and intercalate within the DNA helix, inducing mutation, DNA adduct formation and carcinogenesis (Baird et al., 2005). All these mechanisms could also explain abnormal oocyte nuclear maturation.

Cigarette smoke is associated with impairment of folliculogenesis. Ovaries retain smoke compounds, resulting in a toxic follicle environment, inducing increased oxidative stress, abnormal intercellular cross-talk, meiosis impairment and activation of cell death pathways. Consequences are follicle loss, abnormal follicle growth, and impairment of morphology and oocytes maturation.

Cigarette smoking and steroidogenesis

Effects of cigarette smoking on steroidogenesis

Among cigarette smoke compounds, some display properties of endocrine disruptors (Mlynarcikova et al., 2005). Smokers present an abnormal endocrine profile characterized by higher testosterone level (Barbieri et al., 2005), higher level of FSH (Cooper et al., 1995) and lower E2 level during ovarian stimulation in IVF (Van Voorhis et al., 1992,, 1996). Several authors have observed that smoke compounds disrupt steroidogenesis, leading to impairment of E2 synthesis (Barbieri et al., 1986; Osawa et al., 1990; Piasek and Laskey, 1994; Bodis et al., 1997; Gocze et al., 1999; Sanders et al., 2002; Vidal et al., 2006) and progesterone synthesis deficiency (Paksy et al., 1989,, 1997; Piasek and Laskey, 1994). The analysis of follicular fluid components in smokers treated with IVF revealed a decreased estrogenic concentration with an increased androgen/estrogen ratio, indicative of an androgenic follicular environment (Gustafson et al., 1996; Van Voorhis et al., 1996).

Cigarette smoke compounds and endocrine disruptors

Cadmium

Cd is an endocrine disruptor which is involved in the impairment of steroidogenesis (Paksy et al., 1989,, 1997; Piasek and Laskey, 1994; Henson and Chedrese, 2004). Cd decreases expression of the low-density lipoprotein receptor implicated in cholesterol internalization, the first step in steroidogenesis (Jolibois et al., 1999). In porcine granulosa cell lines exposed to low doses of Cd, an increased genomic expression of P450 side-chain cleavage (SCC) enzyme, involved in the conversion of cholesterol to pregnenolone, was observed. At high doses, Cd was shown to inhibit P450scc expression, resulting in a decreased E2 synthesis (Smida et al., 2004). Cd was reported to have an inhibitory effect on 3-β-hydroxysteroid-dehydrogenase gene expression (Smida et al., 2004). The chemical structure of Cd is close to that of calcium: this property facilitates interaction with intra-cellular calcium signalling (Lacroix and Hontela, 2006; Costa and Varanda, 2007) and Cd is probably also involved in FSH and LH intra-cellular signalling mechanisms.

Nevertheless, Cd was also found to act as an estrogen-like factor, particularly in endocrine tissues (Stoica et al., 2000). This property is related to its ability to link with estrogen receptors (Nesatyy et al., 2005), resulting in an enhanced expression of estrogen-dependent genes (Darbre, 2006; Alonso-Gonzalez et al., 2007).

Benzo(a)pyrene

BaP was described as an endocrine disruptor (Inyang et al., 2003). In experimental studies, BaP was shown to inhibit P450 aromatase expression and activity (Dong et al., 2008) and to decrease 17-β-hydroxysteroid-dehydrogenase and 17–20 lyase activities, which are all involved in steroidogenesis (Rocha Monteiro et al., 2000).

Similar to Cd, BaP presents estrogen-like properties (Charles et al., 2000; Gozgit et al., 2004), owing to the steric resemblance of PAH to sex steroids. Thus, PAH might act on the same sites as steroid hormones (Charles et al., 2000). DNA binding was observed in vitro with high doses of BaP (Charles et al., 2000; Fertuck et al., 2001). In human tissue, and particularly in ovarian tissue, BaP levels and biodisponibility were lower, and an estrogen-like effect still needs to be demonstrated (Fertuck et al., 2001).

Compounds in cigarette smoke can act as endocrine disruptors in a number of different ways, and opposite consequences have been observed, such as estrogenic and anti-estrogenic effects. These opposite effects could be explained by actions on the different stages and various targets of the steroidogenesis. The complexity of the effects of smoke compounds must be investigated to elucidate the consequences of cigarette smoke on steroidogenesis.

Cigarette smoking and preimplantation embryo development

Embryos and smoke metabolites

Several metabolites of cigarette smoke have been identified in the embryo and its environment. BaP was detectable in the embryo, at three and eight blastomere stages, in the cytoplasm and nucleus (Fabro and Sieber 1969; Zenzes et al., 1999). Nicotine was also identified in the endometrium (Fabro and Sieber, 1969) and uterine fluid (Poppe et al., 1995), suggesting that embryo development started in a ‘toxic’ environment.

Mechanisms and effects of cigarette smoke compounds on embryo development

Current knowledge of the potential effects of smoking on embryo development remains poor. Shiloh et al. (2004) evaluated the zona pellucida thickness in women who did, and did not, smoke: a thicker zona pellucida was observed in female smokers (20.1 µm in smokers versus 15.3 µm in non-smokers). Gruber et al. (2008) evaluated the effect of female smoking on IVF embryo quality; they found that the smoking status had no influence on embryo morphology score, the rate of fragmentation and arrested embryos. However, a lower fertilization rate was observed in smokers than non-smokers (78.2 versus 85.7%). Using female mice exposed to cigarette smoke, Hassa et al. (2007) found that the rate of growing and not arrested embryos on Day 2 was lower in exposed mice as compared with controls (32 versus 75%); however, on Day 3, the rate of arrested embryos was identical in the two groups. Liu et al. (2008b) evaluated bovine embryo development after exposure to cigarette smoke and reported a higher rate of multinucleated blastomeres.

Zenzes et al. investigated preimplantation embryo development using 1682 embryos from couples who underwent IVF. Surprisingly, they found the fertilization rate and the proportion of good-quality embryos to be increased with increasing follicular cotinine levels. According to the authors, these results may be explained by a cotinine-mediated inhibition of apoptosis in developing embryos of smokers, resulting in an increased ability to survive (Zenzes et al., 1999).

The effects of Cd were also studied in mouse embryos: although no effect was observed at low levels of exposure, high doses led to embryo degeneration with a necrotic appearance (Yu et al., 1985). At the blastocyst stage, Cd induced inner cell mass cells necrosis with appearance of cytoplasmic vacuoles and residual bodies (Abraham et al., 1984).

The effects of PAH were studied on murine embryos: s.c. PAH exposure led to fewer morula and blastocyst stage embryos and fewer cells per embryo, resulting in a 20% loss of total cell number in embryos exposed to PAH (Detmar et al., 2006). BaP effects are mediated via the AhR. In rabbit embryos, AhR expression was confirmed in blastomeres at the morula stage, trophoblast cells and inner cell mass at the blastocyst stage (Tscheudschilsuren et al., 1999). There seems to be a gradual appearance of AhR during embryonic development and this time-dependent expression could account for the late effects of smoke components on embryonic development. Detmar et al. (2006) observed, in mice embryos, that exposure to PAH for 24 h significantly increased the level of Bax transcript by a factor of two and the level of caspase activity by 35%. In mice blastocysts exposed to BaP, Pedersen et al. (1985) observed an increase in sister chromatid exchanges, correlated with increasing BaP exposure.

Different molecules contained in cigarette smoke have different pro- or/and anti-apoptosis properties, leading to a probable impairment of embryo development. The increased apoptosis phenomenon observed in experimental studies could be accounted for by high levels of exposure: these levels were probably higher than those observed in vivo, explaining the controversial results observed in IVF studies. Mechanisms involved in the effects of smoke on embryo apoptosis or survival remain unclear and must be elucidated.

Cigarette smoking and Fallopian tubes

Effects of cigarette smoke on embryo transport through Fallopian tubes

The hypothesis that the oviduct could be considered as a target of cigarette smoke was raised after observation of an increased rate of ectopic pregnancies following exposure to tobacco smoke (Chow et al., 1988; Saraiya et al., 1998; Stergachis et al., 1991; Bouyer et al., 2003; Karaer et al., 2006), with an increased risk with increasing number of cigarettes smoked (Saraiya et al., 1998; Bouyer et al., 2003; Karaer et al., 2006) and when cigarette consumption was active (Stergachis et al., 1991; Bouyer et al., 2003; Karaer et al., 2006). These observations suggest that cigarette smoke could have deleterious consequences on tubal functions. Smoking cessation seems to be beneficial to tubal function, although a risk remains, suggesting chronic and irreversible tubal lesions. Even if multivariate analysis with adjustment for confounding variables has often revealed associations between smoke and ectopic pregnancy, categorizing smoking as a strong risk factor should be done with caution. In fact, smoking is also associated with risk behaviours (Jonsson et al., 1997), such as alcohol intake, with pelvic inflammatory diseases and also multiplicity of sexual partners, which are individual risk factors for ectopic pregnancy.

Cigarette smoke and tubal dysfunction

Migration of the COC and embryo through the Fallopian tubes involves adhesion between the COC or embryo and tubal epithelium, ciliary activity and tubal muscular contraction (Table III). All these steps could represent targets of smoke toxicants. In hamster oviducts exposed to smoke solutions and gas phase extracted from MS and sidestream smoke (SS), decreased ciliary beat frequency (CBF), inhibition of oocyte retrieval and infundibular smooth muscle contractions (ISMC) were observed (Knoll et al., 1995; Magers et al., 1995; Knoll and Talbot, 1998; Talbot et al., 1998; Riveles et al., 2003,, 2004,, 2005,, 2007; Gieseke and Talbot, 2005), which could explain abnormal embryo transport and ectopic implantation (Knoll and Talbot, 1998; DiCarlantonio and Talbot, 1999; Riveles et al., 2003, 2005). All negative effects were observed in a dose-dependent manner (Knoll et al., 1995; Knoll and Talbot, 1998; Riveles et al., 2003). Moreover, Riveles et al. (2007) suggested that SS had more inhibitory effects than MS. While studying the effects of MS and SS compounds from traditional commercial cigarettes, Riveles et al. found that all of them inhibited CBF, oocyte retrieval rate and ISMC. Using ex vivo hamster oviducts, they demonstrated that smoke solutions extracted from MS of Marlboro red cigarettes decreased oocyte retrieval rate by 20%, CBF by 70% and ISMC by 99.4% (Riveles et al., 2007). When studying effects on the oviduct, Riveles et al. assessed the levels of many compounds contained in MS and SS, establishing for each one the lowest observable adverse effect levels (LOAEL). The LOAEL for nicotine and cotinine was high, with inhibitory effects on oocyte retrieval rate at 10−2M for nicotine and 10−5M for cotinine, suggesting that both nicotine and cotinine were not the major compounds involved in tubal dysfunction. However, for many other compounds, such as cyanide, pyridine and pyridine derivatives, and pyrazine and pyrazine derivatives, the LOAEL was lower than the concentration contained in MS and SS (Riveles et al., 2004). Cyanide is present in both MS and SS at concentrations of 167 and 67 µM, respectively, and had inhibitory effects on CBF at concentrations ranging from 50 to 100 µM (Talbot et al., 1998), suggesting involvement of cyanide in tubal dysfunction.

Table III

Effects of cigarette smoke on tubal functions.

Reference Model Exposure Dose of toxicants Effects 
Magers et al. (1995Female hamster Exposure chambers to mainstream and sidestream smoke Serum cotinine levels:
  • 72.8 ± 40.9 ng/ml under mainstream smoke exposure

  • 14.45 ± 8.9 ng/ml under sidestream smoke exposure

 
Blebs on the surface of epithelial cells 
 Histologic analysis of oviducts   Decreased ciliary cell quantity 
Knoll et al. (1995Female hamster oviducts ex vivo Smoke solution and gas phase from 60 puffs of mainstream and sidestream smoke Nicotine levels in
  • mainstream smoke solution: 129 ± 48 µg/ml

  • mainstream gas: 0.7 ± 0.2 µg/ml

  • sidestream smoke solution: 279 ± 57 µg/ml

  • sidestream smoke gas: 54 ± 7 µg/ml

 
Dose-dependent decreased ciliary beat frequency after exposure to smoke solutions and gas phase 
Knoll and Talbot (1998Female hamster oviducts ex vivo Smoke solution and gas phase from 60 puffs of mainstream and sidestream smoke Nicotine levels in
  • mainstream smoke solution: 129 ± 48 µg/ml

  • mainstream gas: 0.7 ± 0.2 µg/ml

  • sidestream smoke solution: 279 ± 57 µg/ml

  • sidestream smoke gas: 54 ± 7 µg/ml

 
Dose-dependant decreased oocyte retrieval rate 
Persistence of decreased oocyte retrieval after washing 
Dose-dependent decreased infundibular ciliary beat frequency 
Reversible ciliary beat frequency after washing 
Talbot et al. (1998Female hamster oviducts ex vivo Smoke solution and gas phase from 60 puffs of mainstream and sidestream smoke Concentration of ciliotoxic agents in mainstream smoke solution Dose that inhibits ciliary beat frequency 
   Acrolein: 50 ± 9 µM Acrolein: 1.78 mM 
   Formaldehyde: 166 ± 47 µM Formaldehyde: 1.66 mM 
   Phenol: 447 ± 16 µM Phenol: 10 mM 
   Cyanide: 167 ± 43 µM Cyanide: 50 µM 
Riveles et al. (2003Female hamster oviducts Smoke solution and gas phase from 60 puffs of mainstream and sidestream smoke Pyridine compounds isolated in smoke solutions and tested ex vivo: 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,3-dimethylpyridine, 2,5-dimethylpyridine, 2,6-dimethylpyridine, 3,4-dimethylpyridine, 2-ethylpyridine, 3-ethylpyridine, 3-vinylpyridine, 4,4-bipyridine, nicotine, cotinine, nornicotine, β-nicotyrine Mainstream cigarette smoke solutions:
  • oocyte retrieval rate decreased by 60%

  • ciliary beat frequency decreased by 35%

  • infundibular smooth muscle contraction decreased by 57%

 
   Consecutive doses in the range of 10−13–10−1M was used to determine the dose that caused inhibition of oocyte retrieval rate, ciliary beat frequency and infundibular smooth muscle contraction Inhibitory effects are observed at picomolar dose for 2-ethylpyridine, 4-methylpyridine, 2-methylpyridine, 3-vinylpyridine and 3-ethylpyridine 
    Inhibitory effect on oocyte retrieval rate was observed at 10−2M for nicotine and 10−5M for cotinine 
Riveles et al. (2004Female hamster oviducts ex vivo Smoke solution and gas phase from 60 puffs of mainstream and sidestream smoke Pyrazines were identified in smoke solutions and gas phase and were tested to define the LOAEL: Pyrizine inhibited ciliary beat frequency and oocyte retrieval rate at picomolar dose and infundibular smooth muscle contraction at nanomolar dose 
2-methylpyrazine, 2,5-dimethylpyrazine, 2,6-dimethylpyrazine, 2,3,5-trimethylpyrazine, 2-ethylpyrazine, 2-methoxy-3-methylpyrazine Pyrazine derivatives also inhibited ciliary beat frequency, oocyte retrieval rate and infundibular smooth muscle contraction at picomolar dose 
Gieseke and Talbot (2005Female hamster oviducts ex vivo Smoke solution and gas phase from 60 smoke puffs of mainstream and sidestream smoke Nicotine levels in
  • mainstream smoke solution: 129 ± 48 µg/ml

  • mainstream gas: 0.7 ± 0.2 µg/ml

  • sidestream smoke solution: 279 ± 57 µg/ml

  • sidestream smoke gas: 54 ± 7 µg/ml

 
Decreased COC adhesion to infundibulum 
    Decreased oocyte retrieval 
    More inhibitory effect with sidestream solutions 
    Decreased size of COC 
    Loss of cumulus cells 
    Extracellular matrix COC disruption 
    Increased adhesion between oocyte and infundibulum 
Riveles et al. (2005Female hamster oviducts ex vivoEstablishment of the LOAEL on oocyte retrieval rate, ciliary beat frequency, and infundibular smooth muscle contraction Smoke solution from 10 puffsMainstream and sidestream Compounds isolated in solid phase extraction of mainstream smoke solution: 2-methylphenol, 4-methylphenol, 2,4-dimethylphenol, 2,5-dimethylphenol, 2-methoxyphenol, 4-methoxyphenol, 2,6-dimethoxyphenol, 2-ethylphenol, 4-ethylphenol, hydroquinone, indole, 5-methylindole, quinoline, isoquinoline, benzene, 2-cyclopenten-1-one and 3-methyl-2-cyclopenten-1-one Decreased ciliary beat frequencyLOAELs from 10−12 to 10−1 M for phenolic compoundsDecreased oocyte retrievalLOAELs from 10−12 to 10−2 M for phenolic compoundsDecreased muscle contractionLOAELs from 10−12 to 10−2 M for phenolic compounds 
Riveles et al. (2007Female hamster oviducts ex vivo Solution and gas from 10 smoke puffs of traditional commercial cigarettes (Malboro red and light, Camel filtered and unfiltered, Advance, Omni and Omni light) Identification of compounds in smoke solutions and gas phase of traditional commercial cigarettes Mainstream and sidestream smoke solutions of all commercial cigarettes tested inhibited oocyte retrieval rate, ciliary beat frequency and infundibular smooth muscle contraction 
  Mainstream and sidestream smoke For Marlboro red, composition of smoke solution: 4-methylpyridine, 106.34 mg/ml; 2-ethylpyridine, 1.1 pg/ml; 3-ethylpyridine, 9.20 mg/ml; 2-methylpyrazine, 19.19 mg/ml; 2-ethylpyrazine, 0.239 mg/ml; 4-methylphenol, 5.32 mg/ml; 4-ethylphenol, 6.23 mg/ml; quinoline, 0.61 mg/ml; indole, 1.82 mg/ml Sidestream smoke solutions were more inhibitory than mainstream smoke solutions 
   Establishment of the LOAEL for all these compounds on oocyte retrieval rate, ciliary beat frequency and infundibular smooth muscle contraction Mainstream smoke solutions from Marlboro red decreased oocyte retrieval rate by 20%, ciliary beat frequency by 70% and infundibular smooth muscle contraction by 99.4% 
    LOAEL for oocyte retrieval rate was 9 × 10−9 mg/ml for 4-methylpyridine, 1 × 10−9 mg/ml for 2-ethylpyridine, 1 × 10−7 mfg/ml for 3-ethylpyridine, 9 × 10−10 mg/ml for 2-methylpyrazine, 1 × 10−9 mg/ml for 2-ethylpyrazine, 1.08 × 10−9 mg/ml for 4-methylphenol, 1 × 10−10 mg/ml for 4-ethylphenol, 1 × 10−9 mg/ml for quinoline and 1 × 10−12 mg/ml for indole 
Reference Model Exposure Dose of toxicants Effects 
Magers et al. (1995Female hamster Exposure chambers to mainstream and sidestream smoke Serum cotinine levels:
  • 72.8 ± 40.9 ng/ml under mainstream smoke exposure

  • 14.45 ± 8.9 ng/ml under sidestream smoke exposure

 
Blebs on the surface of epithelial cells 
 Histologic analysis of oviducts   Decreased ciliary cell quantity 
Knoll et al. (1995Female hamster oviducts ex vivo Smoke solution and gas phase from 60 puffs of mainstream and sidestream smoke Nicotine levels in
  • mainstream smoke solution: 129 ± 48 µg/ml

  • mainstream gas: 0.7 ± 0.2 µg/ml

  • sidestream smoke solution: 279 ± 57 µg/ml

  • sidestream smoke gas: 54 ± 7 µg/ml

 
Dose-dependent decreased ciliary beat frequency after exposure to smoke solutions and gas phase 
Knoll and Talbot (1998Female hamster oviducts ex vivo Smoke solution and gas phase from 60 puffs of mainstream and sidestream smoke Nicotine levels in
  • mainstream smoke solution: 129 ± 48 µg/ml

  • mainstream gas: 0.7 ± 0.2 µg/ml

  • sidestream smoke solution: 279 ± 57 µg/ml

  • sidestream smoke gas: 54 ± 7 µg/ml

 
Dose-dependant decreased oocyte retrieval rate 
Persistence of decreased oocyte retrieval after washing 
Dose-dependent decreased infundibular ciliary beat frequency 
Reversible ciliary beat frequency after washing 
Talbot et al. (1998Female hamster oviducts ex vivo Smoke solution and gas phase from 60 puffs of mainstream and sidestream smoke Concentration of ciliotoxic agents in mainstream smoke solution Dose that inhibits ciliary beat frequency 
   Acrolein: 50 ± 9 µM Acrolein: 1.78 mM 
   Formaldehyde: 166 ± 47 µM Formaldehyde: 1.66 mM 
   Phenol: 447 ± 16 µM Phenol: 10 mM 
   Cyanide: 167 ± 43 µM Cyanide: 50 µM 
Riveles et al. (2003Female hamster oviducts Smoke solution and gas phase from 60 puffs of mainstream and sidestream smoke Pyridine compounds isolated in smoke solutions and tested ex vivo: 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,3-dimethylpyridine, 2,5-dimethylpyridine, 2,6-dimethylpyridine, 3,4-dimethylpyridine, 2-ethylpyridine, 3-ethylpyridine, 3-vinylpyridine, 4,4-bipyridine, nicotine, cotinine, nornicotine, β-nicotyrine Mainstream cigarette smoke solutions:
  • oocyte retrieval rate decreased by 60%

  • ciliary beat frequency decreased by 35%

  • infundibular smooth muscle contraction decreased by 57%

 
   Consecutive doses in the range of 10−13–10−1M was used to determine the dose that caused inhibition of oocyte retrieval rate, ciliary beat frequency and infundibular smooth muscle contraction Inhibitory effects are observed at picomolar dose for 2-ethylpyridine, 4-methylpyridine, 2-methylpyridine, 3-vinylpyridine and 3-ethylpyridine 
    Inhibitory effect on oocyte retrieval rate was observed at 10−2M for nicotine and 10−5M for cotinine 
Riveles et al. (2004Female hamster oviducts ex vivo Smoke solution and gas phase from 60 puffs of mainstream and sidestream smoke Pyrazines were identified in smoke solutions and gas phase and were tested to define the LOAEL: Pyrizine inhibited ciliary beat frequency and oocyte retrieval rate at picomolar dose and infundibular smooth muscle contraction at nanomolar dose 
2-methylpyrazine, 2,5-dimethylpyrazine, 2,6-dimethylpyrazine, 2,3,5-trimethylpyrazine, 2-ethylpyrazine, 2-methoxy-3-methylpyrazine Pyrazine derivatives also inhibited ciliary beat frequency, oocyte retrieval rate and infundibular smooth muscle contraction at picomolar dose 
Gieseke and Talbot (2005Female hamster oviducts ex vivo Smoke solution and gas phase from 60 smoke puffs of mainstream and sidestream smoke Nicotine levels in
  • mainstream smoke solution: 129 ± 48 µg/ml

  • mainstream gas: 0.7 ± 0.2 µg/ml

  • sidestream smoke solution: 279 ± 57 µg/ml

  • sidestream smoke gas: 54 ± 7 µg/ml

 
Decreased COC adhesion to infundibulum 
    Decreased oocyte retrieval 
    More inhibitory effect with sidestream solutions 
    Decreased size of COC 
    Loss of cumulus cells 
    Extracellular matrix COC disruption 
    Increased adhesion between oocyte and infundibulum 
Riveles et al. (2005Female hamster oviducts ex vivoEstablishment of the LOAEL on oocyte retrieval rate, ciliary beat frequency, and infundibular smooth muscle contraction Smoke solution from 10 puffsMainstream and sidestream Compounds isolated in solid phase extraction of mainstream smoke solution: 2-methylphenol, 4-methylphenol, 2,4-dimethylphenol, 2,5-dimethylphenol, 2-methoxyphenol, 4-methoxyphenol, 2,6-dimethoxyphenol, 2-ethylphenol, 4-ethylphenol, hydroquinone, indole, 5-methylindole, quinoline, isoquinoline, benzene, 2-cyclopenten-1-one and 3-methyl-2-cyclopenten-1-one Decreased ciliary beat frequencyLOAELs from 10−12 to 10−1 M for phenolic compoundsDecreased oocyte retrievalLOAELs from 10−12 to 10−2 M for phenolic compoundsDecreased muscle contractionLOAELs from 10−12 to 10−2 M for phenolic compounds 
Riveles et al. (2007Female hamster oviducts ex vivo Solution and gas from 10 smoke puffs of traditional commercial cigarettes (Malboro red and light, Camel filtered and unfiltered, Advance, Omni and Omni light) Identification of compounds in smoke solutions and gas phase of traditional commercial cigarettes Mainstream and sidestream smoke solutions of all commercial cigarettes tested inhibited oocyte retrieval rate, ciliary beat frequency and infundibular smooth muscle contraction 
  Mainstream and sidestream smoke For Marlboro red, composition of smoke solution: 4-methylpyridine, 106.34 mg/ml; 2-ethylpyridine, 1.1 pg/ml; 3-ethylpyridine, 9.20 mg/ml; 2-methylpyrazine, 19.19 mg/ml; 2-ethylpyrazine, 0.239 mg/ml; 4-methylphenol, 5.32 mg/ml; 4-ethylphenol, 6.23 mg/ml; quinoline, 0.61 mg/ml; indole, 1.82 mg/ml Sidestream smoke solutions were more inhibitory than mainstream smoke solutions 
   Establishment of the LOAEL for all these compounds on oocyte retrieval rate, ciliary beat frequency and infundibular smooth muscle contraction Mainstream smoke solutions from Marlboro red decreased oocyte retrieval rate by 20%, ciliary beat frequency by 70% and infundibular smooth muscle contraction by 99.4% 
    LOAEL for oocyte retrieval rate was 9 × 10−9 mg/ml for 4-methylpyridine, 1 × 10−9 mg/ml for 2-ethylpyridine, 1 × 10−7 mfg/ml for 3-ethylpyridine, 9 × 10−10 mg/ml for 2-methylpyrazine, 1 × 10−9 mg/ml for 2-ethylpyrazine, 1.08 × 10−9 mg/ml for 4-methylphenol, 1 × 10−10 mg/ml for 4-ethylphenol, 1 × 10−9 mg/ml for quinoline and 1 × 10−12 mg/ml for indole 

LOAEL, lowest observable adverse effect level.

Mechanisms involved in alteration of tubal function

The mechanisms involved in impairment of ciliary beating remain poorly understood. Normal ciliary activity is related to ciliary cell quantity (Paltieli et al., 1995). Magers et al. (1995) investigated ciliated cells in the oviductal ampulla of hamsters exposed to smoke and found a lower rate of ciliated cells versus controls (69.2, 62.2 and 65.8%, respectively, in control, MS and SS exposed). A defective quality of ciliary beats was observed after exposure of animal oviducts to smoke (Riveles et al., 2005). This ciliary dyskinesia observed after exposure to cigarette smoke was also described in other epithelia, such as the bronchial epithelium (Wyatt et al., 2000; Elliott et al., 2006). Some components of cigarette smoke interfere with proteic complexes involved in ciliary mobility, such as axoneme and dynein (Sisson et al., 1991) or calcium signalling and protein kinase-mediated pathways (Villalon et al., 1989; Wyatt et al., 2000), which could all contribute to impairment of ciliary activity. In animal models, it was also demonstrated that CBF was influenced and dependent on sex steroids, acting through steroid receptors which were identified in ciliary epithelial cells (Paltieli et al., 2000; Shao et al., 2007). As previously described, smoke exposure, acting through impairment of steroidogenesis, could also disturb ciliary activity. Decreased oocyte retrieval could be explained by abnormal and increased adhesion between COC and tubal epithelium, leading to a slow migration of COC. Decreased CBF could obviously contribute to slow COC migration. A quantitative and qualitative impairment of ciliated cells resulting from smoke exposure could account for excessive adhesion between COC and tubal epithelium (Magers et al., 1995), whereas an abnormal COC extracellular matrix (Vrsanska et al., 2003; Gieseke and Talbot, 2005) was thought to be implicated in the abnormal relationship between COC and tubal epithelium, abnormal oocyte retrieval and abnormal migration through Fallopian tubes.

Fallopian tubes seem to be targets of cigarette smoke with deleterious consequences on ciliary cell quantity and quality, oocyte retrieval deficiency, CBF impairment and COC–epithelial cell excessive adhesion. These findings could easily explain abnormal tubal function and the higher rates of ectopic pregnancy observed in patients who smoke.

Cigarette smoking and embryo implantation

Embryo implantation requires a properly prepared endometrium. Site and quality of implantation play a major role in determining the risk of morbidity and mortality during pregnancy.

Impairment of embryo implantation was suspected in cigarette smokers: lower implantation rates were observed in smokers who underwent IVF, even if the results were controversial (Winter et al., 2002; Freour et al., 2008). Using human oocyte donation models, Soares et al. (2007) studied implantation rates in recipients according to their smoking status: implantation rates were lower in heavy smokers (>10 cigarettes/day) than in non-smokers (25.8 and 32.3%, respectively).

Effects of cigarette smoke on the endometrium

The potential effects of cigarette smoke compounds on the endometrium are not well known (Table IV). Using female rats exposed to nicotine, Card and Mitchell investigated the potential effects of nicotine on endometrial decidualization by assessing the weight of the uterus after mechanically induced decidualization. They found a lower uterus weight after nicotine administration and concluded that there was an adverse effect on the decidualization process (Card and Mitchell, 1978). Using primary endometrial cells from hysterectomy specimens and human endometrial epithelial cell lines, Khorram et al. studied the effects of an aqueous cigarette smoke solution. They observed a significant dose-dependent decrease in endometrial proliferation, involving nitric oxide (NO)-mediated pathways (Khorram et al., 2010).

Table IV

Effects of cigarette smoke on implantation.

Reference Model Dose of toxicants Effects 
Smoke effects on endometrium 
Card and Mitchell (1978Rat uterus s.c. nicotine injection 0.5–5.0 mg/kg Decreased uterus weight 
   Nicotine suppressed uterine responsivity to decidualization 
Soghomonians et al. (2004Human uterine endothelial cell culture in a smoking chamber Nicotine levels 1.25–10 mg/m3 Increased PECAM-1 synthesis 
   Abnormal endothelial cell PECAM-1 distribution 
   Decreased endothelial cell mobility and migration 
Zhang et al. (2007Rat uterus and endometrium i.p. cadmium injection 0.12–1.20 mg/kg Thicker luminal epithelial cell layer, endometrium and myometrium 
   Stromal inflammation 
   Cellular oedema 
   Decreased PCNA expression 
Tsutsumi et al. (2009Human endometrial stromal cells Cadmium 10–100–1000 nmol/l Increased prolactin gene expression 
   Earlier decidualization and disrupted timed decidualization 
Khorram et al. (2010Human endometrial surface epithelial cell line and human endometrial cells Aqueous cigarette smoke-saturated solution Smoke solution inhibited cell proliferation in a dose-dependent manner 
  Nicotine: 10−5 mol/l No effect on cell viability by smoke solution 
  BaP: 10−5 mol/l Increased proliferation via NO pathway 
   BaP and nicotine activated NO synthase expression 
Smoke effects on implantation and placentation 
Zhang et al. (1995Human choriocarcinoma cell lines BeWo BaP in culture medium: 1 nM–50 µM Decreased binding of EGF to BeWo 
   Decreased EGF receptor protein levels but not EGF mRNA levels 
   Inhibition of cell proliferation 
   Decreased EGF-stimulated hCG secretion 
Zhang and Shiverick (1997Human placental trophoblastic choriocarcinoma cell line JEG-3 BaP 10 µM for 1, 3, 5 and 7 days Decreased cell proliferation 
   Decreased EGF receptor level 
   Decreased TGF-β1 mRNA level 
Genbacev et al. (2000Placenta from 6–8, 8–10 and 10–12 gestational weeks for in situ study 0 cig/day Thin syncytiotrophoblast 
  <10 cig/day Reduced number of villous cytotrophoblast 
  11–20 cig/day Areas of discontinuity in cytotrophoblast layer 
  >20 cig/day Highly circonvoluted fetal blood vessels 
   Increasing number of blindly ended cytotrophoblast columns 
   Amorphous matrix in cytotrophoblast columns 
   Increased number of cell islands 
   Decreased Ki67 reactivity of villous and columns cytotrophoblasts 
 Placenta from first trimester termination of non-smokers leading to anchoring villi culture Nicotine in culture medium: 0.23, 2.3 or 6.0 µM Increased rate of apoptosis 
   Decreased expression of fibronectin and fibronectin receptor integrin α5/β1 
   Decreased trophoblast proliferation and invasion 
Zdravkovic et al. (2006Placenta from first trimester termination at 6–8 weeks of gestation (smoker and non-smokers) 0 cig/day Increased number of cell islands 
  <10 cig/day Increased number of nonadherent cell columns 
  11–20 cig/day Decreased cytotrophoblast l-selectin expression 
  >20 cig/day  
 Organ culture of placental anchoring villus explants Nicotine in culture medium: 0.23, 2.3, 4.6, or 6.0 µM Decreased l-selectin expression 
   Lowest effective dose of nicotine on l-selectin expression 4.2 µM 
   Decreased development of cell columns 
Genbacev et al. (1995Placenta from first trimester termination at 6–8 weeks of gestation (smoker and non-smokers) 0 cig/day Decreased anchoring villi 
  >20 cig/day Less prominent cytotrophoblast columns 
 Culture of human cytotrophoblasts Nicotine in culture medium: 0.23, 1.15 or 2.3 µM Decreased cytotrophoblast proliferation and differentiation 
   Decreased cytotrophoblast invasion 
   Dose-dependent effect 
   Decreased MMP-9 production and activation 
Thirkill et al. (2006Trophoblast cells from term macaque placentas Cigarette smoke-conditioned medium Decreased trophoblast migration 
 Human uterine microvascular endothelial cells Nicotine 1.25–10 mg/m3 Reduced chemokine RANTES expression 
Jolibois et al. (1999Culture of human trophoblast cells Cadmium in culture medium 0, 5, 10 and 20 µM Inhibition of syncytial maturation 
   No effect on DNA fragmentation and cell viability 
Reference Model Dose of toxicants Effects 
Smoke effects on endometrium 
Card and Mitchell (1978Rat uterus s.c. nicotine injection 0.5–5.0 mg/kg Decreased uterus weight 
   Nicotine suppressed uterine responsivity to decidualization 
Soghomonians et al. (2004Human uterine endothelial cell culture in a smoking chamber Nicotine levels 1.25–10 mg/m3 Increased PECAM-1 synthesis 
   Abnormal endothelial cell PECAM-1 distribution 
   Decreased endothelial cell mobility and migration 
Zhang et al. (2007Rat uterus and endometrium i.p. cadmium injection 0.12–1.20 mg/kg Thicker luminal epithelial cell layer, endometrium and myometrium 
   Stromal inflammation 
   Cellular oedema 
   Decreased PCNA expression 
Tsutsumi et al. (2009Human endometrial stromal cells Cadmium 10–100–1000 nmol/l Increased prolactin gene expression 
   Earlier decidualization and disrupted timed decidualization 
Khorram et al. (2010Human endometrial surface epithelial cell line and human endometrial cells Aqueous cigarette smoke-saturated solution Smoke solution inhibited cell proliferation in a dose-dependent manner 
  Nicotine: 10−5 mol/l No effect on cell viability by smoke solution 
  BaP: 10−5 mol/l Increased proliferation via NO pathway 
   BaP and nicotine activated NO synthase expression 
Smoke effects on implantation and placentation 
Zhang et al. (1995Human choriocarcinoma cell lines BeWo BaP in culture medium: 1 nM–50 µM Decreased binding of EGF to BeWo 
   Decreased EGF receptor protein levels but not EGF mRNA levels 
   Inhibition of cell proliferation 
   Decreased EGF-stimulated hCG secretion 
Zhang and Shiverick (1997Human placental trophoblastic choriocarcinoma cell line JEG-3 BaP 10 µM for 1, 3, 5 and 7 days Decreased cell proliferation 
   Decreased EGF receptor level 
   Decreased TGF-β1 mRNA level 
Genbacev et al. (2000Placenta from 6–8, 8–10 and 10–12 gestational weeks for in situ study 0 cig/day Thin syncytiotrophoblast 
  <10 cig/day Reduced number of villous cytotrophoblast 
  11–20 cig/day Areas of discontinuity in cytotrophoblast layer 
  >20 cig/day Highly circonvoluted fetal blood vessels 
   Increasing number of blindly ended cytotrophoblast columns 
   Amorphous matrix in cytotrophoblast columns 
   Increased number of cell islands 
   Decreased Ki67 reactivity of villous and columns cytotrophoblasts 
 Placenta from first trimester termination of non-smokers leading to anchoring villi culture Nicotine in culture medium: 0.23, 2.3 or 6.0 µM Increased rate of apoptosis 
   Decreased expression of fibronectin and fibronectin receptor integrin α5/β1 
   Decreased trophoblast proliferation and invasion 
Zdravkovic et al. (2006Placenta from first trimester termination at 6–8 weeks of gestation (smoker and non-smokers) 0 cig/day Increased number of cell islands 
  <10 cig/day Increased number of nonadherent cell columns 
  11–20 cig/day Decreased cytotrophoblast l-selectin expression 
  >20 cig/day  
 Organ culture of placental anchoring villus explants Nicotine in culture medium: 0.23, 2.3, 4.6, or 6.0 µM Decreased l-selectin expression 
   Lowest effective dose of nicotine on l-selectin expression 4.2 µM 
   Decreased development of cell columns 
Genbacev et al. (1995Placenta from first trimester termination at 6–8 weeks of gestation (smoker and non-smokers) 0 cig/day Decreased anchoring villi 
  >20 cig/day Less prominent cytotrophoblast columns 
 Culture of human cytotrophoblasts Nicotine in culture medium: 0.23, 1.15 or 2.3 µM Decreased cytotrophoblast proliferation and differentiation 
   Decreased cytotrophoblast invasion 
   Dose-dependent effect 
   Decreased MMP-9 production and activation 
Thirkill et al. (2006Trophoblast cells from term macaque placentas Cigarette smoke-conditioned medium Decreased trophoblast migration 
 Human uterine microvascular endothelial cells Nicotine 1.25–10 mg/m3 Reduced chemokine RANTES expression 
Jolibois et al. (1999Culture of human trophoblast cells Cadmium in culture medium 0, 5, 10 and 20 µM Inhibition of syncytial maturation 
   No effect on DNA fragmentation and cell viability 

BaP, benzo(a)pyrene; PECAM, platelet endothelial cell adhesion molecule 1; PCNA, proliferating cell nuclear antigen; NO, nitric oxide; EGF, epidermal growth factor; mRNA, messenger ribonucleic acid; TGF-β1, transforming growth factor beta-1; MMP-9, matrix metallopeptidase-9; DNA, deoxyribonucleic acid; RANTES, regulated upon activation normal T-cells expressed and secreted.

BaP acts through AhR, a receptor located in the endometrial stroma and epithelial cells. The AhR levels were shown to vary during the entire cycle and peri-implantation period (Kuchenhoff et al., 1999; Kitajima et al., 2004). A potential implication of this receptor was demonstrated using a mouse model: AhR knockout mice were characterized by early pregnancy loss and intrauterine fetal death (Abbott et al., 1999), suggesting that AhR plays a role in the mechanism of implantation and trophoblast invasion.

By interfering with cytochromes involved in estrogen metabolism, BaP and PAH derivatives could act as an anti-estrogenic factor, thereby compromising endometrial maturation (Fertuck et al., 2001; Bao et al., 2002). Using immortalized human endometrial cells, Bao et al. (2002) investigated the effects of BaP on CYPA1, a cytochrome involved in estrogen catabolism and demonstrated that incubation with BaP increased CYPA1 expression and activity (12-fold at 1 µM). These observations could explain abnormal endometrial maturation. Cd could also disturb endometrial maturation. Zhang et al. (2007) demonstrated that animal models exposed to i.p. Cd had a thicker endometrial epithelial layer and stromal inflammation. Tsutsumi et al. investigated the effects of Cd on endometrial maturation using human endometrial stromal cell cultures, with prolactin as a marker of decidualization; when exposed to low doses of Cd (10 and 100 nmol/l), no change in prolactin expression was observed. At 1 µmol/l, prolactin concentration showed a significant 2.4-fold increase, indicating a CdCl2-induced decidualization process: the authors concluded that an earlier CdCl2-induced decidualization process could have been the cause of the lower implantation rates seen in heavy smokers (Tsutsumi et al., 2009).

Effects on endometrial angiogenesis

The hypothesis that smoke compounds, particularly BaP, influence angiogenesis is strongly supported by (i) the presence of AhR, in endometrial vessels walls (Kitajima et al., 2004) and (ii) observation of hypertrophic vessel walls in AhR knockout mice (Fernandez-Salguero et al., 1997). Thus, a BaP-induced inhibitory effect on endothelial cell proliferation is strongly suspected. Soghomonians et al. investigated the in vitro effects of cigarette smoke on human uterine endothelial cells incubated with smoke-conditioned medium as well as on PECAM-1, a molecule involved in endothelial cell adhesion. They found that cigarette smoke compounds (i) influenced human endothelial cell mobility and morphology, (ii) increased PECAM-1 surface expression and (iii) induced aberrant localization of PECAM-1 (Soghomonians et al., 2004), suggesting an aberrant regulation of the angiogenic process caused by smoke compounds. The effects of nicotine on angiogenesis have been studied more comprehensively using placenta, in the later stages of pregnancy: nicotine was implicated in the activation of endothelial cell migration and proliferation, and presented pro-angiogenic properties (Cooke and Bitterman, 2004; Dasgupta and Chellappan, 2006), resulting in increased placental capillary development (Pfarrer et al., 1999).

Smoke compounds seem to present pro- and anti-angiogenic properties, probably involving complex mechanisms. Further studies are necessary to understand the consequences of, and to clarify the mechanisms involved in, the effects of smoke on angiogenesis, impairment of embryo implantation and early placental development.

Effects of cigarette smoking on trophoblastic adhesion and invasion

Effects of cigarette smoking on the implantation process were demonstrated using mouse models: Esposito et al. (2008) studied fetal outcomes in pregnant mice exposed to cigarette smoke only during the peri-implantation period and found a lower fetal weight (1.10 g) than in the control group (1.18 g).

Histological studies of first trimester placenta demonstrated that smoking was associated with abnormal placental morphology such as a thinner syncytiotrophoblast, fewer villous cytotrophoblasts, a discontinuous cytotrophoblast layer, presence of highly circonvoluted fetal blood vessels, an increased number of blindly ending cytotrophoblast columns and fewer anchoring villi (Genbacev et al., 1995; Zhang et al., 1995; Genbacev et al., 2000; Zdravkovic et al., 2006).

Implantation and early placentation require adhesion between blastocyst and endometrium, trophoblastic proliferation, differentiation, migration and invasion. Using human trophoblastic cells, it was demonstrated that cigarette compounds decreased the likelihood of normal placental formation, trophoblastic migration (Genbacev et al., 2000; Thirkill et al., 2006; Zdravkovic et al., 2006), invasion and differentiation (Genbacev et al., 1995, 2000) (Table IV). Using human trophoblast cells, Genbacev et al. (2000) investigated cytotrophoblast mitotic ability and observed a dose-dependent decrease in mitotic and proliferative ability after smoke exposure. They also studied the migration ability by in vitro analysis of cytotrophoblast outgrowth of cultured villous tissue after the addition of increasing doses of nicotine and found a dose-dependent decrease in migration and invasion ability (Genbacev et al., 1995).

Migration and invasion require an interaction between trophoblast and endometrium and involves molecules located on the endometrium layer and the trophoblast surface. The l-selectin receptor and its oligosaccharide ligand are implicated in the trophoblast–endometrium adhesion process (Genbacev et al., 2003) as well as in the interaction between the extra-villous cytotrophoblast and the endometrium (Prakobphol et al., 2006). In smokers, Zdravkovic et al. (2006) described lower levels of l-selectin in trophoblast and cytotrophoblast cells, explaining adhesion impairment and the deleterious interaction between the endometrium and the cytotrophoblast cells.

Trophoblastic invasion is controlled by molecules such as matrix metalloproteases (MMP), epidermal growth factor (EGF) and hCG (Cameron, 1998; Bischof and Campana, 2000; Isaka et al., 2003; Lala and Chakraborty, 2003; Staun-Ram et al., 2004).

In the placental tissue of smokers, lower levels of MMP-9 were observed in cytotrophoblastic cells and MMP-9 activity was decreased by 90% when high doses of nicotine were added to the culture medium (Genbacev et al., 1995). On the promoter of the MMP-1 gene, a response element was identified as a target of smoke compounds, which suggested that smoke compounds had a direct influence on MMP gene expression (Mercer et al., 2009). Zhang et al. demonstrated that human placental trophoblastic cell lines exposed to BaP showed an altered ability to proliferate owing to lower EGF and EGF receptor expression (Zhang et al., 1995; Zhang and Shiverick, 1997). hCG is a key regulator implicated in endometrial receptivity and trophoblastic invasion through MMP regulation (Fluhr et al., 2008). In floating villi, the fusion of cytotrophoblast is regulated by hCG. Using human placental explants cultured in vitro, hCG secretion by trophoblast cells was shown to be influenced by cigarette smoke compounds: when exposed to low doses of Cd or BaP, hCG pulse amplitude and secretion were increased and, in contrast, in the case of high doses of Cd, hCG pulse amplitude was inhibited (Barnea and Shurtz-Swirski, 1992; Boadi et al., 1992). A modification of hCG secretion profile, depending on the smoke compounds and the level of exposure, could explain different degrees of implantation impairment as well as the complexity of abnormalities described.

Cigarette smoking and uterine flow velocity

During the menstrual cycle, changes in blood flow velocity occur in the uterine artery. During the implantation window, a low uterine pulsatility index and high uterine flow velocity were observed (Sladkevicius et al., 1993, 1994; Tan et al., 1996).

Goswamy et al. (1988) introduced the concept of infertility related to vascular impairment. Even if the relationship between abnormal uterine or endometrial blood flow velocity and IVF failure remains controversial (Ng et al., 2007b; Hoozemans et al., 2008), several authors have demonstrated that uterine arterial ultrasound abnormalities were associated with a lower implantation rate in IVF (Ng et al., 2007a; Dechaud et al., 2008; Merce et al., 2008).

Effect of cigarette smoking on uterine and endometrial blood flow

Cigarette smoking was shown to induce vascular flow changes with increasing blood pressure and vasoconstriction, immediately following cigarette consumption (Moliterno et al., 1994). Increased levels of vasoactive molecules, such as epinephrine, norepinephrine (Zhu and Parmley, 1995) or endothelin (Haak et al., 1994), were observed immediately after cigarette consumption. Inhibition of NO-induced endothelial relaxation after nicotine exposure was also observed in animal uterine arteries (Xiao et al., 2007) and could participate in haemodynamic changes.

The hypothesis that cigarette smoking could influence uterine artery velocity is controversial (Morrow et al., 1988; Newnham et al., 1990; Muller et al., 2002; Albuquerque et al., 2004). Ng et al. (2006) analysed the effects of cigarette smoking on uterine and endometrial velocity in IVF: no effects were found during Doppler examination of smokers. Lymperopoulou et al. studied uterine blood flow in smoking and non-smoking pregnant women according to cotinine levels (< and ≥20 ng/ml): the mean diastolic index was lower in the group with higher cotinine levels (38.7 versus 44.3%). They also found a negative correlation between the uterine artery resistance index (RI) and cotinine levels (Lymperopoulou et al., 1996). Albuquerque et al. (2004) studied the effects of maternal smoking on uterine and umbilical blood flows, taking into account the interval between the last cigarette and the ultrasound scan. They found a higher incidence of Notch in smokers but failed to find any difference between smokers and non-smokers with respect to the uterine artery RI (0.54 and 0.52, respectively, in the non-smoking and smoking groups). However, RI declined as time after the last cigarette elapsed (Albuquerque et al., 2004). Evaluating uterine artery RI in pregnant women who smoke, before and after smoking 2 cigarettes, Castro et al. (1993) found a significant decrease of uterine RI within 5 min after cigarette consumption (from 0.55 to 0.49) with a return to normal levels within 30 min. These findings indicate a short-lived but substantial effect of smoke compounds on uterine arteries. More studies are necessary to confirm the effects of cigarette smoke on uterine blood flow and to investigate a potential effect on spiral arteries and on implantation.

Cigarette smoking and myometrial activity

During the menstrual cycle, the uterus is characterized by myometrial contractions with variations depending on the phase of the cycle, mainly influenced by hormonal status (Lyons et al., 1991; Shafik, 1997; Bulletti et al., 2000; Kunz and Leyendecker, 2002).

Fanchin et al. (1998) demonstrated that a high myometrial contraction frequency on the day of embryo transfer in IVF was associated with lower plasma progesterone levels and implantation rates, suggesting the important role of myometrial quiescence in the implantation process and the role of progesterone in myometrial quiescence.

The potential effect of cigarette smoking on myometrial activity remains poorly understood. However, a negative effect of smoke compounds on myometrial activity was suspected based on the higher rate of premature labour observed in pregnant women who smoke (Cnattingius et al., 1999; Jaddoe et al., 2008).

Effects of cigarette smoke on myometrial activity

The synthesis of progesterone, a regulator of myometrial quiescence, appeared to be reduced after smoke exposure (Paksy et al., 1989; Piasek and Laskey, 1994). Using rat models, Bojanowska et al. (1985) observed that smoke exposure increased the release of neurohypophysial oxytocin. In rat models and human myometrial cells exposed to cigarette smoke extracts, a higher sensitivity to oxytocin as well as a higher frequency of oxytocin-induced contractions was observed (12.2/10 versus 6.4/10 min in controls). Furthermore, higher oxytocin receptor transcript levels (3- to 4-fold) were found in the myometrium of smokers than non-smokers (Egawa et al., 2003). Likewise, Nakamoto et al. (2006) confirmed higher myometrial sensitivity to oxytocin after smoke exposure, but observed increased levels of oxytocin receptor transcripts in preterm myometrium only. These observations suggest that exposure to smoke led to both an earlier and an overexpression of oxytocin receptors resulting in an increased sensitivity to the ligand, along with an aberrant regulation of myometrial contraction and quiescence.

Mechanisms involved in smoke-induced contractions have not been sufficiently investigated. Cd, whose structure is close to that of calcium, was shown to interact with calcium and oxytocin and, as such, affected myometrial activity. At lower Cd concentrations, spontaneous contractions of ex vivo human myometrial samples were enhanced (Sipowicz et al., 1995).

Steroidogenesis impairment, higher secretion of oxytocin and its receptors, increased oxytocin sensitivity, and interactions with calcium signalling have all been observed after smoke exposure. A possible relationship between abnormal myometrial contractility and exposure to smoke, as well as between smoke consumption and the implantation process, could be suspected. More studies are necessary to confirm the consequences of cigarette smoke on myometrial quiescence.

Factors influencing smoke effects on reproductive tract and function

Human and experimental studies demonstrated deleterious effects of smoke on reproductive functions. However, conclusions remain heterogeneous. Many factors could explain different consequences observed in these different studies: smoking behaviour, individual sensitivity, interaction with other toxicants, presence of environmental tobacco smoke (ETS) and time and duration of exposure.

Smoking behaviour and inter-individual sensitivity

In a study involving men smoking the same cigarette brand, blood nicotine levels ranged from 31.3 to 41.0 ng/ml (Armitage et al., 1975). Such a difference could be partially explained by different smoking behaviour, such as volume, duration and length of puffs (Russel et al., 1980; Sutton et al., 1982). Individual differences in blood nicotine levels are attributable for 50–60% to smoking behaviour while cigarette yield of nicotine influenced <25% of blood cotinine levels (Herning et al., 1983). Inter-individual differences in nicotine and cotinine metabolism could also explain differing cotinine and nicotine blood levels. Black smokers were shown to have higher cotinine levels than white smokers, independent of the number of cigarettes smoked (Caraballo et al., 1998; Perez-Stable et al., 1998). In studies with twins, it was demonstrated that the metabolism of nicotine and cotinine was influenced by genetic and environmental effects (Lessov-Schlaggar et al., 2009; Swan et al., 2009). Swan et al., 2009 showed that nicotine metabolism differed depending on individual characteristics, such as sex and BMI. Different smoking behaviours, ethnicity and variation in individual metabolism remain difficult to study but probably contribute to the heterogeneous conclusions derived from human studies.

Interactions and influence of other xenobiotic agents

Interactions with other toxicants could also explain the different effects on reproductive functions. In most animal studies, only the effects of one compound were analysed, but cigarette smoke contains more than 4000 compounds. Using cells in culture, Hewitt et al. demonstrated different levels of Bax and Bcl-2 following exposure to BaP, and depending on the presence or not of other xenobiotic substances, and particularly depending on the presence of E2 (Hewitt et al., 2007). Moreover, Swan et al. (2009) observed a higher nicotine metabolism in women who used oral contraceptives than those who did not. These observations suggest that environmental toxicants could act in a synergystic, inhibitory or antagonist manner, depending on the presence of other substances.

Doses and duration of exposure

A negative association between the number of daily cigarettes and fecundability was observed (Baird and Wilcox, 1985; Howe et al., 1985; Bolumar et al., 1996), in a dose-dependent manner (Curtis et al., 1997). A positive correlation between follicular fluid smoke compounds levels and the number of daily cigarettes smoked was also shown (Zenzes et al., 1996; Neal et al., 2008). In experimental studies, a dose–response relationship was also often observed, confirming that deleterious effects of cigarettes are correlated to the extent of exposure. However, animals were often exposed to acute doses of smoke, different from the level of human exposure, and without taking into consideration, the duration of exposure. In couples undergoing IVF, Klonoff-Cohen et al., (2001) demonstrated that long duration of smoke exposure (>5 years) was associated with IVF failure [RR of not achieving a pregnancy = 4.27 (1.53–11.97)]. In mouse models exposed to a repeated low dose of PAH, a greater ovotoxicity than a single high dose was observed (Borman et al., 2000). These conclusions highlight the importance of taking doses and exposure duration into account for a better understanding of the heterogeneous effects of smoke on human reproductive functions.

MS, SS and environmental smoke exposure

In many human studies, only active smoking has been recorded, without taking ETS into account. The effects of SS smoke are not well investigated and controversial. Pattinson et al. (1991) evaluated IVF outcomes in active, passive and non-smokers; patients were considered as passive smokers if their husbands smoked at least 1 cigarette a day: similar pregnancy rates were observed among non-smokers and passive smokers. Neal et al., (2005) observed a decreased and similar pregnancy rates per transfer in passive and active smoking patients after IVF. Klonoff-Cohen et al. (2001) evaluated the effects of passive smoking on IVF outcomes and found fewer retrieved oocytes in couples in which only the husband smoked. The compositions of MS and SS are different: PAH levels were found to be higher in SS than MS (about 10-fold) (Lodovici et al., 2004; Moir et al., 2008). Follicular fluid analysis of passive smokers revealed the presence of smoke compounds at a higher level when compared with non-smokers (Zenzes et al., 1996; Neal et al., 2008). These observations led to a better understanding of the effects of SS, and that passive smoking should be taken into consideration.

Time of exposure

The hypothesis of deleterious effects of antenatal and childhood exposure to cigarette smoke on adult fertility was raised (Baird and Wilcox, 1986; Weinberg et al., 1989; Wilcox et al., 1989; Jensen et al., 1998; Laurent et al., 1992; Joffe et al., 2000). An association of prenatal exposure and active adult smoking was also demonstrated, being more deleterious on fecundability than adult smoking without prenatal exposure (Jensen et al., 2006). In animal experiments, early deleterious effects on folliculogenesis were demonstrated: using pregnant mice exposed to cigarette smoke, analysis of the ovaries in offspring demonstrated fewer follicles in mice that were exposed to smoke prenatally (Vähäkangas et al., 1985). Using mice models exposed to BaP, Mackenzie and Angevine (1981) studied reproductive function and ovarian histology: fewer litters and hypoplastic ovaries with fewer follicles were observed in mice prenatally exposed. Only one human study has analysed the effects of prenatal exposure on follicle count. Lutterodt et al. investigated the effects of maternal cigarette smoke exposure during the first trimester on human embryonic ovaries obtained from legal abortions. They found fewer oogonia and somatic cells in the exposed group (Lutterodt et al., 2009), suggesting an early, irreversible and deleterious effect of maternal smoke. Moreover, using ovarian cell cultures from mice fetuses, Matikainen et al. (2002) demonstrated that addition of BaP to the culture medium led to fetal oocyte apoptosis and increased Bax expression. Deleterious effects of prenatal exposure have raised questions about the irreversible effects and decreased ovarian reserve at birth. Moreover, prenatal exposure could interact with, or increase, the negative effects arising from active and passive exposure to smoke in both childhood and adulthood. Different effects at different times of exposure explain the difficulties in analysing the consequences of exposure to smoke, as well as the additive and complex effects of different cumulative exposures.

The effects of past smoking on reproductive functions are also not well known. In many studies, past smokers are considered as non-smokers. Few studies have categorized patients into active, past and non-smokers. Curtis et al. (1997) did not find a decreased fecundability ratio in past smokers. Jensen et al. (2006) observed that past smokers showed the same time period necessary for conceiving as non-smokers. As few studies have analysed the effects of past smoking, and because in many studies, past smoking was not categorized, conclusions are difficult to establish. However, given the absence of, or only minor, effects of past smoking on fertility, and the negative effects observed when exposure occurred during prenatal life and childhood, this suggest a critical time of exposure, with a high sensitivity to cigarette smoke during fetal development. However, regardless of the observed effects of past smoking, teenagers, women in reproductive life and pregnant women should all be encouraged to stop smoking.

Limitations of experimental and human studies

Experimental studies showed deleterious effects of cigarette smoke on reproductive function. Doses used in experimental studies likely do not correspond to blood and tissue toxicant levels. Moreover, durations and routes of administration are also different. Only one compound was examined in experimental studies, but humans are exposed to more than 4000 compounds. Owing to the limitations of animal studies, extrapolation to human observations should be carried out with great care. However, experimental studies confirm the deleterious effects observed in human studies, allowing us to better understand the negative effects of cigarette smoking on reproductive function and the mechanisms involved.

Conclusion

Exposure to cigarette smoke impairs every stage of the reproductive process and each part of the reproductive system such as folliculogenesis, steroidogenesis, embryonic development and transport, endometrial maturation, implantation and early placentation, uterine vascular velocity and myometrial activity. Cigarette smoke compounds interact with different reproductive targets, depending on individual sensitivities, the presence of other toxic substances and according to time, dose, type and duration of exposure. Because infertile women are known to be motivated to stop smoking, particularly when they are attending for assisted reproduction treatments (Hughes et al., 2000), physicians should encourage these patients to stop smoking.

Further studies are necessary to understand the deleterious effects of smoke compounds on the reproductive system and to provide better knowledge of the molecular mechanisms involved in reproductive toxicology.

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