DISCUSSION
The role of environmental phthalate exposure on allergic airway diseases
has been a topic of great interest. However, very few studies have
examined the association of phthalate exposure with allergic
inflammation and lung function. Our measurements of IOS in a
population-based sample of children showed that an increased level of
urinary phthalate metabolites was significantly associated with airway
dysfunction, and that this association was partially attributable to an
increased serum periostin level. Moreover, the associations we
identified persisted after adjusting for multiple covariates (height,
gender, BMI z -score, aeroallergen sensitization, secondary
smoking, and vitamin D level).
Phthalate exposure may occur from ingestion, inhalation, dermal
absorption, and parenteral administration.20,21 LMWPs
are used in a variety of personal-hygiene and cosmetic products, such as
nail polish and fragrances, as scent stabilizers.22HMWPs are used in plastic tubing, food packaging, containers, vinyl
toys, vinyl floor coverings, and building
products.21,22 Koch et al.14 showed
that exposure to HMWPs was mostly due to dietary intake, and that
exposure to LMWPs was mainly from non-dietary exposures, such as from
personal care products, dust, and indoor air.14 In the
present study, we showed that children with higher urinary levels of
LMWPs had significantly greater airway resistance after adjusting for
confounding variables.
Experimental studies demonstrated that exposure to phthalates increases
the levels of Th2 cells and multiple cytokines, and thereby enhances
airway inflammation.8,9 Clinical studies found an
association between phthalate exposure and FeNO.5,8Serum periostin is a biomarker of type-2 inflammation in
asthma.23 The exact function of YKL-40 remains
unclear, but it consistently correlates with airway obstruction in
studies of patients with asthma,24-26 and with
measures of airway remodeling, such as bronchial wall thickness and
subepithelial fibrosis.24,25 Little is known about the
function of periostin and YKL-40 in patients with allergic inflammation
related to environmental pollutants. We initially hypothesized that
there may be some differences in serum levels of periostin and YKL-40
following phthalate exposure because type-2 and non–type-2-induced
airway inflammation are involved in phthalate-related airway
inflammation. We therefore evaluated the relationships of serum
periostin and YKL-40 levels in children with phthalate exposure, and
investigated their relevance to clinical characteristics and other
type-2 biomarkers, including blood eosinophil counts, serum total IgE,
and FeNO. We found that FeNO level was significantly associated with the
quartiles of urinary Σ4HMWP metabolites, but not
quartiles of urinary Σ3LMWP metabolites. Our
multivariate linear regression analysis indicated that urinary
Σ4HMWP and Σ3LMWP metabolites were both
significantly associated with serum periostin level. These findings are
clinically significant because they demonstrate an association between
phthalate exposures with serum periostin, an established marker of Th2
inflammation. However, we found no significant associations in the
levels of urinary Σ4HMWP and Σ3LMWP
metabolites with serum YKL-40 level. These results suggest that serum
periostin may be used as a biomarker for type-2 inflammation in children
following phthalate exposure, but serum YKL-40 has less value for this
assessment.
We found that serum periostin level was significantly associated with
Rrs5 and Rrs20-5. This outcome is similar to that of a recent study
which reported the relationship between periostin level and pulmonary
function in asthma patients. This previous study found that patients
with high periostin levels had lower FEV1/FVC
values.27 Although there are reports of associations
between pulmonary function and periostin level, there are only limited
data on the relationships of periostin with small airway function. We
therefore used an objective method — IOS — to evaluate small airway
dysfunction our patients.
We found that periostin had a significant effect in mediating the
relationship between urinary LMWP metabolites and airway resistance. To
quantify this mediating effect, we performed a model-based mediation
analysis by using the mediation package in R
software.19 The algorithm uses a quasi-Bayesian Monte
Carlo method to estimate the presence of mediation (average causal
mediation effect/indirect effect) and the proportion of the link between
phthalate exposure and airway dysfunction that is mediated by
periostin.19
There are several limitations to the present study. First, because this
was a cross-sectional study, we did not obtain any direct evidence for
cause-and-effect relationships. Second, use of periostin as a dependable
biomarker in growing children may be questionable because it is an
extracellular matrix protein that is secreted by osteoblasts. However,
the levels in our study subjects (10-12 years-old) were not higher than
published values for adults28 and were not
significantly associated with age (data not shown).
To the best of our knowledge, this is the first large-sample study of
urban children to comprehensively investigate the role of periostin in
mediating the relationship between phthalate exposure and airway
dysfunction. Previous studies have investigated the association of
phthalate exposure with other inflammation markers, but no previous
studies investigated the role of periostin and YKL-40 on airway
dysfunction in children exposed to phthalates. Another merit of this
study is that we assessed small airway function using IOS.
In conclusion, we found that exposure to low-molecular-weight phthalates
was significantly associated with airway dysfunction, and this effect is
partially attributable to increased serum periostin level. Periostin
appears to function in the Th2 cell-mediated inflammation that causes
pulmonary dysfunction in children exposed to phthalates, but further
studies are required to clarify this relationship.