Background
Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental pollutants that are found in several sources, including vehicular emissions, coal-burning plants, tobacco smoke, and the burning of biomass [
1]. PAH have both carcinogenic and endocrine disrupting properties (pro- or anti-estrogenic effects depending on the compound) [
1‐
3], and mounting evidence supports that PAH exposure is associated with increased breast cancer risk (as reviewed in [
4,
5]). PAH exposure during pregnancy might be particularly detrimental because this is a time when the breast tissue of both the mother and daughter is undergoing structural and functional changes, and is thus potentially more susceptible to environmental carcinogens [
6]. This is supported by animal studies that have found pregnancy-related exposure to certain endocrine disrupting chemicals (e.g., dioxin, atrazine, Bisphenol A) alters mammary gland development and morphology in both the mother and offspring [
7,
8]. In a recent study, we found that prenatal exposure to ambient PAH altered estrogen receptor α mRNA expression and induced methylation in the estrogen receptor
α promoter in the mammary tissue of both offspring and grand-offspring mice, as well as functional outcomes such as mammary cell proliferation in offspring mice [
9]. Yet, there are currently limited epidemiological data to support the hypothesis that pregnancy-related PAH exposure impacts breast tissue composition (BTC) in either the mother or daughter.
Mammographic breast density (MBD), the amount of collagen, epithelial, and stromal cells relative to fat in the breast, is consistently found to be one of the strongest biomarkers of breast cancer risk in older adult women of mammographic screening age (fourfold to sixfold increase in breast cancer risk for women in the highest versus lowest category of density) [
10‐
13]. Therefore, an association between pregnancy-related PAH exposure and MBD, or other measures of BTC that are associated with MBD, could have important implications for breast cancer risk. While it is not yet known if pregnancy-related PAH exposure impacts BTC in mothers or daughters, there are data supporting that BTC can be modified by environmental chemical exposures. This includes a longitudinal study that found prenatal exposure to dichlorodiphenyltrichloroethane was associated with higher MBD in women, aged 44–54 years with a family history of breast cancer [
14]. Cross-sectional studies have found that high versus low urinary concentrations of endocrine disrupting phthalates and phenols are associated with higher MBD in adult women [
15], as well as higher percent fibroglandular volume in the breast tissue of adolescent girls [
16]. Tobacco smoke exposure has been associated with lower MBD [
17‐
19], possibly due to the anti-estrogenic effects of some chemicals found in tobacco smoke [
20]. Studies examining air pollution in association with MBD have produced inconsistent results and were limited by the use of ecological exposure data [
21‐
24]. Further, studies of air pollution and MBD have only been conducted in cohorts of older adult women, likely because mammography is not recommended for routine use until at least age 40 years. In this study, we used prospectively collected data to test the hypothesis that exposure to ambient PAH during pregnancy is associated with BTC, measured by optical spectroscopy (OS) one to two decades later, in adolescent daughters and their mothers.
Discussion
In this prospective cohort study, we found limited evidence of an overall association between pregnancy-related exposure to ambient PAH (Σ8 PAH and pyrene) and BTC in adolescent daughters and their mothers. However, when we stratified by household smoke exposure status during pregnancy, we found that ambient Σ8 PAH (but not pyrene) was associated with higher breast density as indicated by higher water content and optical index in both daughters and mothers, as well as possibly higher collagen content in daughters, in those exposed to household smoke during pregnancy. Ambient Σ8 PAH exposure was not associated with BTC in daughters or mothers in non-smoking households during pregnancy. These findings are biologically plausible given that tobacco smoke contains a number of chemicals, in addition to PAH, that could interact synergistically with PAH to alter BTC. Previous studies conducted in the CCCEH cohort have also found synergistic interactions between prenatal exposure to ambient Σ8 PAH, but not pyrene, and environmental tobacco smoke predicting asthma and other respiratory symptoms in children [
29,
40], although the biological mechanisms through which environmental chemicals interact to impact respiratory outcomes and BTC might differ. The interaction between Σ8 PAH and environmental tobacco smoke observed for BTC might be due, at least in part, to the impact of tobacco smoke on body size across the life course [
41‐
44], especially given our findings related to Σ8 PAH, birthweight, and childhood BMI (described below). However, mechanistic studies and larger cohort studies are needed to explore these relationships further.
As with ambient PAH exposure, we found no overall associations between household tobacco smoke exposure during pregnancy and BTC in daughters or mothers. However, in those with low levels of Σ8 PAH exposure during pregnancy, household tobacco smoke exposure was associated with indicators of lower breast density in daughters (lower water content) and mothers (higher lipid content and lower water content and optical index), which is consistent with findings from a previous study in which we found that prenatal exposure to maternal tobacco smoking was associated with lower MBD in adult women (aged 39–49 years) [
45]. Studies that evaluated contemporary measures of tobacco smoking status and MBD in adult women have also mostly, but not always [
46], found a negative association between active smoking and MBD [
17‐
19]. Our findings suggest that this negative association between tobacco smoke exposure and breast density might only occur in the absence of other environmental chemical exposures, such as PAH.
We also found a statistically significant additive interaction between prenatal Σ8 PAH exposure and childhood BMI (measured at age 9 years) predicting water content in the breast tissue of daughters with a birthweight below the 25th percentile, such that prenatal Σ8 PAH exposure was positively associated with water content in those with lower childhood BMI and negatively associated with water content in those with higher childhood BMI. This additive interaction was not found in girls with a birthweight at or above the 25th percentile. Interestingly, in our previous analysis of pubertal timing in the Columbia-BCERP Study, we found that prenatal exposure to Σ8 PAH was associated with later age at menarche in girls with a birthweight below the 25th percentile, but not in girls with a birthweight at or above the 25th percentile [
36]. Therefore, it is possible that the association between prenatal Σ8 PAH exposure and BTC is mediated by the timing of menarche, especially given that average water content varied by age at menarche within age-groups in our sample. However, because we did not have repeated measures of BTC in this study, further prospective studies are needed to better understand the relationship between prenatal PAH exposure, pubertal timing, and change in BTC over time in adolescent girls.
This study has several strengths including the use of prospectively collected data from a cohort of mothers and daughters followed since pregnancy. We used personal air monitoring data to measure ambient PAH exposure levels and accounted for household smoke exposure, which is another source of exposure to PAH and other environmental chemicals. Further, we used OS to measure BTC in adolescent daughters and mothers, which is a minimally invasive method for obtaining data on individual breast tissue chromophores that is shown to accurately identify women with high MBD (> 75%) and objectively identify breast Tanner Stage [
47,
48]. Limitations of this study include that personal air monitoring was only conducted over a 48-h period during the third trimester of pregnancy, and this short period of exposure assessment may not be representative of long-term exposures throughout pregnancy. However, an indoor air monitoring sub-study conducted in the CCCEH cohort showed that residential indoor PAH exposure levels were fairly stable during the last 6–8 weeks of pregnancy, and home indoor PAH levels were found to be correlated with those in the personal air monitoring samples [
49]. We also did not measure exposure to PAH at later time points after pregnancy (e.g., during puberty for daughters or during perimenopause for mothers), which could theoretically be correlated with exposure levels during pregnancy or wash out some of the effects from pregnancy. Further, we did not have repeated measures of BTC to evaluate change over time, which will be important to evaluate in future studies given that BTC is dynamic over the life course. Finally, we did not adjust for multiple comparisons and thus some of the statistically significant findings could be due to chance. However, the consistency in findings across the BTC measures in daughters and mothers (e.g., Σ8 PAH consistently positively associated with indicators of higher breast density in smoking households) gives weight to our findings.
Conclusions
In conclusion, this study suggests that exposure to PAH and environmental tobacco smoke during pregnancy might interact synergistically to impact BTC in both mothers and daughters. Given that our sample was restricted to non-smoking mothers, these findings suggest that exposures external to the mother, such as paternal smoking, contribute to BTC in daughters. Therefore, more research is needed on the role of paternal factors in breast cancer risk, especially given that most life course studies have predominantly focused on maternal factors. If replicated in other cohorts, our study findings might have important implications for the role of pregnancy-related environmental exposures in breast cancer risk across generations.
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