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\begin{document}

\title{Association of phthalate exposure and airway dysfunction, with mediation
by serum periostin}



\author[1]{Heysung Baek}%
\author[2]{Ha Young Won}%
\author[3]{Ju Hee Kim}%
\author[4]{Eun Kyo Ha}%
\author[4]{Hye Mi Jee}%
\author[5]{Youn Ho Shin}%
\author[6]{Mi Ae Kim}%
\author[4]{Man Yong Han}%
\affil[1]{Hallym University Kangdong Sacred Heart Hospital }%
\affil[2]{Clinical Research Institute, Kangdong Sacred Heart Hospital, Hallym University College of Medicine}%
\affil[3]{CHA Bundang Medical Center}%
\affil[4]{CHA University School of Medicine}%
\affil[5]{CHA Gangnam Medical Center, CHA University School of Medicine}%
\affil[6]{, CHA Medical Center, CHA University School of Medicine}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background: Phthalates can cause respiratory and immunological
disorders. However, little is known about the role of serum periostin
and YKL-40 levels in mediating the effects of phthalates. We
investigated the mediating role of these biomarkers in the relationship
between phthalates and airway dysfunction. Methods: A total of 487
children (aged 10 to 12 years-old) were examined. Four
high-molecular-weight phthalate (HMWP) {[}\selectlanguage{greek}Σ\selectlanguage{english}4HMWP{]} metabolites and 3
low-molecular-weight phthalate (LMWP) {[}\selectlanguage{greek}Σ\selectlanguage{english}3LMWP{]} metabolites in urine
samples were measured. Serum periostin and YKL-40 levels were measured.
Airway function was measured using impulse oscillometry. A mediation
model was used to quantify the mediating effects of periostin and YKL-40
on airway dysfunction. Results: After adjustment for height, gender, BMI
z-score, aeroallergen sensitization, secondary smoking, and vitamin D
level, the level of urinary \selectlanguage{greek}Σ\selectlanguage{english}3LMWP metabolites was significantly
associated with respiratory system resistance at 5 Hz (Rrs5; adjusted \selectlanguage{greek}β:
\selectlanguage{english}0.020, 95\% CI: 0.005 to 0.034; P = .010). The levels of urinary \selectlanguage{greek}Σ\selectlanguage{english}4HMWP
and \selectlanguage{greek}Σ\selectlanguage{english}3LMWP metabolites were significantly associated with periostin
level, but not with YKL-40 level. In addition, the periostin level was
associated with Rrs5 (adjusted \selectlanguage{greek}β: \selectlanguage{english}0.048, 95\% CI: 0.015 to 0.081; P =
.005) and Rrs20-5 (adjusted \selectlanguage{greek}β: \selectlanguage{english}0.040, 95\% CI: 0.011 to 0.069; P =.007).
Serum periostin level had a significant effect in mediating the
relationship between \selectlanguage{greek}Σ\selectlanguage{english}3LMWP and Rrs5 (13.9\%, 95\% CI: 10.7 to 77.0; P
\textless{} .001). Conclusion: Exposure to LMWPs was significantly
associated with airway dysfunction, and this effect was partially
attributable to increased serum periostin level.%
\end{abstract}%



\sloppy


\textbf{Association of phthalate expxosure and airway dysfunction, with
mediation by serum periostin}

a running title : \textbf{Phthalate, airway dysfunction and periostin}

Hey Sung Baek\selectlanguage{ngerman}¹, Ha Young Won ², Ju Hee Kim³, Eun Kyo Ha\selectlanguage{english}4, Hye Mi Jee\selectlanguage{ngerman}³,
Youn Ho Shin\textsuperscript{5}, Mi\selectlanguage{english}-Ae Kim\textsuperscript{6}, Man Yong
Han3

Author affiliations:

1. Department of Pediatrics, Kandong Sacred Heart Hospital, Hallym
University College of Medicine, Seoul, Korea

2. Clinical Research Institute, Kangdong Sacred Heart Hospital, Hallym
University College of Medicine, Seoul, Korea

3. Departments of Pediatrics, CHA Bundang Medical Center, CHA University
School of Medicine, Seongnam, Korea

4. Department of Pediatrics, Kangnam Sacred Heart Hospital, Hallym
University Medical Center, Seoul, Korea

5. Department of Pediatrics, CHA Gangnam Medical Center, CHA University
School of Medicine, Seoul, Korea

6. Department of Internal Medicine, CHA Bundang Medical Center, CHA
University School of Medicine, Seongnam, Korea

*Corresponding author

Professor Man Yong Han, MD

Department of Pediatrics, CHA University School of Medicine

59, Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, Republic of
Korea

Phone: +82-31-780-6262; Fax: +82-31-780-5239

\textbf{The contribution of each author}

Heysung Baek, MD, PhD: conception and design of the study, analysis and
interpretation of the data

paviola7@gmail.com

Ha Young Won, MS: collection of the data and interpretation of the data

why3719@kdh.or.kr

Ju Hee Kim, MD: collection of the data and interpretation of the data

2004052@gmail.com

Eun Kyo Ha, MD: collection of the data and interpretation of the data

dmsry1@gmail.com

Hye Mi Jee MD, PhD: collection of the data and interpretation of the
data

hyemijee@gmail.com

Youn Ho Sheen, MD, PhD: analysis and interpretation of the data

epirubicin13@gmail.com

Mi\selectlanguage{english}-Ae Kim, MD, PhD: analysis and interpretation of the data

makim7851@gmail.com

ManYong Han, MD, PhD: conception and design of the study, collection of
the data and analysis and interpretation of the data

drmesh@gmail.com

\textbf{Total Word Count: 2,492}

\textbf{Number of tables and figures; 6}

\textbf{Association of phthalate exposure and airway dysfunction, with
mediation by serum periostin}

\textbf{Conflicts of interest}

All authors declare no conflict of interest.

\textbf{Funding}

This research was supported by the Hallym University Kangdong Sacred
Heart hospital Research Fund (grant number: 2018-05) and by a grant from
the Seongnam Atopy Project of the Seongnam City Government, Republic of
Korea.

\textbf{ABSTRACT}

\textbf{Background} : Phthalates can cause respiratory and immunological
disorders. However, little is known about the role of serum periostin
and YKL-40 levels in mediating the effects of phthalates. We
investigated the mediating role of these biomarkers in the relationship
between phthalates and airway dysfunction.

\textbf{Methods:} A total of 487 children (aged 10 to 12 years-old) were
examined. Four high-molecular-weight phthalate (HMWP) {[}\selectlanguage{greek}Σ\selectlanguage{english}4HMWP{]}
metabolites and 3 low-molecular-weight phthalate (LMWP) {[}\selectlanguage{greek}Σ\selectlanguage{english}3LMWP{]}
metabolites in urine samples were measured. Serum periostin and YKL-40
levels were measured. Airway function was measured using impulse
oscillometry. A mediation model was used to quantify the mediating
effects of periostin and YKL-40 on airway dysfunction.

\textbf{Results:} After adjustment for height, gender, BMI z-score,
aeroallergen sensitization, secondary smoking, and vitamin D level, the
level of urinary \selectlanguage{greek}Σ\selectlanguage{english}3LMWP metabolites was significantly associated with
respiratory system resistance at 5 Hz (Rrs5; adjusted \selectlanguage{greek}β: \selectlanguage{english}0.020, 95\% CI:
0.005 to 0.034; P = .010). The levels of urinary \selectlanguage{greek}Σ\selectlanguage{english}4HMWP and \selectlanguage{greek}Σ\selectlanguage{english}3LMWP
metabolites were significantly associated with periostin level, but not
with YKL-40 level. In addition, the periostin level was associated with
Rrs5 (adjusted \selectlanguage{greek}β: \selectlanguage{english}0.048, 95\% CI: 0.015 to 0.081; P = .005) and Rrs20-5
(adjusted \selectlanguage{greek}β: \selectlanguage{english}0.040, 95\% CI: 0.011 to 0.069; P =.007). Serum periostin
level had a significant effect in mediating the relationship between
\selectlanguage{greek}Σ\selectlanguage{english}3LMWP and Rrs5 (13.9\%, 95\% CI: 10.7 to 77.0; P \textless{} .001).

\textbf{Conclusion:} Exposure to LMWPs was significantly associated with
airway dysfunction, and this effect was partially attributable to
increased serum periostin level.

\textbf{Key words}

1. Phthalate

2. perisotin

3. chitinase-like proteins (YKL-40)

4. airway dysfunction

\textbf{Key Messages}

Phthalates have known adverse effects on the respiratory and
immunological systems. However, the mechanisms by which they promote
asthma, impaired lung function, and airway inflammation are unknown
because few studies have thoroughly examined this topic. 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. Our results suggest that periostin
might stimulate Th2 cell-mediated inflammation and thereby cause
pulmonary dysfunction in children exposed to phthalates.

\textbf{INTRODUCTION}

Previous studies reported that exposures to environmental pollutants are
responsible for the increasing prevalence of allergic
diseases.\textsuperscript{1,2} Here, we focused on phthalates, a group
of chemicals commonly used as plasticizers that commonly have higher
concentrations in children than adults.\textsuperscript{3} Phthalates
can have adverse effects on the respiratory and immunological systems.
Epidemiological studies reported positive associations between
indicators of phthalate exposure and risk of asthma, and allergic
diseases.\textsuperscript{4,5} Other studies reported that phthalates
also adversely affect pulmonary
functions.\textsuperscript{6,7}Experimental studies demonstrated that
exposure to phthalates increased the levels of T helper 2 (Th2) cells
and cytokines, and also increased airway
inflammation.\textsuperscript{8,9} Several clinical studies found an
association between phthalate exposure and fractional exhaled nitric
oxide (FeNO).\textsuperscript{5,8} The immunological mechanisms by which
phthalate exposure leads to asthma and disruptions of lung function and
airway inflammation are unknown. In addition, few studies have examined
the association of phthalate exposure with allergic inflammation and
lung function.

Recent studies identified periostin and chitinase-like proteins as
biomarkers of asthma. Periostin promotes chronic allergic inflammation
in response to Th2-associated cytokines by inducing proinflammatory
cytokines.\textsuperscript{10} Chitinase-3-like protein 1, also known as
YKL-40, is a glycoprotein secreted by various cell types, including
macrophages, neutrophils, and airway epithelial
cells.\textsuperscript{11} However, little is known about the levels or
function of periostin and YKL-40 following exposure to environmental
pollutants or other chemicals. We hypothesized that phthalate exposure
may alter the serum levels of periostin and YKL-40.

Our primary objective was to determine the associations between
phthalate exposure and pulmonary functions in a population-based sample
of randomly selected sixth-grade students from 11 elementary schools in
Korea. Our secondary objective was to examine the potential role of
periostin and YKL-40 in mediating the relationship between phthalate
exposure and airway dysfunction.

\textbf{METHODS}

\textbf{Subjects and Protocol}

A total of 620 fifth- and sixth-grade elementary school students (10--12
years old) who participated in the Seongnam Atopy Project (SAP) 2017
cohort were enrolled. This study was sponsored by the Seongnam City
Government for the prevention and education of allergic diseases in
Korean children and was conducted between January 2017 and October
2017.\textsuperscript{12}

Demographic data were collected, and questionnaires completed by the
parents were used to record symptoms of the children during the previous
12 months (wheezing, nasal symptoms, and eczema), based on the
International Study of Asthma and Allergies in Childhood (ISAAC)
questionnaire.\textsuperscript{13}. Urine samples were collected in
sterile cups and stored at -70\selectlanguage{ngerman}°C for up to 3 months before analysis.
Blood samples were stored at \selectlanguage{english}-70degC until determination of the levels of
serum periostin, serum YKL-40, and total and allergen-specific
immunoglobulin (Ig) E. FeNO levels were measured by a physician and
impulse oscillometry (IOS) was performed by a well-trained technician.
The study protocol was approved by the appropriate Institutional Review
Board of CHA University (2017-04-049), and written informed consent
documents were obtained from all parents or guardians of participating
children.

\textbf{Measurement of phthalate metabolites}

Phthalate metabolite concentrations were determined by gas
chromatography/tandem mass spectroscopy.\textsuperscript{14} Reported
phthalate concentrations were expressed relative to urinary creatinine
(\selectlanguage{greek}µ\selectlanguage{english}g/g UCr) to control for urine dilution. A total of 455 urine samples
were analyzed for the following 7 phthalate metabolites:
mono-(iso-butyl) phthalate (MiBP), mono-isononyl phthalate (MNP),
mono-benzyl phthalate (MBzP), mono-(3-carboxypropyl) phthalate (MCPP),
mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP),
mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and
mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP). (Appendix S1: Fig.
E1). Phthalate metabolites were grouped based on molecular weight and
reported as the sum of 4 major high-molecular weight phthalate
(\selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP) metabolites (MEHP, MEOHP, MECPP, and MCPP), or
the sum of the 3 major low-molecular weight phthalate
(\selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP) metabolites (MiBP, MNP, and MBzP). They were
further divided into quartiles according to concentration (lowest to
highest,Q1 to Q4). Previous research indicated these two groups of
metabolites have different physicochemical
properties.\textsuperscript{14,15}

\textbf{Lung function measurements and FeNO}

IOS was performed in accordance with established
guidelines.\textsuperscript{16}The difference of the respiratory system
resistance (Rrs) at 5 Hz and 20 Hz (Rrs5-20) has a high sensitivity for
detecting small airway dysfunction.\textsuperscript{17}Airway resistance
was also measured at 1, 2, 3, 5, 10, 15, and 20 Hz for calculation of
area of reactance (AX) as a function of frequency. The signals were
analyzed for 30 s at each frequency. Oscillometric tests were performed
using a Jaeger MasterScreen device (Jaeger Co., Wurzburg, Germany).

The FeNO concentration in exhaled breath in parts per billion (ppb) was
measured using a portable nitric oxide analyzer (NIOX MINO\selectlanguage{ngerman}®; Aerocrine,
Solna, Sweden) according to the American Thoracic Society (ATS)
guidelines.\textsuperscript{18}

\textbf{Measurement of serum biomarkers}

Serum total and specific IgE antibodies for common aeroallergens
(\emph{Dermatophagoides farinae} , cat dander, dog dander,
birch,\emph{Alternaria alternata} , and \emph{Humulus japonicus} ) were
measured using the ImmunoCAP system (Phadia, Uppsala, Sweden). Atopy was
defined by positive specific IgE antibodies to at least one common
inhaled allergen. Serum periostin was determined using the Human
Periostin/OSF-2 DuoSet ELISA Kit (catalog number DY3548B; R\&D Systems,
Inc., Minneapolis, MN). Serum YKL-40 was determined using the Human
Chitinase 3-like 1 Quantikine ELISA Kit (catalog number DC3L10; R\&D
Systems, Inc., Minneapolis, MN).

\textbf{Statistical analysis}

The data were analyzed using SPSS version 21.0 (SPSS, Chicago, IL) and R
software version 3.6.3. Continuous data are expressed as means with
standard deviations or as medians with the interquartile ranges,
depending on the data distribution. The relationships of the
concentrations of different of urinary phthalates with serum periostin
level, Rrs5, and Rrs5-20 were analyzed using linear regression with
adjustment for height, gender, BMI \emph{z} -score, aeroallergen
sensitization, secondary smoking, and vitamin D level. The estimates
were regression slopes for phthalate concentration \emph{vs.} periostin
level and Rrs5. Beta (\selectlanguage{greek}β\selectlanguage{english}) and a 95\% confidence interval (CI) were
obtained from a generalized linear regression model with the gamma
function. The R package, ``Mediation''\textsuperscript{19} was used to
quantitatively estimate the mediating effect of periostin level in the
association of phthalate concentration with Rrs5 and Rrs5-20. This
package estimates confidence intervals using bootstrapping with 1000
resamples. A two-sided \emph{P} value of .05 or less indicated
statistical significance.

\textbf{RESULTS}

\textbf{Characteristics of study subjects}

We recruited 487 fifth- and sixth-grade students for this study (Table
1). The average age was 11.01 years (95\% CI: 10.9 to 11.1) and the
average BMI \emph{z-} score was -0.02 (95\% CI: -0.11 to 0.07).
Fifty-six children (11.7\%) had wheezing at some time, 28 (5.8\%) had
asthma, and 25 (10.9\%) were born premature and/or had low birth weight.
A total of 61.4\% of the children had atopic sensitization. The median
level of serum periostin was 35.7 (ng/mL) and the median level of YKL-40
was 21.47 (ng/mL). Table 1 shows the IOS parameters.

\textbf{Association of phthalate concentration with lung function and
FeNO level}

Analysis of the association of the quartiles of phthalate metabolites
with Rrs5 (Table 2, Figure 1) indicated the quartiles of urinary
\selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP metabolites were associated with greater Rrs5
(Crude \selectlanguage{greek}β: \selectlanguage{english}0.028; 95\% CI: 0.011 to 0.046; \emph{P} = .001), but these
associations were not significant after adjusting for height, gender,
BMI \emph{z-} score, aeroallergen sensitization, secondary smoking, and
vitamin D level. However, after adjusting for these same confounders,
\selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP was significantly associated with Rrs1 (Q1/Q4,
adjusted \selectlanguage{greek}β: \selectlanguage{english}0.047, 95\% CI: 0.009 to 0.084, \emph{P} = .015), Rrs2
(Q1/Q4, adjusted \selectlanguage{greek}β: \selectlanguage{english}0.046, 95\% CI: 0.007 to 0.084, \emph{P} = .021),
and Rrs3 (Q1/Q4, adjusted \selectlanguage{greek}β: \selectlanguage{english}0.057, 95\% CI: 0.015 to 0.099, \emph{P} =
0.008) (Figure 1A).

Children with higher quartiles of \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP metabolites
(Table 2, Fig. 1) also had significantly greater Rrs5 (Crude \selectlanguage{greek}β: \selectlanguage{english}0.028,
95\% CI: 0.011 to 0.045; \emph{P} = .001) and this relationship remained
significant after adjustment for confounding (adjusted \selectlanguage{greek}β: \selectlanguage{english}0.020, 95\%
CI: 0.005 to 0.034; \emph{P} = .010). In addition, after adjusting for
confounding, quartiles of \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP was also significantly
associated with Rrs1 (Q1/Q4, adjusted \selectlanguage{greek}β: \selectlanguage{english}0.046, 95\% CI: 0.008 to
0.083,\emph{P} = .018), Rrs2 (Q1/Q4, adjusted \selectlanguage{greek}β: \selectlanguage{english}0.051, 95\% CI: 0.012
to 0.089, \emph{P} = .010), Rrs3 (Q1/Q4, adjusted \selectlanguage{greek}β: \selectlanguage{english}0.057, 95\% CI:
0.015 to 0.099, \emph{P} = .008), Rrs10 (Q1/Q4, adjusted \selectlanguage{greek}β: \selectlanguage{english}0.055, 95\%
CI: 0.010 to 0.099, \emph{P} = .016), and Rrs15 (Q1/Q4, adjusted \selectlanguage{greek}β:
\selectlanguage{english}0.055, 95\% CI: 0.001 to 0.109, \emph{P} = .044).

After adjustment for confounding, there was a significant association in
the quartiles of urinary \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP metabolites with FeNO
(adjusted \selectlanguage{greek}β: \selectlanguage{english}0.053, 95\% CI: 0.007 to 0.099; \emph{P} = 0.024), but no
significant association in the quartiles of urinary
\selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP metabolites with FeNO (Table 2).

\textbf{Associations of phthalate concentrations with serum periostin
level, YKL-40 level, and lung function}

Analysis of the relationships of urinary phthalate metabolites with
serum periostin level and serum YKL-40 level indicated significant
associations in the quartiles of urinary \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP and
\selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP metabolites with periostin (Table 3). After
adjustment using a generalized linear regression model with the logit
function, these relationships remained significant. After adjustment,
the level of urinary \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP metabolites was also
significantly associated with YKL-40 (adjusted \selectlanguage{greek}β: \selectlanguage{english}0.882, 95\% CI: 0.687
to 0.983; \emph{P} =.032), but level of urinary \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP
metabolites was not significantly associated with YKL-40 level.

Analysis of the relationships of serum periostin and serum YKL-40 levels
with pulmonary function indicated periostin level was significantly
associated with Rrs5 (adjusted \selectlanguage{greek}β: \selectlanguage{english}0.048, 95\% CI: 0.015 to
0.081;\emph{P} = .005), but not with FeNO (Table 4). There was also a
significant association between periostin level and Rrs5-20 (adjusted \selectlanguage{greek}β:
\selectlanguage{english}0.040, 95\% CI: 0.011 to 0.069; \emph{P} = .007). The serum YKL-40 level
was not significantly associated with Rrs5 or Rrs5-20.

\textbf{Mediating effect of periostin on lung function}

We performed an in-depth analysis of the potential role of periostin in
mediating the association between the level of urinary phthalate
metabolites and Rrs5 (Fig. 2). The results indicated that a higher
\selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP level had a significant and direct association
with a higher Rrs5 (\selectlanguage{greek}β: \selectlanguage{english}0.084, 95\% CI: 0.005 to 0.14, \emph{P} = 0.04),
and that some of the effect of \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP was mediated by an
increased periostin level (\selectlanguage{greek}β: \selectlanguage{english}0.013, 95\% CI: 0.002 to 0.030,
\emph{P}\textless{} 0.001). Periostin mediates the relationship between
\selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP level and Rrs5 (13.9\% mediation, 95\% CI: 10.7
to 77.0; \emph{P} \textless{}.001).

\textbf{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 \emph{z} -score, aeroallergen sensitization, secondary
smoking, and vitamin D level).

Phthalate exposure may occur from ingestion, inhalation, dermal
absorption, and parenteral administration.\textsuperscript{20,21} LMWPs
are used in a variety of personal-hygiene and cosmetic products, such as
nail polish and fragrances, as scent
stabilizers.\textsuperscript{22}HMWPs are used in plastic tubing, food
packaging, containers, vinyl toys, vinyl floor coverings, and building
products.\textsuperscript{21,22} Koch et al.\textsuperscript{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.\textsuperscript{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.\textsuperscript{8,9} Clinical studies found an
association between phthalate exposure and
FeNO.\textsuperscript{5,8}Serum periostin is a biomarker of type-2
inflammation in asthma.\textsuperscript{23} The exact function of YKL-40
remains unclear, but it consistently correlates with airway obstruction
in studies of patients with asthma,\textsuperscript{24-26} and with
measures of airway remodeling, such as bronchial wall thickness and
subepithelial fibrosis.\textsuperscript{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 \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP metabolites, but not
quartiles of urinary \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP metabolites. Our
multivariate linear regression analysis indicated that urinary
\selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP and \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP 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 \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP and \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP
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 FEV\textsubscript{1}/FVC
values.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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 adults\textsuperscript{28} 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.

\textbf{Acknowledgments}

We are grateful to the children and families who participated in the
study for their support and dedication. We thank the Department of
Environment Policy of the Seongnam City Government for its assistance
and cooperation.

\textbf{REFERENCES}

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developing immune system: a missing link in the global battle against
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2. Yang SI. Particulate matter and childhood allergic
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3. Brock JW, Caudill SP, Silva MJ, Needham LL, Hilborn ED. Phthalate
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4. Jaakkola JJ, Knight TL. The role of exposure to phthalates from
polyvinyl chloride products in the development of asthma and allergies:
a systematic review and meta-analysis. \emph{Environ Health
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5. Just AC, Whyatt RM, Miller RL, et al. Children's urinary phthalate
metabolites and fractional exhaled nitric oxide in an urban
cohort.\emph{Am J Respir Crit Care Med.} 2012;186(9):830-837.

6. Cakmak S, Dales RE, Hebbern C, Saravanabhavan G. The association
between urinary phthalates and lung function. \emph{J Occup Environ
Med.} 2014;56(4):376-381.

7. Kim MA, Yon DK, Jee HM, et al. Association of phthalates with nasal
patency and small airway dysfunction in first-grade elementary school
children. \emph{Allergy.} 2020.

8. Jahreis S, Trump S, Bauer M, et al. Maternal phthalate exposure
promotes allergic airway inflammation over 2 generations through
epigenetic modifications. \emph{J Allergy Clin
Immunol.}2018;141(2):741-753.

9. Oie L, Hersoug LG, Madsen JO. Residential exposure to plasticizers
and its possible role in the pathogenesis of asthma. \emph{Environ
Health Perspect.} 1997;105(9):972-978.

10. Masuoka M, Shiraishi H, Ohta S, et al. Periostin promotes chronic
allergic inflammation in response to Th2 cytokines. \emph{J Clin
Invest.} 2012;122(7):2590-2600.

11. Tong X, Wang D, Liu S, et al. The YKL-40 protein is a potential
biomarker for COPD: a meta-analysis and systematic review. \emph{Int J
Chron Obstruct Pulmon Dis.} 2018;13:409-418.

12. Lee S, Koh HY, Yon DK, et al. Association of Sensitization to
Different Aeroallergens With Airway Function and Nasal Patency in Urban
Children. \emph{Allergy Asthma Immunol Res.} 2019;11(4):572-582.

13. Lee SI, Shin MH, Lee HB, et al. Prevalences of symptoms of asthma
and other allergic diseases in korean children: a nationwide
questionnaire survey. \emph{J Korean Med Sci.} 2001;16(2):155-164.

14. Koch HM, Lorber M, Christensen KL, Palmke C, Koslitz S, Bruning T.
Identifying sources of phthalate exposure with human biomonitoring:
results of a 48h fasting study with urine collection and personal
activity patterns. \emph{Int J Hyg Environ Health.} 2013;216(6):672-681.

15. Gascon M, Casas M, Morales E, et al. Prenatal exposure to bisphenol
A and phthalates and childhood respiratory tract infections and
allergy.\emph{J Allergy Clin Immunol.} 2015;135(2):370-378.

16. Beydon N, Davis SD, Lombardi E, et al. An official American Thoracic
Society/European Respiratory Society statement: pulmonary function
testing in preschool children. \emph{Am J Respir Crit Care
Med.}2007;175(12):1304-1345.

17. Boccaccino A, Peroni DG, Pietrobelli A, et al. Assessment of
variable obstruction by forced expiratory volume in 1 second, forced
oscillometry, and interrupter technique. \emph{Allergy Asthma
Proc.}2007;28(3):331-335.

18. Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical
practice guideline: interpretation of exhaled nitric oxide levels (FENO)
for clinical applications. \emph{Am J Respir Crit Care
Med.}2011;184(5):602-615.

19. Tingley D, Yamamoto T, Hirose K, Keele L, Imai K. mediation: R
Package for Causal Mediation Analysis. \emph{J Stat Softw.} 2014;59(5).

20. Shea KM, American Academy of Pediatrics Committee on Environmental
H. Pediatric exposure and potential toxicity of phthalate
plasticizers.\emph{Pediatrics.} 2003;111(6 Pt 1):1467-1474.

21. Kueseng P, Thavarungkul P, Kanatharana P. Trace phthalate and
adipate esters contaminated in packaged food. \emph{J Environ Sci Health
B.} 2007;42(5):569-576.

22. In: \emph{Phthalates and Cumulative Risk Assessment: The Tasks
Ahead.} Washington (DC)2008.

23. Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven
inflammation defines major subphenotypes of asthma. \emph{Am J Respir
Crit Care Med.} 2009;180(5):388-395.

24. Chupp GL, Lee CG, Jarjour N, et al. A chitinase-like protein in the
lung and circulation of patients with severe asthma. \emph{N Engl J
Med.} 2007;357(20):2016-2027.

25. Konradsen JR, James A, Nordlund B, et al. The chitinase-like protein
YKL-40: a possible biomarker of inflammation and airway remodeling in
severe pediatric asthma. \emph{J Allergy Clin
Immunol.}2013;132(2):328-335 e325.

26. Tang H, Fang Z, Sun Y, et al. YKL-40 in asthmatic patients, and its
correlations with exacerbation, eosinophils and immunoglobulin
E.\emph{Eur Respir J.} 2010;35(4):757-760.

27. Shirai T, Hirai K, Gon Y, et al. Combined Assessment of Serum
Periostin and YKL-40 May Identify Asthma-COPD Overlap. \emph{J Allergy
Clin Immunol Pract.} 2019;7(1):134-145 e131.

28. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in
adults with asthma. \emph{N Engl J Med.} 2011;365(12):1088-1098.

\textbf{Tables}

\textbf{Table 1.} Demographic and clinical characteristics of study
subjects (N=487)\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Variable & Value & Value\tabularnewline
\midrule
\endhead
& Mean & 95\% CI\tabularnewline
Age, years & 11.0 & 10.9 to 11.1\tabularnewline
BMI \emph{z-}score & -0.02 & -0.11 to 0.07\tabularnewline
Height, cm & 149.4 & 148.7 to 150.1\tabularnewline
& n\textsuperscript{*} & \%\tabularnewline
Wheezing (ever) & 56/479 & 11.7\tabularnewline
Asthma, physician diagnosis & 28/486 & 5.8\tabularnewline
Passive smoking & 211/483 & 43.6\tabularnewline
Atopic sensitization\textsuperscript{+} & 289/479 & 61.4\tabularnewline
& Median & IQR\tabularnewline
Blood periostin,ng/mL & 35.7 & 27.3 to 43.6\tabularnewline
Blood YKL-40, ng/mL & 21.4 & 17.4 to 27,4\tabularnewline
Total IgE, IU/mL\textsuperscript{3} & 103.0 & 40.9 to
276.0\tabularnewline
Blood eosinophil, 10\textsuperscript{9} cells/L\textsuperscript{4} &
170.2 & 107.5 to 277.3\tabularnewline
Vitamin D, ng/ml\textsuperscript{5} & 21.0 & 17.1 to 25.4\tabularnewline
FeNO, ppb\textsuperscript{6} & 15.0 & 11.0 to 22.0\tabularnewline
& Median & IQR\tabularnewline
Rrs5, hPa/L/s & 4.92 & 4.32 to 5.60\tabularnewline
Rrs5-20, hPa/L/s & 1.74 & 1.33 to 2.29\tabularnewline
AX, hPa/L/sc & 10.90 & 7.87 to 14.93\tabularnewline
\bottomrule
\end{longtable}

IQR, interquartile range; BMI, body mass index; IgE: immunoglobulin E;
FeNO, fractional nitric oxide; Rrs5, resistance of respiratory system at
5 Hz; Rrs5-20, the difference of the Rrs at 5 Hz and 20 Hz; AX,
reactance area

\textsuperscript{*}Number of exposed or cases.

\textsuperscript{+}Inhalant allergen-specific IgE \textgreater{} 0.35
kU/L for at least 1 of 6 allergens (\emph{Alternaria} , birch, cat
dander, dog dander, \emph{Dermatophagoides farina} , Japanese hop).

\textbf{Table 2.} Association of low and high MWP metabolites with Rrs5
and FeNO.\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllll@{}}
\toprule
\begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Quartiles of urinary phthalate\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Rrs5\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Rrs5\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Rrs5\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Rrs5\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Rrs5\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
FeNO\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
FeNO\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
FeNO\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
FeNO\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
FeNO\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Crude \selectlanguage{greek}β \selectlanguage{english}(95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\emph{P} value\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Adjusted \selectlanguage{greek}β \selectlanguage{english}(95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\emph{P} value\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Crude \selectlanguage{greek}β \selectlanguage{english}(95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\emph{P} value\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Adjusted \selectlanguage{greek}β \selectlanguage{english}(95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\emph{P} value\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
High MWP\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.039 (-0.015 to 0.093)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.160\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.017 (-0.030 to 0.063)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.490\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-0.062 (-0.215 to 0.090)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.425\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-0.07 (-0.153 to 0.138)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.920\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.036 (-0.018 to 0.090)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.195\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.017 (-0.029 to 0.064)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.466\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-0.074 (-0.226 to 0.077)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.334\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-0.043 (-0.188 to 0.102)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.559\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.096 (0.042 to 0.150)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.043 (-0.004 to 0.090)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.076\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.144 (-0.008 to -.295)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.064\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.185 (0.038 to 0.332)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.014}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{P} for trend\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.028 (0.011 to 0.046)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.013 (-0.002 to 0.028)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.090\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.042 (-0.005 to 0090)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.077\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.053 (0.007 to 0.099)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.024}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Low MWP\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.070 (0.014 to 0.124)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.012}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.033 (-0.014 to 0.080)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.167\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.002 (-0150 to 0.154)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.980\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.015 (-0.133 to 0.164)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.840\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.086 (0.032 to 0.140)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.002}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.047 (-0.000 to 0.094)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.050\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-0.124 (-0.276 to 0.028)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.110\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-0.108 (-0.255 to 0.039)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.150\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.088 (0.034 to 0.142)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.061 (0.014 to 0.108)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.011}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.145 (-0.006 to 0.295)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.059\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.137 (-0.008 to 0.283)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.064\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{P} for trend\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.028 (0.011 to 0.045)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.020 (0.005 to 0.034)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.010}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.034 (-0.013 to 0.081)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.158\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.032 (-0.014 to 0.077)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.172\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

MWP, molecular weight phthalate; Rrs5, resistance of respiratory system
at 5 Hz; FeNO, fractional nitric oxide; CI, confidence interval; Ref,
reference

Rrs5 evaluations adjusted for height, gender, BMI \emph{z} score,
secondary smoking, aeroallergen sensitization, and vitamin D level. FeNO
evaluations adjusted for age, gender, BMI \emph{z} score, secondary
smoking, aeroallergen sensitization, and vitamin D level. \emph{P}values
are from a generalized linear regression with a gamma function.

\textbf{Table 3.} Association of serum periostin and YKL-40 levels with
high and low MWP metabolites.\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllll@{}}
\toprule
\begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Quartiles of urinary phthalate\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Periostin (high \emph{vs.} low)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Periostin (high \emph{vs.} low)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Periostin (high \emph{vs.} low)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Periostin (high \emph{vs.} low)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
Periostin (high \emph{vs.} low)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
YKL-40 (high \emph{vs.} low)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
YKL-40 (high \emph{vs.} low)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
YKL-40 (high \emph{vs.} low)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
YKL-40 (high \emph{vs.} low)\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
YKL-40 (high \emph{vs.} low)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
OR (95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\emph{P} value\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
aOR (95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\emph{P} value\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
OR (95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\emph{P} value\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
aOR (95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\emph{P} value\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
High MWP\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{2.322 (1.349 to 3.998)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.002}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{2.134 (1.232 to 3.696)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.007}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.926 (0.543 to 1.581)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.778\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.055 (0.604 to 1.842)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.851\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{2.259 (1.306 to 3.906)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.004}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{2.022 (1.166 to 3.508)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.012}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.617 (0.360 to 1.056)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.078\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.593 (0.339 to 1.038)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.067\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{2.259 (1.306 to 3.906)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.004}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{1.994 (1.141 to 3.484)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.015}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.655 (0.380 to 1.130)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.128\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.634 (0.360 to 1.118)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.115\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{P} for trend\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{1.270 (1.070 to 1.507)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.006}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{1.222 (1.026 to 1.455)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.025}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.845 (0.711 to 1.003)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.054\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.882 (0.687 to 0.983)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.032}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Low MWP\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ref\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.538 (0.897 to 2.639)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.118\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.679 (0.972 to 2.899)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.063\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.505 (0.880 to 2.573)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.135\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.468 (0.838 to 2.573)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.179\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.481 (0.868 to2.528)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.150\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.342 (0.774 to 2.329)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.295\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.056 (0.619 to 1.801)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.843\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.929 (0.530 to 1.626)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.796\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Q4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{2.436 (1.408 to 4.216)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{2.313 (1.322 to 4.048)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.003}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.050 (0.612 to 1.800)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.843\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.891 (0.508 to 1.563)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.687\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{P} for trend\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{1.299 (1.094 to 1.542)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.003}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{1.257 (1.054 to 1.498)}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.011}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.980 (0.827 to 1.162)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.820\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.924 (0.773 to 1.103)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.382\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

YKL-40, chitinase-like proteins; MWP, molecular weight phthalate; OR,
odds ratio; CI, confidence interval

Periostin and YKL-40 (high \emph{vs.} low) adjusted for age, gender,
BMI\emph{z} score, aeroallergen sensitization, and secondary
smoking.\emph{P} values are from a generalized linear regression with
the logit function.

\textbf{Table 4.} Relationship of periostin and YKL-40 levels with lung
function (Rrs5 and FeNO).\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllll@{}}
\toprule
& Rrs5 & Rrs5 & Rrs5 & Rrs5 & Rrs5 & FeNO & FeNO & FeNO & FeNO &
FeNO\tabularnewline
\midrule
\endhead
& Crude \selectlanguage{greek}β \selectlanguage{english}(95\% CI) & \emph{P} value\textsuperscript{*} & & Adjusted \selectlanguage{greek}β
\selectlanguage{english}(95\% CI) & \emph{P} value & Crude \selectlanguage{greek}β \selectlanguage{english}(95\% CI) & \emph{P} value & &
Adjusted \selectlanguage{greek}β \selectlanguage{english}(95\% CI) & \emph{P} value\tabularnewline
Periostin & & & & & & & & & &\tabularnewline
Low level & Ref & - & & Ref & - & Ref & - & & Ref & -\tabularnewline
High level & \textbf{0.053 (0.013 to 0.092)} & \textbf{0.008} & &
\textbf{0.048 (0.015 to 0.081)} & \textbf{0.005} & 0.055 (-0.057 to
0.168) & 0.334 & & 0.065 (-0.043 to 0.173) & 0.238\tabularnewline
Chitinase & & & & & & & & & &\tabularnewline
Low level & Ref & - & & Ref & - & Ref & - & & Ref & -\tabularnewline
High level & 0.024 (-0.016 to 0.064) & 0.240 & & 0.007 (-0.031 to 0.045)
& 0.731 & 0.031 (-0.082 to 0.143) & 0.591 & & 0.008 (-0.102 to 0.118) &
0.893\tabularnewline
\bottomrule
\end{longtable}

YKL-40, chitinase-like proteins; Rrs5, resistance of respiratory system
at 5 Hz; FeNO, fractional nitric oxide

\textsuperscript{*}Adjusted for gender, height, BMI z score,
aeroallergen sensitization, secondary smoking, and vitamin D level using
a generalized linear regression with the gamma function.

\textbf{Figure legends}

\textbf{Figure 1.} Effect of frequency on impulse oscillometry
resistance in children with different levels of \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP
metabolites (A) and \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP metabolites (B). Lines were
determined by locally weighted smoothing functions and shaded areas
indicate 95\% confidence intervals. The level of \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{4}HMWP
metabolites (A) was significantly associated with Rrs1, Rrs2, and Rrs3
after adjusting for height, gender, BMI \emph{z-} score, aeroallergen
sensitization, secondary smoking, and vitamin D level. The level of
\selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP metabolites (B) was significantly associated with
Rrs1, Rrs2, Rrs3, Rrs5, Rrs10, and Rrs15 after adjusting for these same
factors. LMHP, low molecular weight phthalate; HMWP, high molecular
weight phthalate; Rrs, respiratory system resistance.

\textbf{Figure 2.} Mediation model used to investigate the effect of
serum periostin on the relationship between LMWP metabolites and lung
dysfunction (Rrs5). The level of \selectlanguage{greek}Σ\selectlanguage{english}\textsubscript{3}LMWP metabolites was
significantly and directly associated with Rrs5 (\selectlanguage{greek}β: \selectlanguage{english}0.084, 95\% CI:
0.005 to 0.14, \emph{P} = 0.04), and periostin (\selectlanguage{greek}β: \selectlanguage{english}0.013, 95\% CI: 0.002
to 0.030, \emph{P} \textless{} 0.001) mediated 13.8\% of this effect
(95\% CI: 10.7 to 77.0, \emph{P} \textless{} 0.001). The analysis
adjusted for height, gender, BMI \emph{z-} score, aeroallergen
sensitization, secondary smoking, and vitamin D level. LMWP, low
molecular weight phthalate; Rrs5, respiratory system resistance at 5 Hz.

\textbf{Supplementary Figure E1.} Concentrations (\selectlanguage{greek}μ\selectlanguage{english}g/g creatinine) of
LMWP metabolites (top) and HMWP metabolites (bottom) in 487 urine
samples. MEHHP, mono-(2-ethyl-5-hydroxyhexyl) phthalate; MCPP,
mono-(3-carboxypropyl) phthalate; MECPP, mono-(2-ethyl-5-carboxypentyl)
phthalate; MiBP, mono-(iso-butyl) phthalate; MEOHP,
mono-(2-ethyl-5-oxohexyl) phthalate; MNP, mono-isononyl phthalate;
MBzP), mono-benzyl phthalate. Horizontal lines separate the different
quartiles.

\textbf{Hosted file}

\verb`Phthalate Periostin Figure.pptx`  available at \url{https://authorea.com/users/335900/articles/493170-association-of-phthalate-exposure-and-airway-dysfunction-with-mediation-by-serum-periostin}

\selectlanguage{english}
\FloatBarrier
\end{document}

