Lower placental telomere length may be attributed to maternal residential traffic exposure; a twin study
Introduction
Telomeres consist of TTAGGG tandem repeats and cap chromosomes (Blackburn, 2001). They undergo progressive attrition in somatic cells because DNA polymerase is unable to fully replicate the ends of DNA caused by the unidirectional growth and the requirement for a primer to initiate synthesis (Levy et al., 1992). This is referred to as the end-replication problem. As a result telomeres progressively shorten in somatic cells and a mean leukocyte telomere length has been observed to diminish with age (Benetos et al., 2001, Slagboom et al., 1994). As aging starts before birth, not only establishing the telomere length at birth is a prerequisite, but also investigating environmental and genetic factors influencing telomere length is needed. The placenta plays a pivotal role in fetal development and functions as a barrier between fetal and maternal circulation. In utero telomere attrition is prevented by telomerase activity but as pregnancy progresses its activity in placental tissue declines making telomeres more sensitive to degradation (Chen et al., 2002, Gielen et al., 2014, Kyo et al., 1997). Maternal stress (Class et al., 2011, Lee et al., 2011, Torche, 2011), under nutrition (Schulz, 2010), exposure to cigarette smoke (Ko et al., 2014, Wahabi et al., 2013) and air pollution (Ballester et al., 2010, Brauer et al., 2008, Dadvand et al., 2013, Liu et al., 2003, Pedersen et al., 2013) have been linked to fetal growth retardation, with compromised fetal cerebral development, and might be linked with early onset of insulin resistance (Entringer et al., 2012). It has been suggested that telomere length underlies this fetal programming (Entringer et al., 2012). For instance, exposure to maternal psychosocial stress during intrauterine life has been associated with shorter leukocyte telomere length in young adulthood (Entringer et al., 2011). In adults telomere length was observed to be strongly related to the telomere length at birth, which widely varied and showed synchrony with telomere length of different organs (Heidinger et al., 2012, Okuda et al., 2002, Youngren et al., 1998).
Ambient air pollution is considered as a global public health threat (Adar et al., 2013, Brunekreef and Holgate, 2002, Katsouyanni et al., 1997, Nawrot et al., 2011). Recent studies of maternal exposure to particulate matter (PM), a constituent of ambient air pollution, support evidence for detrimental effects of PM exposure on the health of fetuses (Ballester et al., 2010, Dadvand et al., 2013) and neonates (Ritz et al., 2006, Scheers et al., 2011), and has been associated with cardiovascular morbidity and mortality later in life (Brook et al., 2010, Grahame and Schlesinger, 2012, Nawrot et al., 2011). Oxidative stress and inflammation are mechanisms linking exposure to particulate air pollution with premature aging (Reliene et al., 2005, von Zglinicki, 2000). Accelerated shortening of telomeres is an important pathway by which oxidative stress may accelerate biological aging and age-related diseases (Haycock et al., 2014, Monickaraj et al., 2012). In adults shorter telomere length has been linked with long-term exposure to traffic exposure. Hoxha et al. (2009) reported lower leukocyte telomere length in traffic officers compared to office workers and an inverse association between telomere length and occupational exposures to benzene and toluene (Hoxha et al., 2009). The Veteran study reported faster telomere attrition in 70-year olds with long-term exposures to airborne particles, especially those related to traffic exposure (McCracken et al., 2010). The effect size for an interquartile range (IQR) increase in black carbon was equivalent to a 3.04 year increase in age on telomere attrition. However, the effect of prenatal traffic exposure on the telomere length in the placenta is unknown. Although there is a synchrony in length among tissues of the human fetus, significant variations in telomere length among fetuses have been observed (Youngren et al., 1998). This variation was also found at birth and the variation among newborns appears to be as wide as the variation in adults (Okuda et al., 2002). This variation may be the result of both genetic and environmental factors. Indeed, based on twin studies (Andrew et al., 2006, Bischoff et al., 2005, Slagboom et al., 1994) and familial studies (Nawrot et al., 2004), telomere length has been shown to have genetic determinants. A recent meta-analysis combining estimates of six independent studies reported a heritability coefficient for leukocyte telomere length of 0.70 in adults (95% CI 0.64–0.76) (Broer et al., 2013). However, until now it is largely unknown to what extent genetic versus environmental factors exert their effect in utero and attribute to the variation in telomere length at birth.
As telomere attrition already starts before birth, we examined the association of placental telomere length in twins and residential traffic exposure, an important environmental source of free radicals that might accelerate aging (Iwai et al., 2000). Next, we intend to unravel the nature-nurture contribution to placental telomere length by estimating the heritability of placental telomere length.
Section snippets
Subjects
The East Flanders Prospective Twin Survey (EFPTS) was initiated in 1964 and is a population based register of multiple births in the province of East Flanders (Belgium). We selected 231 twins of Caucasian origin (99% naturally conceived), born between 1975 and 1982, who participated in a prenatal programming study (Loos et al., 2001). We excluded twins with bad or doubtful DNA quality (n = 13), or no information on maternal residential address (n = 7).
Zygosity determination and tissue sampling
A trained midwife examined the placentas within
Characteristics of the study population
Table 1 summarizes the characteristics of the 130 mothers and the 211 twins. Maternal age averaged 27.5 years and ranged from 19 to 40 years. Of the mothers, 12.3% (n = 15) smoked during pregnancy, and 51.6% (n = 63) had ever smoked. The newborn population, including 122 girls (53.1%) had a mean gestational age of 37.3 weeks (range 28–42). Birth weight averaged (± SD) 2582 ± 476 g. We observed 128 (60.7%) monozygotic twins and 83 (39.3%) dizygotic twins. In 76.8% (n = 162) of the newborns both twins
Discussion
Among 211 twins from the East Flanders Prospective Twin Study, we investigated the association between traffic exposure and placental telomere length. We observed that maternal residential proximity to major roads was associated with a lower placental telomere length. A doubling in residential distance to a major road was associated with a 5.32% increase (95% CI: 1.90, 8.86%, p = 0.003) in placental telomere length. In addition, the percentage of surrounding greenness within 5 km of maternal
Conclusions
To summarize, we showed for the first time that traffic related exposures and lower maternal residential greenness surrounding access during pregnancy may be a risk factor for shorter placental telomere length at birth. Moreover, genetic factors appear to be of minor importance since telomere length in placental tissue is mainly determined by the common environment. The consequences of environmentally induced shorter placental telomere length for health in later life should be further
Competing interests
All authors declare that they have no competing interests.
Acknowledgments
The project is supported by the EU Programme “ENVIRONAGE” (ERC-2012-StG 310890), the Flemish Scientific Fund (G087311N10/GOA7814N/1516112N) and the Bijzonder Onderzoeksfonds (tUL-funding). Michal Kicinski is a Ph.D. fellow at the Research Foundation — Flanders (FWO). Since its origin the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium).
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