Abstract
Epidemiologic and experimental evidences converge to indicate that air pollution, at the current levels, play a deleterious role on reproductive health. Higher levels of air pollution are found in developing and underdeveloped countries in regions with high population density and higher fertility rates and although the risks associated with the negative reproductive outcomes tend to be small, the number of people that might be affected is significantly large. In this chapter we review the major epidemiological findings (decreased fertility, adverse gestational outcomes, reproductive system cancer, low vitamin D and immune system alterations), current experimental evidence, and possible molecular mechanisms involved in the impairment of the reproductive health and gestation associated with exposures to common urban air pollution.
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2.1 Introduction
Humans are continuously exposed to mixtures of environmental contaminants and a vast body of evidence now link exposure to these chemicals with an increased incidence of reproductive and developmental disorders (Woodruff and Walker 2008; Sadeu et al. 2010).
Since the second half of the twentieth century, the harmful effects of air pollution on human health have been the subject of many studies. Episodes of high levels of air pollution experienced by cities in Europe and the United States have enlightened both government agencies and the global community public about the harmful effects of air pollution on human health. Infamous examples include both the London Fog of 1952 and Donora Smog of 1948 that were associated with significantly elevated rates of hospital admissions and mortality (Logan 1953; Helfand et al. 2001). Similarly the more recent Bophal gas disaster (India, 1984) should also be remembered. In this tragic example, a methyl isocyanate gas leak killed 2,500 people in 5 days and many more were condemned to long-term morbidity including serious reproductive dysfunctions (Sriramachari 2005). Subsequent to these episodes, clean air legislations and other regulatory actions have significantly reduced ambient air pollution in many regions of the world, especially in both North America and Europe (Chen et al. 2007). Despite successful regulatory oversight, air pollution in urban centers remains a substantial risk factor to global human health.
The respiratory tract is the first system to be in contact with the air pollutants. Respiratory and cardiovascular diseases are the most commonly observed effects associated with exposure to low levels of air pollution followed by neoplasia (Schwartz 2006; Pope et al. 2009; Dockery 2009). Recent studies support that common environmental air pollutants that we contact in our daily life and to which exposures are unavoidable could also affect both reproductive health and fetal development. Exposure to ambient air pollution appears to adversely impact fertility, pregnancy outcomes, and fetal health and development (Maisonet et al. 2004; Parker and Woodruff 2008).
Epidemiological studies suggest the association between exposures to air pollution and impairment of reproductive health. However, these studies also recognize and acknowledge many uncertainties with regard to this association (Slama et al. 2008), such as few evidence of plausible biological mechanisms, limited information on personal exposures, difficulties in linking particulate matter (PM) composition or single constituent to the biological effects (Pope 2000; Chen et al. 2008; Valavanidis et al. 2008; Ren and Tong 2008). Despite the adoption of different study designs and statistical evaluations and the potential of confounding variables (e.g. maternal smoking, gestational age, and socioeconomic factors), and lack of consistency in findings, these epidemiological investigations suggest a causal association.
Epidemiological studies are important to help guide further investigation. However, many unanswered questions remain with regard to the association between air pollution and reproductive health including;
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What are the mechanisms involved in decreased fertility due to the exposure to increased PM concentration?
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Which trimester of pregnancy is most relevant to the impairment of fetal development?
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Which component of the PM presents a higher risk for reduced birth weight?
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Are the mechanisms involved in decreased male fertility the same as in females?
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Could multigenerational exposure to ambient PM concentration present cumulative effects?
Future studies utilizing animal models and carefully designed human clinical investigation will help address the current gap in knowledge. Toxicological and clinical studies are necessary to confirm associations elucidate mechanisms involved, identify most susceptible subgroups, and to create ways to reduce these impacts on human health.
In this chapter, we will focus on the major epidemiological findings, current experimental evidence, and possible molecular mechanisms involved in the impairment of the reproductive process associated with exposure to common urban air pollution.
2.2 Urban Air Pollution
Air pollution is a widespread environmental contaminant. Expansion of industry and vehicular traffic has had a major impact on the overall air quality in urban areas over the last decades. This contributed to widespread contamination of the environment by thousands of harmful compounds derived from exhaust emissions. In a broad sense, air pollution can be defined as a mixture of gaseous, liquid, and solid substances containing many toxic components which include; CO, NO2, SO2, O3, Pb, polycyclic aromatic hydrocarbons (PAH) and particulate matter (PM) (WHO 2005).
Because of the recognized health impacts, significant efforts have been placed on investigation and regulation of the particulate fraction of air pollution. As defined by Collbeck and Lazaridis (2010), particulate matter (PM) is a complex mixture of solid particles, liquid droplets, and liquid components contained in the solid particles constituted by many different chemical species originating from a wide variety of sources. Particles can be produced by combustion, suspension of soil material, and also from chemical reactions in the atmosphere. Nitrates, sulphates, elemental carbon, organic substances (VOC, PAH), metals (Cd, Pb) and mineral material (Al, SI, Fe and Ca) are major constituents of airborne PM (Colbeck and Lazaridis 2010; Heal et al. 2012). Particle size ranges vary considerably from a few nanometers (nm) to several micrometers (um), which strongly determine particle lifetime in the atmosphere and deposition in the respiratory tract.
The particles are classified according to their aerodynamic diameter, as PM10 [particles with an aerodynamic diameter smaller than 10 μm], PM2.5 [aerodynamic diameter smaller than 2.5 μm] and PM0.1 [aerodynamic diameter smaller than 0.1 μm] (Colbeck and Lazaridis 2010). The size and its composition are directly linked to negative health effects. The observed high toxicity of the smaller size fractions is believed to be due to the fact that they may reach the deeper portion of the lungs and may translocate into the circulation. Further these fractions contain higher concentrations of polycyclic aromatic hydrocarbons (PAH), semiquinones, metals, transition metals, and have a higher radical generating capacity (Squadrito et al. 2001; Kok et al. 2006).
2.3 Epidemiological Findings
The evidence for harmful effects at realistic urban air concentrations of air pollutants predominantly come from epidemiological studies (Slama et al. 2008; Stillerman et al. 2008). In this section, we will present recent reports that indicate that exposures to ambient levels of air pollutants (PM, NO2 SO2 and O3), in addition to the recognized adverse cardio respiratory effect are associated with negative impacts on reproductive health.
Increased risks for low birth weight, prematurity, neonatal and post-neonatal mortality and congenital defects have been reported to be associated with exposures to ambient air pollution. Beyond the recognized adverse consequences on pregnancy outcomes, exposure to air pollution is associated with adverse impact on reproductive function including fertility. Furthermore, studies have shown that periods of elevated air pollution were significantly associated with changes in semen quality and damages in sperm DNA (Dejmek et al. 2000; Rubes et al. 2005).
2.3.1 Fertility and Fecundability
Very few studies have addressed the effects of ambient air pollution on human fertility. Available studies focus on the primarily impact on male fertility, probably due to readily accessible semen acquisition and analysis (Sokol et al. 2006). Detrimental changes in various semen parameters such as motility, sperm morphology, and DNA are reported, which may cause reduced fertility in males or miscarriage in females.
The positive association of the adverse effects of air pollution exposures on pregnancy outcomes has redirected the attention of the researchers to other important aspects of reproductive health including fertility. One of the first studies that investigated the effects of air pollution on fertility was conducted by Djemek et al. (2000). In this study, they have evaluated the impact of SO2 on fecundability (the probability of conceiving during the menstrual cycle) in the first unprotected menstrual cycle (FUMC) of 2,585 parental pair in a heavily polluted region of Northern Bohemia. They found that adjusted odds ratios of conception in the FUMC may be reduced in couples exposed to mean SO2 levels > 40 pg/m3 in the second month before conception. In a previous study with the same population, they have also found an association between PM10 and reduced conception rates (Dejmek et al. 1998). Slama et al. (2013) reanalyzed the data of the study by Dejmek et al. (2000) and defined the exposure window with respect of the start of the period of unprotected intercourse and considered the impact of PM2.5, carcinogenic polycyclic aromatic hydrocarbons (c-PAH), ozone (O3), nitrogen dioxide (NO2) levels, in addition to SO2 on fecundability. Their new results highlight that PM2.5 and NO2 levels in the 2 months before the end of the first month of unprotected intercourse were associated with decreased fecundability. This observation highlights the important concept of lag time between exposure and observed health consequences.
Selevan et al. (2000) showed that elevated period of air pollution were significantly correlated with changes in various semen parameters of young Czech men including; proportionately fewer motile sperm, less sperm with normal morphology or normal head shape, and proportionately more sperm with abnormal chromatin. Based on this preliminary findings, Rubes et al. (2005) monitored semen quality in a cohort of young Teplice residents over longer periods of time (periods of exposure to both low and high air pollution) and found a significant association between exposure to high levels of air pollution and decreased sperm chromatin integrity.
In the United States (Salt Lake City), Hammoud et al. (2010) demonstrated that PM2.5 concentration was negatively correlated to sperm motility 2 months and 3 months after exposure, which coincides with the duration of spermatogenesis (72 days). However, a study of Hansen et al. (2010) did not support a consistent pattern of association between O3 and PM2.5. They performed analysis of several measures of semen quality and found only statistically significant adverse association between increased PM2.5 averaged over the 0- to 90-day period before semen sampling and an increase in the percentage of sperm with abnormally shaped heads and the percentage of sperm with cytoplasmic droplets. However, after controlling for season and temperature results failed to reach statistical significance.
In the study of Sokol et al. (2006), there was a significant negative correlation between O3 levels (70–90 days before collection) and average sperm concentration, which was maintained after correction for birth date, age at donation, temperature, and seasonality. These epidemiological results are in line with occupational exposures (De Rosa et al. 2003; Guven et al. 2008) and experimental studies of diesel exhaust inhalation and detrimental effects on sperm (Izawa et al. 2007).
There are very limited studies on the impact of air pollution on female fertility. We are aware of only two studies available in the literature on female fertility that were conducted by Perin et al. (2010a, b). These studies evaluated the impact of PM exposure during the follicular phase of the menstrual cycle or during the pre-conceptional period of women undergoing IVF/ET on early pregnancy loss and miscarriage. Both studies support an association between brief exposure to high levels of PM and the adverse gestational outcomes. This is an area that would likely benefit from additional studies.
Human fertility is declining in different parts of the world for unclear reasons. There are many hypothesis that have been used to explain this observation. Among the most supported causes of worldwide declining fertility are the delay of childbearing by modern women and other changes in social factors. However, there is also a growing incidence of impaired fecundity among young women and men, which cannot be easily explained by societal factors. Nutritional status, obesity, drugs, smoking habits, stress and increasing exposures to environmental pollutants, such as air pollution, are also plausible factors involved in human reduced fertility that deserve more attention.
2.3.2 Low Vitamin D and Immune System Alterations
Besides the “visible” effects of air pollution on fetal health, there is growing evidence of the impact of maternal exposure to urban air pollution on “non-visible” fetal outcomes. Serum vitamin D levels in the mother and fetus seems to be affected by air pollution. Vitamin D is scarce in natural food and the main source of vitamin D for humans is its synthesis from 7-dehydrocholesterol upon exposure to UVB solar radiation and conversion to circulating metabolite called 25-hydroxyvitamin D [25(OH)D] in the liver. Deficiencies in vitamin D are associated with different bone diseases and more recently it has been involved in other diseases including cardiovascular (Kim et al. 2008) and autoimmune diseases (Lange et al. 2009).
In general, low intake of vitamin D and insufficient exposure to sunlight constitute the main causes of vitamin D deficiency. However, recent studies point out that exposure to air pollution may also contribute to low serum levels of vitamin D in women and in the unborn child as a consequence of maternal deficiency. In the study conducted by Baïz et al. (2012), maternal exposure to ambient urban levels of NO2 and PM10 during the whole pregnancy was a strong predictor of low vitamin D status in newborns. Moreover, Kelishadi et al. (2013) have also found that air quality had an inverse and independent association with 25(OH)D levels of mothers and their neonates and Hosseinpanah et al. (2010) have shown that deficiency in vitamin D to be prior to pregnancy. In their study, they found that women living in polluted areas present with lower levels of serum 25-OH-D which is comparable to vitamin D deficiency.
Potential mechanisms that could explain this relationship are based on the impact of smoking on vitamin D status (Brot et al. 1999). It has been suggested that changes in inflammatory profile and oxidative stress caused by smoking affects liver function and hence vitamin D synthesis or affecting maternal intestinal absorption of vital vitamins and minerals (Need et al. 2002). Exposure to air pollutants may have similar impact on vitamin D status. Beyond observed differences in vitamin D, exposure to air pollution could result in changes of the immune system including; NK, T lymphocytes, and IgE content of umbilical blood (Herr et al. 2010, 2011). Maternal exposure to air pollution could have lasting effects of either gestational or pre-gestational exposures on their offspring. The consequences for the future health of these individuals remains unknown, but these effects could have far reaching impacts.
2.3.3 Gestational Outcomes
Studies conducted in different continents (Europe, Asia and Americas) consistently report that expectant mothers exposed to air pollution have greater risks of having negative gestational outcomes (Gouveia et al. 2004; Ha et al. 2001; Wang et al. 1997). However, it is not clear from the studies whether the effects are due to a specific pollutant or to the interactions of different pollutants and in which trimester exposures are more detrimental to fetal development. Negative gestational outcomes are predominant reproductive effects associated with exposures to ambient air pollution and are discussed in detail in Chap. 3. In this section, we will briefly highlight the gestational outcomes and its association with criteria pollutants in order to compare with experimental evidence.
The causes of the negative pregnancy outcomes are not well understood but it is clear that these outcomes have multifactorial causes and there are scientific evidence that environmental factor, such as air pollution, can contribute or aggravate these outcomes. Furthermore, there are groups within population that may be more susceptible to air pollution exposure. These groups include individuals with preexisting circulatory and respiratory conditions and those socially and economically disadvantaged. In general people with low social and economic status live in more polluted areas, lack adequate health care, and spend more time near high traffic roads that may increase exposures to air pollutants and consequently increase the risks of adverse birth outcomes (Woodruff et al. 2003; O’Neill et al. 2003; Ponce et al. 2005; Gilbert et al. 2007; Ono et al. 2013).
2.3.3.1 Low Birth Weight
The prevalence of low birth weight (LBW), as defined by WHO as weight at birth of less than 2,500 g (5.5 lb) is estimated to be 15 % worldwide with a range of 3.3–38 % (http://www.who.int/nutrition/topics/lbw_strategy_background.pdf) and occurs mostly in developing countries; coincidentally these countries has elevated levels of air pollution (http://www.who.int/gho/phe/outdoor_air_pollution/phe_012.jpg). This topic is covered in more detail in Chap. 3.
Birth weight is an important indicator of subsequent health issues; low-birth-weight babies are more prone to develop hypertension, coronary heart disease, and non-insulin-dependent diabetes during adulthood (Osmond and Barker 2000). Evidence from studies conducted in developed and developing countries, China (Wang et al. 1997), Australia (Mannes et al. 2005), Chezec Republic (Dejmek et al. 1999); and USA (Ritz et al. 2000) point out that PM10, PM2.5 and SO2 are the major pollutants associated with increased risks of LBW. However, other studies verified that exposures during pregnancy to CO, O3, and NO2 could also be associated with LBW (Morello-Frosch et al. 2010).
2.3.3.2 Preterm Birth, Intrauterine and Neonatal Mortality
Although less frequently reported, intrauterine and neonatal mortality and pre-term birth (PTB) (Glinianaia et al. 2004; Maisonet et al. 2001; Srám et al. 2005) are also outcomes associated with air pollution. Maternal first trimester exposure to ambient air pollutant exposure seems to be the critical period for PTB. However, Huynh et al. (2006) observed no association between PTB and ambient air PM2.5 levels near the maternal residence during early pregnancy and late gestation.
In Australia, Hansen et al. (2006) observed that increased levels of O3, NO2 and SO2 during 1st trimester increases the risk of PTB (OR = 1.26, 95 % CI 1.10–1.45). Another study from Korea (Leem et al. 2006) reported that increased levels of CO level during 1st trimester are responsible for the increased risk for PTB [OR = 1.26, 95 % CI 1.11–1.44, p-trend < .001]. Considering traffic proximity, the risk of PTB in Taiwan was elevated among women living close to a major freeway [<0.5 vs. 0.5–1.5 km, OR = 1.30, 95 % CI 1.03–1.65] (Yang et al. 2003). In Los Angeles, Wilhelm and Ritz (2003) found that there was a dose-response relationship between preterm birth and inverse-distance-weighted traffic density among women in their 3rd trimester [OR = 1.15, 95 % CI 1.05–1.26].
2.3.3.3 Fetal Growth and Developmental Abnormalities
Although evidence is less consistent, exposures accrued during gestation and sensitive periods of fetal organ development may be related to developmental abnormalities/congenital defects. Jedrychowski et al. (2004) observed that not only birth weight is affected; changes in other anthropometric measurements were observed, such as reduction in head circumference. Studies conducted by van den Hooven et al. (2012a) using ultrasound measurements observed that NO2 levels were inversely associated with fetal femur length in the second and third trimester, and both PM10 and NO2 levels both were associated with smaller fetal head circumference in the third trimester. Vrijheid et al. (2011) systematically reviewed epidemiologic studies on ambient air pollution and congenital anomalies and conducted a meta-analysis for a number of air pollutant–anomaly combinations. They conducted meta-analyses for 18 combinations of pollutants and cardiac anomaly groups and found that NO2 and SO2 exposures were related to increases in the risk of coarctation of the aorta and tetralogy of Fallot and PM10 exposure was related to an increased risk of atrial septal defects.
A large case-control study conducted in California reported a weak association between cleft lip/palate and ambient air O3 levels near the maternal residence during the second month of gestation. Few studies evaluated if there were associations between maternal exposure to air pollutants and stillbirths. Results from these studies remain inconclusive. Pereira et al. (1998) found an association between daily counts of intrauterine mortality and NO2, SO2, and CO concentrations before (≤5 days) delivery. Similarly, Faiz et al. (2013) reported that increased stillbirth is associated with increases in NO2, SO2, CO, and PM2.5 concentrations in the immediate few days before delivery. In a study by Bobak and Leon (1999) stillbirth rates were not significantly associated with any indicator of air pollution.
2.3.3.4 Preeclampsia
Emerging evidence from a large European study and from three previous studies (Woodruff et al. 2008; Wu et al. 2009; Rudra et al. 2011; Olsson et al. 2013) further indicates that that there is also a positive associations between exposure to air pollution and risks of preeclampsia. However, the studies diverge to in terms of the pollutant associated with preeclampsia. In the largest study conducted in Europe, Olsson et al. (2013) found that exposure to O3 in the first trimester of gestation are associated with increased risks of preeclampsia. Rudra et al. (2011) found a weak association between CO exposure during the first 7 months of pregnancy (per 0.1 ppm) and preeclampsia (OR = 1.07, 95 %, CI = 1.02–1.13). In another study conducted in the USA, Wu et al. (2009) reported odds ratios of 1.33 (95 %, CI = 1.18–1.49) and 1.42 (95 % CI = 1.26–1.59) for preeclampsia in the highest exposure quartiles for NOx and PM2.5. Increased blood pressure throughout pregnancy has also been observed in mothers who are exposed to air pollution (van den Hooven et al. 2012b; Lee et al. 2013) and both available studies agree that PM10 and O3 are associated to this effect.
2.3.4 Secondary Sex Ratio
In the literature, there are many examples of studies suggesting the impact of both environmental pollution and occupational exposure to certain substances and changes in secondary sex ratio (SSR) (Terrell et al. 2011; Tragaki and Lasaridi 2009; Schnorr et al. 2001). Previous studies have shown changes in sex ratios of populations living near incinerators [lower sex ratio] (Williams et al. 1992) as well as in areas exposed to polluted air from steel foundries (higher sex ratio) (Lloyd et al. 1985). In urban areas with high levels of particulate pollution derived from traffic, there is only one study that investigated if the secondary sex ratio could be affected by air pollution. In this study, Miraglia et al. (2013) have found a significant negative association between SSR and PM10 concentration in São Paulo city, Brazil. Although the causality between environmental exposures and declines in secondary sex ration are still controversial, some authors suggest that the SSR as a sentinel indicator of reproductive injury (Davis et al. 1998).
2.3.5 Reproductive System Cancer
Little is known about the role of air pollution in cancers of the reproductive system cancer (e.g. prostate, ovarian and breast cancer). However, an increased risk of lung cancer associated with exposures to outdoor air pollution was consistently observed in studies from Europe, North America, and Asia (Fajersztajn et al. 2013). Thus it is reasonable to suspect that other types of cancer could be caused by long term exposure to air pollutants. The latest IARC release on cancer incidence mortality and prevalence worldwide predict a substantive increase to total 19.3 million new cancer cases per year by 2025, due to growth and ageing of the global population. However, environmental influences and lifestyle factors may also be implicated in this increase; and they highlight the fact that breast cancer incidence has increased by more than 20 %. Vehicular emission is the primary contributor to air pollution in urban areas, its composition include compounds that are recognized as carcinogens, such as diesel exhaust. Recently, the International Agency for Research on Cancer (IARC) of the World Health Organization has classified diesel and gasoline exhaust as carcinogenic to humans as possibly carcinogenic (Loomis et al. 2013).
Few studies have been conducted to evaluate if there is an association between reproductive system cancer and air pollution. These types of studies are limited by difficulties in the assessment of long term exposures, the presence of a myriad of confounding factors and co-exposures to other known carcinogens in food and water. Disinfection by products and even infections make it difficult the establishment strong associations between air pollution and cancer risk factors.
Prostate Cancer
There are only two studies in the literature that found an association between prostate cancer and air pollution (Soll-Johanning and Bach 2004; Parent et al. 2013). Recently, a case–control study conducted in Montreal evaluated environmental risk factors for prostate cancer and found associations between exposures to traffic related air pollution, assessed by exposures to NO2, and increased risks of prostate cancer incidence. Limitations of the study include exposure assessment based on home address and time of exposure which was 25 years prior to the interview and thus which could misclassify an individual’s exposure (Parent et al. 2013).
Breast Cancer
In women, breast cancer has the highest incidence rate. Many risk factors have been pointed out such as genetic factors, lifestyle, reproductive history, smoking and alcohol consumption. Although many factors have been identified most of the cases remain with unknown etiology (Coyle 2004). The first evidence of a possible relationship between breast cancer and air pollution levels came from the observation that the incidence was higher in urban areas compared to rural areas (Bako et al. 1984; Hall et al. 2005; Reynolds et al. 2004). Human studies are limited, however there at least 30 substances present in urban air pollution that are known to be associated with increased mammary tumors in animals such as benzene (diesel exhaust) and polycyclic aromatic hydrocarbons (PAHs). Thus, it is plausible that traffic-related exposures may contribute to the incidence of breast cancer (reviewed by Rudel et al. 2007). In the USA, few studies assessed the relationship between air pollution exposure and breast cancer. Lewis-Michl et al. (1996) conducted a case-control interview study in New York (USA) and suggested a possible increased risk [OR = 1.29; 95 % CI: 0.77–2.15] of breast cancer among postmenopausal women who live near areas with high traffic density. Bonner et al. (2005) found that early-life exposures to relatively high concentrations of air pollution (i.e., >140 μg/m3) were associated with an increased risk of developing postmenopausal breast cancer (OR = 2.42; 95 % CI, 0.97–6.09). In Canada, Crouse et al. ( 2010) found evidence of an association between the incidence of postmenopausal breast cancer and exposure to ambient concentrations of NO2. In China, Huo et al. (2013) have shown that long-term air pollution exposure may contribute to the development of breast cancer.
Ovary Cancer
In the literature, there are only two studies that have found an association between air pollution and ovarian cancer. In the first study published in 2005, Iwai et al. (2005) conducted a cross-sectional epidemiological study using the annual vital statistics and air pollution throughout Japan and found that breast, endometrial, and ovarian cancer showed significant increases in mortality rates in relation to particulate pollution. More recently in Taiwan, Hung et al. (2012) showed that individuals who resided in municipalities with higher PM2.5 levels were at a significantly increased risk of death from ovarian cancer.
2.4 Experimental Evidence
All of the published studies acknowledged that there are many uncertainties on the association between adverse reproductive outcomes and air pollution (Pope 2000; Chen et al. 2008; Valavanidis et al. 2008; Ren and Tong 2008). Undoubtedly these aspects point out that there is a need for further toxicological and clinical studies to confirm, to strengthen and elucidate the mechanism involved in this association, to identify most susceptible subgroups and to create ways to reduce these impacts on human health. The scientific literature is extremely scarce with regard to experimental studies conducted to evaluate reproductive efficiency using laboratory animals exposed to real urban air pollution. Available studies conducted on experimental animals, mainly mice, have corroborated human epidemiological data and have provided data showing additional effects not yet investigated in humans.
Studies using a multigenerational mouse model of exposure to “real world” ambient concentrations of air pollution, (i.e. mice mates and their litters were continuously exposed inside chambers to either filtered-clean air or non-filtered air-polluted air), found that urban air pollution compromises reproductive health in different ways across generations. This series of studies has shown that in the first generation (G1) of mice exposed to air pollution there were significant reductions in the number of viable fetuses, increased numbers of implantation failures, and a decreased male/female secondary sex ratio (Mohallem et al. 2005; Lichtenfels et al. 2007). In the second generation of mice (G2), females exposed to air pollution during gestation gave birth to litters with reduced birth weights, but no differences in litter size and viable fetuses were observed. Birth weight was significantly lower with a mean reduction of 21 % compared to fetuses from non-exposed females (Veras et al. 2009).
The negative effect of air pollution exposure during pregnancy and birth outcomes are increasingly recognized, but most epidemiological studies have focused only on exposure during the gestational period. Evidence from animal studies explored the effects of maternal exposure before pregnancy on fetal development and demonstrates that maternal exposure not only during pregnancy, but also before conception, adversely affected fetal birth weight (Veras et al. 2008; Rocha et al. 2008). In the same way, exposure to air pollutants during gestation and/or during the pre-gestational period was associated with increased post-implantation loss rates in exposed females (Veras et al. 2009). These results support the findings from Perin et al. (2010a, b) on the importance of the pre-gestational period on gestation establishment. Examination of the placenta from dams exposed to air pollution before and/or during pregnancy revealed that both pre-pregnancy and pregnancy periods of exposure to polluted air resulted in morphological changes in the placenta (Veras et al. 2008). Veras et al. (2008) found that decreases in fetal weight were accompanied by decreases in the volume of maternal blood spaces, in the mean diameter of maternal blood spaces, and in maternal:fetal surface ratio. These features were accompanied by increases in the surface area of fetal capillaries, the total diffusive conductance of the intervascular barrier, and the mass-specific conductance of that barrier. None of the studies conducted in human has evaluated whether placental changes are associated with adverse pregnancy outcomes in humans. Recently, van den Hooven et al. (2012a) using ultrasound measurements and markers of placental growth and function have shown that in human the placenta development, as observed in animals, is impaired by maternal exposure to air pollution.
Umbilical cords were also evaluated and exposures to air pollution were associated with thinner and less voluminous umbilical cords (loss of mucoid connective tissue and collagen content). Structural changes in umbilical arteries and veins and elevated immunoreactivity for 15-F2t-IsoP (oxidative stress), ETAR and ETBR (vascular tone) in their walls were found. Together these findings indicate compromised fetal development evidenced by reduced birth weight might be mediated by alteration in placental and umbilical structure and function as well as by imbalances in the endogenous regulators of vascular tone and oxidative stress (Veras et al. 2012).
The reproductive capacity of G2 nulliparous female mice was also examined and results have shown changes to estrous cyclicity and in ovarian follicle counts (decreased numbers of antral follicles) (Veras et al. 2009). Antral follicles represent the last stage in follicle development prior to ovulation and are the only follicle type capable of releasing an oocyte for fertilization and synthesizing estrogen (Hoyer and Sipes 1996; Hirshfield 1997). Increases in the rate of follicle depletion can potentially raise the possibility of premature ovarian failure and early menopause in the case of humans (Rowe 2006). Observed changes in estrous cyclicity are indicative of persistent estrus, which may reflect an impairment of ovulation as well as changes in the levels of circulating ovarian hormones (EPA 1996).
Further, in the second generation it was observed changes in couple-based outcomes. Couples exposed to air pollution presented decreased fertility indices, decreased pregnancy success and delayed onset of reproductive maturity, as evidenced by extended times to mating (Veras et al. 2009). In humans, air pollution exposures seemed to decrease conception rates (Dejmek et al. 1998). However, we still do not know if the effects are associated with impairments on female or male health.
It is important to point out that the mean concentration of PM2.5 (24-h average concentration) used in some studies (27.5 μg/m3, Veras et al. 2008, 2009), is less than the 35 μg/m3 established by the U.S. National Ambient Air Quality Standards [US-NAAQS] (http://www.epa.gov/air/criteria.html) and, approximately equivalent to the World Health Organization (WHO) air quality guideline (25 μg/m3; WHO 2005) raising the question of whether these proposed values are safe for reproductive health.
Two recent mechanistic experimental studies (unpublished) addressed the associations between air pollution exposure during the initial stages of pregnancy in mice and uterine response to embryo implantation. Scoriza et al. (2009) observed that in early pregnancy (6 and 8 GD) that reductions in the number of uterine natural killer (uNKcells) and mast cells could contribute to the increased rates of post implantation losses observed in mice. uNK cells are a subpopulation of lymphocytes that in normal mice promote decidual angiogenesis, trophoblast and placental cell growth, provide immunomodulation at the maternal-fetal interface for a healthy pregnancy (Bilinski et al. 2008). The role of mast cells in pregnancy is less known. However, during normal early pregnancy, the number of mast cells and their activation change (Gibbons and Chang 1972; Marx et al. 1999). These data suggest that components present in air pollution may indirectly interfere with or impair embryonic development through changes to the maternal environment including maternal immune responses. In another study, nulliparous mice were exposed to two different doses of fine particulate air pollution (PM2.5) for 45 days before pregnancy until gestational day 4 and expression of different uterine receptivity markers were evaluated (Lif, leukemia inhibitory factor; and Muc1, mucin, pinopods) as well as uterine histopathology. Histopathology revealed a decrease in the volume and thickness of the endometrium as well as changes in the diameter and thickness of the glandular and luminal epithelia. No significant alteration was observed in the expression (qPCR/IHC) of Muc1 but there was significant suppression of Lif during the window of implantation. These findings suggest that air pollutants may affect the fine regulation of proliferation and differentiation of uterine stromal cells during decidualization via reduced LIF expression (Castro et al. 2013).
Evidences from experimental studies linking and chronic exposure to air pollution are in line with the epidemiological findings (Knottnerus et al. 1990; Peters et al. 1997; Pekkanen et al. 2000). However, the mechanisms involved in this association are not clearly known. There are many suggested potential mechanisms which include induction of p450 enzymes, DNA damage, and systemic alterations in hematocrit, blood viscosity, blood coagulation, endothelial dysfunction, oxidative stress, and inflammation (Baskurt et al. 1990; Sørensen et al. 2003; Andrysík et al. 2011). The mechanisms proposed are described in more detail in the next section.
2.5 Biological Mechanisms
The mechanisms, by which, air pollution could cause adverse health effects are characterized by their ability to directly act as pro-oxidants of lipids and proteins or as free radical generators, promoting oxidative stress, inflammatory responses and damage to mitochondrial function (Menzel 1994; Rahman and MacNee 2000; Li et al. 2003).
The first system to in contact with air pollution is the respiratory tract. Epidemiologic and experimental data show that the air pollution can cause pulmonary inflammation, decrease of pulmonary function, and aggravation of pre-existing pulmonary diseases such as asthma and bronchitis (Laumbach 2010; Saldiva et al. 2002; Seaton et al. 1995).
The bigger fraction of the PM gets trapped on the superior respiratory tract, and the smaller fraction can reach the lungs and these particles can be deposited (Amdur and Corn 1963; Amdur and Creasia 1966). In an attempt to remove such particles, alveolar macrophages phagocytize the particles, penetrating into the cellular interstitium, but part of these fine particles can be translocate across the air–blood barrier into circulation and towards secondary target organs, suggesting that the smaller the particle diameter, the greater the possibility of translocation to other organs (Takenaka et al. 1986; Ferin et al. 1992; Oberdorster and Utell 2002; Chen et al. 2006).
The majority of fine and ultrafine (<PM0.1) particles found in the urban atmosphere derive from engine combustion. Ultrafine particles have very low mass typically with magnitudes higher particle numbers and therefore a high surface area relative to fine and coarse particles for adsorption of toxic species (Sioutas et al. 2005). Studies suggest that only a small fraction of PM can pass rapidly into systemic circulation, and that pulmonary inflammation seems to play a major role in enhancing the extra-pulmonary translocation of particles (Chen et al. 2006; Brown et al. 2002; Burch 2002; Mills et al. 2006; Wiebert et al. 2006a, b; Möller et al. 2008). Organic components of particles, which comprise a large proportion of freshly emitted exhaust and secondary aerosols, can induce a broad polyclonal expression of cytokines and chemokines in respiratory epithelium and this effect may be due to the action of PAHs, metals and related compounds that lead to the production of cytotoxic reactive oxygen species (ROS); and these inflammatory and oxidant stress responses are expected to occur at extra-pulmonary sites, as well (Sioutas et al. 2005; Ritz and Wilhelm 2008).
Several hypotheses have been proposed that air pollution can affect the reproductive system causing negative effects, such as impairment of male and female reproductive capacity, placental alterations and fetal health.
As we have previously described, exposure to air pollution is associated with detrimental pregnancy outcomes and these outcomes can be caused by a combination of maternal, fetal, and placental factors or a combination of them. . For example, air pollution can affect the utero-placental and umbilical cord flow and consequently the transport for glucose and oxygen though the placenta (Veras et al. 2008, 2012; Ritz and Wilhelm 2008; Vorherr 1982).
According to the review of Kannan and collaborators (Kannan et al. 2006, 2007), the particulate matter present on the air pollution can affect pregnancy outcomes due to:
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Increase in oxidative stress: an important mechanism of action PM can be the DNA damage induced by oxidative stress, also some metals in PM may inhibit the DNA repair enzymes.
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Inflammation: Inflammation could be associated with inadequate placental perfusion and impaired transplacental nutrient exchange, which may cause growth restriction in utero due to interference with some process or processes such as affecting nutrition of the fetus, reduced oxygenation of maternal blood, or both.
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Coagulation and blood pressure: PM exposures may increase any of the proteins of the clotting cascade, indicating a higher possibility for coagulation and may also lead to changes in hemoglobin, platelets, and white blood cells, which may potentially contribute to adverse fetal growth. PM exposure is also associated with elevations on the blood pressure in pregnant women and this could increase the risk of adverse outcomes, especially if there is preexisting hypertension (pregnancy-induced or not). Elevation of blood pressure in pregnant women has been associated with IUGR and preterm delivery.
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Hemodynamic responses: an impaired adaptation of maternal hemodynamic may lead to an impaired fetal growth. These changes may force the fetus to adapt, down-regulate growth, and prioritize the development of essential tissues.
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Endothelial function: PM exposure may cause endothelial dysfunctions leading to vasoconstriction and could be considered as an intervening pathway in subsequent impact on fetal growth.
These pathways may or may not act independently, but it is more likely that the outcomes of the exposure to air pollution are an association among these pathways and they are probably related to the composition of the particulate matter (Saldiva et al. 2002).
There are evidences that the air pollution can affect not only the pregnancy but also the male and female reproductive fertility (Somers and Cooper 2009).
Based on epidemiological studies it was observed that exposure to air pollution affects fertility rates (Dejmek et al. 2000; Selevan et al. 2000) at different seminal parameters, motility and morphology and the sperm DNA (Rubes et al. 2005; Hansen et al. 2010; Jafarabadi 2007).
In a study conducted by Somers et al. (2002), a significant elevation in mutation frequency was reported in the offspring of animals exposed to air pollution; primarily through expanded simple tandem repeat (ESTR) DNA loci mutation events in the paternal germline.
In other studies conducted by Somers et al. (2004) and Yauk et al. (2008), they noted that ESTR mutation frequencies were also elevated the paternal germline of mice exposed to whole ambient air at the polluted industrial site, indicating that mutations were induced in spermatogonial stem cells. Maternal ESTR mutation frequencies were similar in all groups, and therefore unaffected by air pollution exposure (Somers et al. 2004). Bulky DNA adducts were not significant, suggesting that DNA reactive chemicals do not reach the germ line and cause ESTR mutation. In contrast, DNA strand breaks were elevated after 3 weeks of exposure, possibly resulting from oxidative stress arising from exposure to air pollution and its particulate matter (Yauk et al. 2008).
Sperm DNA in mice exposed to whole ambient air was globally hypermethylated compared to those exposed to filtered air. These methylation changes appeared early in the environmental exposure and were still present after 6 weeks without the air pollution exposure. Persistent changes in the methylation status of genes may have health implications for the next generation through altered gene expression (Somers et al. 2004; Yauk et al. 2008).
Environmental toxicants can alter the female reproduction by direct mechanisms (hormone disruptors) or indirect (immunological toxicants). Direct effects typically occur if an environmental chemical is structurally similar to a molecule capable of interacting with endogenous reproductive organs. Indirect effects can occur if a chemical interferes with the hormonal action. Natural hormones are critical for development, behavior, puberty beginning, sexual function, and gametogenesis. Some environmental chemicals can mimic or block the action of the natural hormone, thus negatively altering reproductive processes (McLachlan and Arnold 1996).
As steroid hormones, some environmental toxicants are lipo-soluble and cross the cell membrane by passive diffusion, thereby allowing access to any animal cell. Once these chemicals cross the cell membrane, which may interact with steroid receptors, access to the nucleus as a dimer hormone-receptor induces the activation or suppression of genes causing a biological response (McLachlan and Arnold 1996).
Several compounds present in air pollution (heavy metals, environmental oestrogens, diesel and PAHs) are able to suppress or interfere with the regulation of the hypothalamic-pituitary-gonadal axis; resulting in changes in growth and development of ovarian follicles and estrous cyclicity (Veras et al. 2009; Mamatsashvili 1970; Borgeest et al. 2004), affecting the whole process of pregnancy, including signaling pathways between the conceptus-mother or, the uterus preparation for implantation (Hoyer and Sipes 1996; Mattison and Thomford 1989; Tsukue et al. 2001; Takeda et al. 2004; Telisman et al. 2007). However, the specific contaminants that caused sperm damage and the potential impact on fertility or pregnancy outcomes were undetermined (Somers 2011).
PAHs in air pollution have the capacity to bind to steroid receptors, mimicking their action, and thus altering the production of these hormones, which can result in adverse consequences for the development and reproductive health (Kristensen et al. 1995; Wenger et al. 2009; Han et al. 2010). For example, Hood (2006) in his study suggests that exposure prior to conception, both female as male, can lead to a hormonal dysregulation causing direct damage to the reproductive organs and gametes.
Studies suggest that PAHs are able to cross the placenta and reach fetal organs causing adverse reproductive outcomes, including; stillbirths, reabsorptions, congenital abnormalities, and decreases in fetal weight. The exposure to PAHs may lead to increased DNA adducts, resulting to LBW and intrauterine growth restriction. Furthermore, the PM may bind receptors for placental growth factors leading to decreased fetal-placental exchange of oxygen and nutrients (Dejmek et al. 2000; Ritz and Wilhelm 2008).
2.6 Prevention
There are sufficient evidence of the harmful effects of exposures to environmental air pollution on reproductive health. Furthermore, it is clear that increased levels of air pollution are found in developing and underdeveloped countries in regions with high population density and higher fertility rates (Fig. 2.1). Although the risks associated with the negative reproductive outcomes tend to be small, the number of people that might be affected is significantly large. Furthermore, if we consider that negative influence on the initial stages of life (embryo/fetus) increases the risks of later life diseases, such as diabetes, metabolic syndromes and cardiovascular diseases (Osmond and Barker 2000; Gluckman and Hanson 2004) exposures to air pollution during pregnancy would have a profound impact in public health strategies to prevent most common health issues
The most effective way to reduce health risks associated with air pollution is to implement air quality management strategies and National Air Quality Standards (Thurston and Balmes 2012). The U.S. Environmental Protection Agency (EPA) projections that by 2020 adherence to the Clean Air Act standard for ozone alone will prevent 230 million premature deaths and 280 infant–mortalities (EPA 2011). Indeed, increasingly stringent (NAQS) already proved effectiveness in improving air quality in the United States and Western Europe in recent decades (Van Erp et al. 2008) and a global analysis concluded that flexible air quality standards lead to higher air pollution concentrations (Vahlsing and Smith 2012).
2.7 Concluding Remarks
Epidemiologic and experimental evidences converge to indicate that air pollution, at the current levels, play a deleterious role on reproductive function. In addition to the scientific questions raised from the aforementioned evidences presented in this chapter – which are the mechanisms, which are the most important pollutants or are the observed effects the result of a mixture of mixtures – some ethical considerations emerged at this moment. Indeed, the options of energy use, industrial production and mobility made by our and our preceding generations, may be affecting those that did not participate in the decision process. Moreover, there is a marked contrast in ambient air pollution concentrations, creating an uneven attributable risk across the globe. As a general rule, air pollution is the result of bad technologies, usually present in the less privileged countries. These points deserve serious consideration when translating knowledge into public policies aimed to protect children globally.
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Veras, M.M., de Souza Xavier Costa, N., Fajersztajn, L., Saldiva, P.H.N. (2015). Impacts of Air Pollution on Reproductive Health. In: Nadadur, S., Hollingsworth, J. (eds) Air Pollution and Health Effects. Molecular and Integrative Toxicology. Springer, London. https://doi.org/10.1007/978-1-4471-6669-6_2
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