Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances and childhood atopic dermatitis: a prospective birth cohort study

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are synthetic compounds with strong fluorine-carbon covalent bonds. PFASs have strong thermal, biological, and chemical stability as well as hydrophobic and lipophobic properties, and have been widely used worldwide in industrial (lubricants, surfactants) and consumer products such as non-stick cookware, waxes, paints, cosmetics and as water and oil repellents for leather, paper, and textiles since 1950s [1]. Most of the PFASs members are resistant to degradation and bio-accumulative and are ubiquitous in environment such as air, water, sediment and sludge; as well as wildlife [2]. The half-lives in human bodies (t1/2) of three common PFASs, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS), are 3.8, 5.4 and 8.5 years, respectively [3]. Although the production of PFOA and PFOS and related compounds has been phased out in some countries, the production of these chemicals or their precursors has actually increased in Asia, especially in China [4–6]. Environmental exposure to PFASs has been of increasing public health concern.

Extensive researches have associated exposure to PFASs with immunotoxicity, hepatotoxicity, developmental toxicity, reproductive toxicity, neurotoxicity, endocrine toxicity, liver tumor, impaired thyroid function, and mammary glands development [7–11]. Experimental studies suggested that PFOA and PFOS may cause immune suppression at doses of daily exposure in human and animals [12, 13]. However, findings from epidemiologic studies were far from consistent [14, 15]. Furthermore, these were cross-sectional or case-control studies, and evidence of PFASs causing allergic disorders is still limited, particularly from prospective studies.

Atopic dermatitis (AD) is a skin disease due to skin barrier dysfunction, resulting in eczematous and itchy lesions at the flexural folds and other typical distributions [16]. It is often caused by a combination of immune dysfunction and environment. Most AD occurs before 1 year of age, and it is generally considered as the first sign of the development of allergic diseases, including asthma, allergic rhinitis and conjunctivitis [17, 18]. The prevalence of AD ranges from 2.4% to 37% in children and 6.8%–10.6% in adults worldwide [19, 20], and was 12.9% in children aged 1–7 years in China in a previous study [21].

Given the facts that fetuses are more vulnerable to PFASs and PFASs might impair immune function [22], we investigated the effects of prenatal exposure to PFASs on AD in children up to 24 months of age in a prospective cohort study in Shanghai, China.

Our prospective cohort study suggests that prenatal PFASs exposures may increase the risk of childhood AD. In particular, we found that PFOA, PFDA, PFDoA and PFHxS in cord blood increased the risk of childhood AD in girls only. In addition, the associations between AD with prenatal exposure to PFNA were close to statistical significance.

Five studies have reported the association between prenatal exposure and childhood AD, but the results were inconsistent. In a cohort study conducted in Taiwan, the highest quartile of PFOS appeared to be positively associated with AD with an OR of 2.79 (95% CI: 1.06, 7.38) [25]. However, after adjusted by potential confounders, the association was no longer statistically significant. Another two birth cohort studies from Norway and Japan found no significant associations between PFOA, PFOS, PFNA and PFHxS and AD or eczema in early childhood [26, 27]. Likewise, a birth cohort study in 1024 infants conducted in Greenland and Ukraine, reported that principal component (PC) score, dominated by PFOA, was not associated with eczema [28]. In contrast, a birth cohort study in Japan involving 2063 subjects found that prenatal exposure to perfluorotridecanoic acid (PFTrDA) was associated with a decreased risk of developing eczema in female infants at 24 months (OR = 0.39; 95% CI: 0.23, 0.64) [29]. After following for another 2 years, PFOS levels in the highest quartile were associated with an increased risk of total infectious diseases in all children (OR = 1.61; 95% CI: 1.18, 2.21), while the highest quartile of PFHxS was associated with a higher risk of total infectious diseases only among girls (OR = 1.55, 95% CI: 0.976, 2.45) [30]. These studies provided evidence for the potential long-lasting effect of PFASs on children’s immune system.

Several studies also reported associations between PFASs and other allergic disorders in children and adults. A US national study found that serum PFOA was positively associated with asthma (OR = 1.18, 95% CI: 1.01, 1.39) in adolescents aged 12–19 years, while PFOS was inversely associated with both asthma and wheezing (OR = 0.88; 95% CI: 0.74, 1.04, and OR = 0.83; 95% CI: 0.67, 1.02, respectively) [15]. In addition, a case-control study with 231 asthmatic and 225 non-asthmatic children aged 10–15 years in Taiwan found that PFOA and PFOS were associated with asthma in a dose-response pattern [14].

The mechanisms of prenatal PFASs exposure on the development of AD have not been fully understood. Animal and human studies suggest that PFOA and PFOS may increase IgE levels in blood. For example, PFASs concentrations in cord blood were positively associated with cord blood IgE levels in Taiwan infants (per ln-unit: β = 0.134 KU/l, p = 0.047 for PFOA; β = 0.161 KU/l, p = 0.017 for PFOS) [25]. Furthermore, both animal and human studies suggested that PFOS may increase Th2 cytokines secretion (IL-4 and IL-10) and decrease Th1 cytokines (IL-2 and IFN-γ) at doses comparable to those in humans, shifting immune response toward Th2 state [31, 32]. A previous study showed that PFOA, PFOS and PFDA suppressed LPS-induced TNF-α production; PFOS and PFDA inhibited PHA-induced IL-10 release in human peripheral blood leukocytes (hPBL) and human promyelocytic cell line THP-1 [33].

Oxidative stress might be another potential mechanism of the immunotoxic effects of PFASs. Wielsøe et al. exposed human hepatoma cell line (HepG2) with PFHxS, PFOA, PFOS and PFNA for 24 h and found a dose-dependent increase in DNA damage and increased ROS generation [34]. PFNA was also found to have immunomodulatory effects on leukocyte populations and immune function, including decreased spleen size and a decreased ratio of CD4+/CD8+ double-positive population in thymus of mice [35].

In addition, peroxisome proliferator activated receptors (PPARs) signaling pathway might also play a role in the effects of PFASs on childhood AD. Previous study showed that PFOA and PFOS significantly increased PPAR-α and PPAR-γ in human cells [36], which, in turn, could shift cytokine secretion by inhibiting IFN-γ and promoting IL-4 secretion in human T-cell lines [37, 38]. The changes of these cytokines resulted from PFASs exposure might impair the immune system and immune responses, especially in young children when the immune system is still developing.

Nonetheless, a prospective cohort study in Japan found an inverse association between maternal PFOS concentration and cord blood IgE levels among female infants (β = −3.08, 95%CI: -5.43, −0.73) [26]. Thus, the evidence is far from consistent, and our understanding of the underlying biological mechanisms is still incomplete.

A birth cohort study conducted in Japan between 2002 and 2005, showed that cortisol and cortisone concentrations were significantly lower in cord blood of infants with prenatal PFOS exposure in Q4 compared with those in Q1 (β = −23.98 ng/mL, 95% CI: -47.12, −11.99 for cortisol; β = −63.21 ng/mL, 95% CI: -132.56, −26.72 for cortisone). Meanwhile, the highest quartile of prenatal PFOS exposure was positively associated with a significant higher DHEA level (β = 1.33 ng/mL, 95% CI: 0.17, 1.82), whereas PFOA showed a negative association with DHEA levels (β = −1.23 ng/mL, 95% CI: -1.72, −0.25) [39]. In addition, animal and human data suggested that perinatal exposure to glucocorticoid may program the fetal hypothalamic-pituitary-adrenal (HPA) axis affecting its development, resulting in long-lasting effect in HPA axis function [40, 41]. These findings revealed that prenatal exposure may have an effect on the balance of steroid hormones, which was one of the potential mechanisms of the immunotoxical effects of PFASs [42].

Our study discovered that the association between prenatal exposure to PFASs and childhood AD existed only in girls, but the biologic mechanism is unclear. A previous study showed that exposure to higher levels of PFASs resulted in lower testosterone and higher estradiol levels, and more significant associations of PFASs with reproductive hormones were found in male adolescents than in females [43]. This effect was supported by an experimental study conducted in mice [44]. A case-control study reported that PFASs were positively associated with estradiol levels and negatively associated with testosterone levels among asthmatics [45]. Furthermore, the interactions between estradiol and PFASs were significant for PFOS (p = 0.026) and PFNA (p = 0.043) among girls, suggesting that reproductive hormones might amplify the association between PFASs and asthma.

The PFOA level in our study was higher than that reported in other countries and was the most abundant among all the PFAS members [24]. The higher PFAS levels in Shanghai may be due to higher levels of pollutants in Yangtze river, probably because there are many fluoropolymer factories in the Yangtze Delta. For example, PFAS levels in tap water in Shanghai was higher than that in 19 cities in China, Japan, India, the USA, and Canada between 2006 and 2008 [46].

Our study also showed a very high cesarean section rate. This is consistent with the situation in China where cesarean delivery on maternal request accounts for nearly 50% of all cesarean sections [47]. The effect of cesarean section on AD has not been well studied and the results were inconclusive. The effect of cesarean section on AD during the first 3 years of life was not significant (OR 1.35; 95% CI 0.74–2.47) in a birth cohort study [48]. The OR of having AD in adolescents aged from 12 to 18 years born by caesarean section compared with vaginal delivery was 1.50 (95% CI 1.01–2.22) in a cross-sectional study [49]. However, our study did not show any association (OR 0.94, 95% CI 0.63–1.39).

The prospective cohort study design, the AD diagnosis confirmed by two dermatologists, and the reliable laboratory assessments were strengths of our study. We also adjusted for a number of potential confounders in the multivariable models. On the other hand, it is worth noting that 23.2% of children were excluded from analyses due to missing data or loss to follow-up, resulting in reduced statistical power for sex-stratified analyses. However, there were no significant differences in basic characteristics between those remained in analyses and those excluded. In addition, our study is still not large enough to examine some PFASs with a wider variation of exposure and AD. Finally, unmeasured confounding is possible and residual confounding could not be ruled out.

Prenatal exposure to PFOA, PFDA, PFDoA and PFHxS was positively associated with childhood AD in girls during the first 24 months of life. In addition, the associations between AD with prenatal exposure to PFNA were close to statistical significance. Future studies are warranted to investigate the underlying mechanisms of the effects of PFASs and allergic diseases in early childhood.