We performed this large population-based case-control study to determine the association between maternal PM10 exposure and anorectal atresia/stenosis in offspring in Liaoning Province. This is the first study to investigate aforementioned topic. The high anorectal deformity rate where the PM10 concentration was rather high as well, enabled us to concluded that maternal exposure to PM10 3 months prior to conception and in the 1st trimester was associated with an increased risk of anorectal atresia/stenosis in offspring.
Recently, several studies have suggested that maternal air pollution exposure is associated with birth defects in offspring (Hu et al., 2020; Salavati et al., 2018). Notably, as a main component of air pollutants, additional studies showed that PM10 plays a critical role with respect to birth defects. For example, Vinceti et al. (Vinceti et al., 2016) suggested that higher exposure to PM10 increases the overall risk of birth defects. Anomaly categories suggested that the strongest dose-response associations with exposure to PM10 were musculoskeletal and chromosomal abnormalities, such as Down syndrome (Vinceti et al., 2016). Additionally, Hu et al. (Hu et al., 2020) reported that maternal exposure to PM10 increased the risk of selected subtypes of congenital heart defects in offspring. In addition, Zhang et al. (Zhang et al., 2020) reported that maternal exposure to PM10 prior to conception and during the 1st trimester were related to increased risks of polydactyly and syndactyly in the offspring, suggesting that PM10 has a teratogenic effect. Moreover, there are other studies that have shown that maternal exposure to PM10 is related to birth defects, such as cleft lip with or without cleft palate (Zhang et al., 2020) and neural tube defects (Zhang et al., 2020). Compared with previous studies, our study suggested a teratogenic effect of PM10 in offspring with anorectal atresia/stenosis. Therefore, evidence from these studies showed that pregnant women should avoid exposure to high levels of PM10 because of the increased risk of several types of birth defects in offspring.
The exact physiopathology of anorectal atresia/stenosis remains unclear. Genetic factors are
important contributing factors in the pathogenesis of anorectal atresia/stenosis. The development of the hindgut is governed by multiple genes in the relevant signaling pathways, and each gene may regulate organogenesis of the anorectal region at different stages of hindgut development. Specifically, cloacal septation depends on epithelial-to-mesenchymal signaling mediated by Shh signaling from
endoderm in the early stage (Wang et al., 2015). The Bmp signaling pathway plays a critical role in mesoderm induction and patterning (Wang et al., 2015). Hox genes and Fgf signaling are also involved in the specification of each body part along the anteroposterior body axis during embryogenesis (Wang et al., 2015). In addition, Notch-1 and Jagged-2 have been shown to be involved in the maintenance and function of neuronal cells in the enteric nervous system (Wang et al., 2015). In addition these important genes, evidence suggests that environmental factors are also involved in the development of anorectal atresia/stenosis. How environmental factors influence the development of anorectal atresia/stenosis remains largely unknown. Further studies are warranted to better understand the effect of environmental factors on the development of anorectal atresia/stenosis, including air pollutants.
The mechanisms underlying the developmental effects from PM exposure, especially PM10, have yet to be fully understood; however, a few studies have suggested that the teratogenic effect of PM might be related to oxidative stress. Specifically, Massarsky et al. (Massarsky et al., 2015) examined the effects of total PM (TPM) on the early development of zebrafish, and showed that TPM increases mortality, delay hatching, and the incidence of deformities, and also affects biomarkers of xenobiotic metabolism and oxidative stress. Similarly, exposure to cigarette smoke in mice prior to conception induces oxidative stress and compromises embryonic development (Huang et al., 2009). At the molecular level, reactive oxygen species (ROS) overproduction induces oxidative stress, a state in which increased ROS generation overwhelms antioxidant protection and subsequently leads to oxidative damage of cellular macromolecules, including proteins, lipids, and nucleic acids (Jezek and Hlavata, 2005). Therefore, intervention strategies, such as antioxidant nutritional therapies, may contribute to embryonic and fetal development and neonatal growth, but further studies are warranted. In addition, angiogenesis and the embryonic movement (EM) pathway are also involved in the process of embryonic development. A study based on a chicken embryo model showed that TPM plays a vital role in endothelial cell proliferation, migration, tube formation, and sprouting, which are crucial factors in angiogenesis (Ejaz et al., 2009). Video recordings and kinematic analyses of TPM-exposed chicken embryos revealed a striking decrease in EM (Ejaz et al., 2009). These limited findings partly explain the mechanisms regarding PM and its teratogenic effect; however, more studies are needed to explore the exact molecular mechanisms between PM, especially PM10 and birth defects, providing preventive strategies of birth defects for pregnant women.
Our study had several strengths. Notably, this is the first study to evaluate the potential association between maternal PM10 exposure and anorectal atresia/stenosis in offspring. Additionally, our study used the Maternal and Child Health Certificate Registry of Liaoning Province, a large database accommodating data on birth defects for six consecutive years. The large number of birth records reduces random errors and increases statistical power in identifying any meaningful relationship. In addition, because teratogen exposure prior to pregnancy may also result in a higher risk of birth defects, we evaluated the potential effect between PM10 and the risk of congenital atresia of the rectum and anus during the 3 months before pregnancy, and investigated the risk each month. Furthermore, because using birth defect controls may create selection bias if the exposure also causes other birth defects, we used unaffected live births as controls in our analysis.
Our study had limitations that necessitate cautious interpretation of the results. First, the air pollution exposure was measured using the average concentration of all monitoring stations in the city where each mother resided, which might not include the small regional variability of some air pollutants, which then compromised our exposure. A more accurate exposure assessment method is needed in future studies on the relationship between newborn defects and the effect of air pollution. For example, the land-use regression model, which takes transportation, population information, meteorologic factors, and industrial emission into account (Schembari et al., 2014). We had no access to indoor or workplace air pollution levels, which limited the accuracy of exposure assessment. In addition, we estimated maternal air pollution exposures during the 3 months prior to conception and the 1st trimester based on the residential address at the time of delivery, whereas gravidas may have incurred a wider range of movement for work and recreation. A previous study suggested that the median distance of migration was < 10 kilometers (Bell and Belanger, 2012) and another study conducted in China reported that only 3.1% of pregnant women relocated during pregnancy (Jin et al., 2015). Consequently, movement is unlikely to affect the exposure estimation. Second, our data were abstracted from the birth registrations. Even though the patients with birth defects were recorded by active surveillance and rigorous quality control, potential defects, including underreported and misclassified congenital atresia of the rectum and anus are difficult to avoid, particularly in regions with limited medical resources (Zhang et al., 2017). Moreover, congenital atresia of the rectum and anus diagnoses were made at different levels of hospitals in Liaoning Province, where consistency and uniformity was difficult to guarantee in the case cohort. Third, certain information, such as maternal diet, income, occupation, and maternal smoking during pregnancy, were absent due to the specific characteristics of the registry data, which may compromise the reported relationship between maternal PM10 exposure and congenital atresia of the rectum and anus. A previous study, however, suggested that when occupation, income, and maternal smoking were adjusted, the estimated effect changed by < 5% (Ritz et al., 2007). Finally, we failed to eliminate the influence of some different baseline characteristics completely using multivariate analysis with adjusted covariates. We used the PSM method to establish a balanced case-control subgroup. A significant positive association was also found in in the PSM subjects; nevertheless, the result should be interpreted with caution because of the biases of control selection.