Prenatal exposure to mixtures of phthalates and phenols and body mass index and blood pressure in Spanish preadolescents

En i onmen In e na ional 169 (2022) 107527
A ailable online 15 Sep embe 2022
0160-4120/© 2022 The Au ho s. Published by Else ie L d. This is an open access a icle unde he CC BY license (h p://c ea i ecommons.o g/licenses/by/4.0/).
Full leng h a icle
P ena al exposu e o mix u es o ph hala es and phenols and body mass
index and blood p essu e in Spanish p eadolescen s
Nu ia Güil-Oum ai
a
,
b
,
c
, Ge man Cano-Sancho
d
, Pa isa Mon aze i
a
,
b
,
c
, Nikos S a akis
a
,
b
,
c
,
Cha line Wa embou g
e
, Ma ia-Jose Lopez-Espinosa
c
,
,
g
, Jesús Vioque
c
,
h
,
Lo e o San a-Ma ina
c
,
i
,
j
, Alba Jimeno-Rome o
c
,
i
,
k
, Rosa Ven u a
l
, Nu ia Mon o
l
,
Ma ine V ijheid
a
,
b
,
c
, Ma ibel Casas
a
,
b
,
c
,
*
a
ISGlobal, Ba celona, Spain
b
Pompeu Fab a Uni e si y (UPF), Ba celona, Spain
c
CIBER de Epidemiología y Salud Pública (CIBERESP), Mad id, Spain
d
LABERCA, UMR1329, Oni is, INRAE, Nan es, F ance
e
Uni Rennes, Inse m, EHESP, I se (Ins i u de eche che en san ´
e, en i onnemen e a ail) - UMR_S 1085, F-35000 Rennes, F ance
FISABIO–Uni e si a Jaume I–Uni e si a de Valencia, Valencia, Spain
g
Facul y o Nu sing and Chi opody, Uni e si y o Valencia, Valencia, Spain
h
Uni e sidad Miguel He n´
andez, Alican e, Spain
i
Biodonos ia, Heal h Resea ch Ins i u e, Donos ia, Gipuzkoa, Spain
j
Depa men o Heal h o he Basque Go e nmen , Subdi ec o a e o Public Heal h o Gipuzkoa, Spain
k
P e en i e Medicine and Public Heal h Depa men , Uni e si y o he Basque Coun y, Leioa, Bizkaia, Spain
l
Ca alonian An idoping Labo a o y, Doping Con ol Resea ch G oup, IMIM, Ba celona, Spain
ARTICLE INFO
Handling Edi o : Ad ian Co aci
Keywo ds:
Ph hala es
Phenols
Pa abens
Benzophenone-3
Body mass index (BMI)
Blood p essu e (BP)
ABSTRACT
Backg ound: P egnan women a e simul aneously exposed o se e al non-pe sis en endoc ine-dis up ing chem-
icals, which may in luence he isk o childhood obesi y and ca dio ascula diseases la e in li e. P e ious
p ospec i e s udies ha e mos ly examined single-chemical e ec s, wi h inconsis en indings. We assessed he
associa ion be ween p ena al exposu e o ph hala es and phenols, indi idually and as a mix u e, and body mass
index (BMI) and blood p essu e (BP) in p eadolescen s.
Me hods: We used da a om he Spanish INMA bi h coho s udy (n =1,015), whe e he 1s and 3 d- imes e
ma e nal u ina y concen a ions o eigh ph hala e me aboli es and six phenols we e quan i ied. A 11 yea s o
age, we calcula ed BMI z-sco es and measu ed sys olic and dias olic BP. We es ima ed indi idual chemical e ec s
wi h linea mixed models and join e ec s o he chemical mix u e wi h hie a chical Bayesian ke nel machine
eg ession (BKMR). Analyses we e s a i ied by sex and by pube y s a us.
Resul s: In single-exposu e models, benzophenone-3 (BP3) was nonmono onically associa ed wi h highe BMI z-
sco e (e.g. Qua ile (Q) 3: β =0.23 [95% CI =0.03, 0.44] s Q1) and highe dias olic BP (Q2: β =1.27 [0.00,
2.53] mmHg s Q1). Me hyl pa aben (MEPA) was associa ed wi h lowe sys olic BP (Q4: β = − 1.67 [−3.31,
−0.04] mmHg s Q1). No consis en associa ions we e obse ed o he o he compounds. Resul s om he
BKMR con i med he single-exposu e esul s and showed simila pa e ns o associa ions, wi h BP3 ha ing he
Abb e ia ions: BKMR, Bayesian ke nel machine eg ession; BMI, body mass index; BP, blood p essu e; BPA, bisphenol A; BP3, benzophenone-3; BUPA, bu yl
pa aben; condPIP, condi ional pos e io inclusion p obabili y; CVDs, ca dio ascula diseases; DEHP, sum o di(2-e hylhexyl) ph hala e me aboli es; ETPA, e hyl
pa aben; GAMM, gene alised addi i e mixed model; g oupPIP, g oup pos e io inclusion p obabili y; ICC, in aclass co ela ion coe icien ; INMA, In ancia y Medio
Ambien e; IQR, in e qua ile ange; LOD, limi o de ec ion; MBzP, mono-benzyl ph hala e; MEP, mono-e hyl ph hala e; MEPA, me hyl pa aben; MECPP, mono-(2-
e hyl-5-ca boxy-pen yl) ph hala e; MEHHP, mono-(2-e hyl-5-hyd oxyhexyl) ph hala e; MEHP, mono-(2-e hylhexyl) ph hala e; MEOHP, mono-(2-e hyl-5-oxohexyl)
ph hala e; MiBP, mono-iso-bu yl ph hala e; MnBP, mono-n-bu yl ph hala e; NIPH, No wegian Ins i u e o Public Heal h; PPARγ, pe oxisome p oli e a o -ac i a ed
ecep o gamma; PRPA, p opyl pa aben; RAAS, ennin-angio ensin-aldos e one sys em; SD, s anda d de ia ion; UHPLC-MS/MS, ul a-high pe o mance liquid
ch oma og aphy coupled o andem mass spec ome y.
* Co esponding au ho a : Ba celona Ins i u e o Global Heal h (ISGlobal), 88 D . Aiguade S ., 08003 Ba celona, Spain.
E-mail add ess: [email p o ec ed] (M. Casas).
Con en s lis s a ailable a ScienceDi ec
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h ps://doi.o g/10.1016/j.en in .2022.107527
Recei ed 2 Feb ua y 2022; Recei ed in e ised o m 29 July 2022; Accep ed 14 Sep embe 2022
En i onmen In e na ional 169 (2022) 107527
2
highes impo ance in he mix u e models, especially among p eadolescen s who eached pube y s a us. No
o e all mix u e e ec was ound, excep o a endency o highe BMI z-sco e and lowe sys olic BP in gi ls.
Conclusions: P ena al exposu e o UV- il e BP3 may be associa ed wi h highe BMI and dias olic BP du ing
p eadolescence, bu he e is li le e idence o an o e all ph hala e and phenol mix u e e ec .
1. In oduc ion
Ca dio ascula diseases (CVDs) a e he leading cause o dea h
wo ldwide (Ro h e al., 2020). Obesi y and high blood p essu e (BP) a e
well-known isk ac o s ha p edispose indi iduals o he occu ence o
CVDs. Child en and adolescen s wi h obesi y and/o high BP le els a e
mo e likely o become obese and hype ensi e as adul s, mani es ing he
impo ance o heal h p e en ion and managemen ea ly in li e (Chen
and Wang, 2008; Simmonds e al., 2016).
P egnan women a e exposed o ph hala es and phenols, wo g oups
o non-pe sis en endoc ine dis up ing chemicals. These compounds a e
widely ound in a mul i ude o consume p oduc s, such as lexible
(high-molecula ph hala es) and ha d plas ics (bisphenol A (BPA)), and
pe sonal ca e p oduc s (low-molecula ph hala es and pa abens),
including sunsc een agen s (benzophenone-3 (BP3)) (Go e e al., 2015).
The e o e, al hough hey a e quickly me abolized in he human body
and exc e ed in he u ine, hei exposu e is ubiqui ous, mul i-sou ce,
mul i- ou e, and o en ch onic (Go e e al., 2015; Lu e al., 2018).
These chemicals can c oss he blood-placen a ba ie (Gil-Solsona e al.,
2021; Sch¨
on elde e al., 2002; Sil a e al., 2004), and ha e been hy-
po hesized o p omo e me abolic changes ha may comp omise ea ly
e al de elopmen al p ocesses and in luence he isk o o sp ing obesi y
and CVDs la e in li e (Egusquiza and Blumbe g, 2020; Ha e inen e al.,
2021). The dis up ion o s e oid and hy oid ho mones, he ac i a ion o
pe oxisome p oli e a o -ac i a ed ecep o γ (PPARγ), and he gene a-
ion o eac i e oxygen species a e among he mechanisms by which
exposu e o ph hala es and phenols may al e he e al p og amming o
ca dio ascula unc ion and adipogenesis, as suppo ed by expe imen al
s udies (Aboul Ezz e al., 2015; Hao e al., 2013; Hu e al., 2013; Ishiha a
e al., 2003; Sau a e al., 2014; Shen e al., 2009; Shin e al., 2020a).
Al hough many p ospec i e bi h coho s udies ha e assessed he
associa ion be ween p ena al ph hala es and BPA wi h o sp ing BMI,
and BP le els o a lesse ex en , he le el o e idence emains inconsis-
en due o mixed esul s, as shown in Appendix 1. E idence is e en less
conclusi e o o he phenols o widesp ead use and eme ging conce n,
such as he pa abens and BP3, due o he limi ed esea ch in p ospec i e
bi h coho s (see Appendix 1). Fo ins ance, only ou and wo s udies
assessed he associa ion be ween p ena al exposu e o pa abens wi h
BMI (Be ge e al., 2021; Leppe e al., 2020; Reimann e al., 2021;
V ijheid e al., 2020) and BP le els (Mon aze i e al., 2022; Wa embou g
e al., 2019), espec i ely. All o hem ob ained null associa ions excep
o p ena al PRPA le els linked wi h inc eased BMI (Be ge e al., 2021),
and p ena al ETPA exposu e wi h a highe isk o o e weigh only in
gi ls (Leppe e al., 2020). Simila ly, o ou s udies ha included BP3
among he exposu es (Buckley e al., 2016; Mon aze i e al., 2022;
V ijheid e al., 2020; Wa embou g e al., 2019), only one epo ed
educed le els o body a % in gi ls (Buckley e al., 2016).
Mos o he abo e-men ioned s udies ha e only conside ed exposu e
o a single chemical a a ime. The eali y, howe e , is ha ph hala es
and phenols a e ound in many consume p oduc s, and he e o e, in-
di iduals can be egula ly exposed o mix u es o hese chemicals.
Addi ionally, he e is expe imen al e idence o a join and in e ac i e
e ec o hose compounds on adipogenic di e en ia ion, in ol ing
mul iple mechanisms o ac ion, u he suppo ing he need o mix u e
models (Biemann e al., 2014; V¨
olke e al., 2022). Only six p ospec i e
bi h coho s udies ha e conside ed hese wo g oups o endoc ine-
dis up ing chemicals a he same ime. In he HELIX s udy, including 6
Eu opean coho s, p ena al exposu e o ph hala es and phenols was
assessed oge he wi h a wide ange o o he en i onmen al exposu es in
ela ion o obesi y and BP (V ijheid e al., 2020; Wa embou g e al.,
2019). Only p ena al BPA was ound o be associa ed wi h inc eased BP
le els in childhood (Wa embou g e al., 2019). In hese s udies,
exposome-wide associa ion s udy and dele ion-subs i u ion-addi ion
a iable selec ion algo i hm we e used, which did no allow o assess-
ing he e ec o he chemical mix u e. In he Spanish In ancia y Medio
Ambien e (INMA) Sabadell coho , (Agay-Shay e al., 2015) used p in-
cipal componen analysis o assess he e ec o he mix u e o many
endoc ine-dis up ing chemicals and ound ha a componen mainly
cha ac e ized by se e al ph hala es was associa ed wi h lowe isk o
being o e weigh /obese a 7 yea s. In his same coho , Mon aze i e al.,
(2021) used a Bayesian weigh ed quan ile sum eg ession and ound no
e idence o an associa ion be ween a ph hala e/phenol mix u e and BP
a 11 yea s. In he US CHAMACOS coho , using Bayesian ke nel ma-
chine eg ession (BKMR), some associa ions we e obse ed be ween a
mix u e o se e al ph hala e me aboli es and BMI a 5 and 12 yea s o
age (Be ge e al., 2021; Ha ley e al., 2017). Con e sely, in a Mexican
coho , al hough some associa ions we e ound be ween indi idual
ph hala e me aboli es and BMI ajec o ies, using he quan ile G-
compu a ion modelling app oach, no mix u e associa ions we e
obse ed (Kupsco e al., 2022).
These s udies ha e been limi ed by hei modes sample size (be-
ween 300 and 400 pa icipan s), which gi es limi ed s a is ical powe ,
especially o he es ima ion o sex-speci ic e ec s. Also, he whole
chemical mix u e o ph hala es and phenols was only assessed in one
s udy in ela ion o BMI a 5 yea s (Be ge e al., 2021) and one s udy in
ela ion o BP a 11 yea s (Mon aze i e al., 2022). Mo eo e , as
desc ibed by Pe ng e al., 2021), he join e ec o ph hala es and phe-
nols on me abolic dis up ion has a ely been assessed du ing p eado-
lescence, a sensi i e pe iod cha ac e ized by he ho monal onse o
pube y wi h endoc ine changes and inc eases in lean and a mass.
Thus, he p esen s udy aims o ill hese c i ical knowledge gaps by
examining whe he p ena al exposu e o ph hala es and phenols (indi-
idually and in combina ion) a e associa ed wi h BMI and BP in a sample
o a ound 1,000 Spanish p eadolescen s.
2. Me hods
2.1. S udy popula ion
We used da a om he INMA bi h coho s udy including h ee
Spanish egions: Gipuzkoa, Sabadell, and Valencia. Women p esen ing
o p ena al ca e we e ec ui ed in he 1s imes e o p egnancy (weeks
10–13 o ges a ion) be ween 2003 and 2008 (n =2,122). Mo he s we e
included i hey (i) we e esiden in he s udy a ea, (ii) we e a leas 16
yea s old, (iii) had a single on p egnancy, (i ) did no ollow any assis ed
ep oduc ion p og am, ( ) wished o deli e in he e e ence hospi al,
and ( i) had no communica ion ba ie s (Guxens e al., 2012). The
popula ion o his analysis comp ised 1,015 mo he –child pai s wi h
a ailable in o ma ion on a leas one ph hala e me aboli e and/o
phenol measu ed du ing p egnancy and BMI (n =954) o BP (n =982)
measu ed a 11 yea s (excep in he INMA-Valencia coho , whe e BP
was measu ed a 9 yea s) (Fig. S1). All pa icipa ing women signed
w i en in o med consen . This s udy was app o ed by he egional
e hical commi ees o each coho .
2.2. Ph hala es and phenols exposu e assessmen
Ph hala es and phenols le els we e measu ed wice in u ine samples
N. Güil-Oum ai e al.
En i onmen In e na ional 169 (2022) 107527
3
collec ed du ing ges a ion. Speci ically, ma e nal u ine samples in he
1s (mean =13.2; s anda d de ia ion (SD) =1.5 weeks) and 3 d i-
mes e s o p egnancy (mean =33.1; SD =1.9 weeks) we e collec ed in
100-mL polyp opylene con aine s and hen aliquo ed in 10 mL poly-
e hylene ubes and s o ed a −20 ◦C p io o analysis. A small numbe o
mo he s (n =98, <10% o he o al) p o ided only one u ine sample. We
measu ed o al u ine concen a ions o eigh ph hala e me aboli es: MEP
(mono-e hyl ph hala e), MiBP (mono-iso-bu yl ph hala e), MnBP (mono-
n-bu yl ph hala e), MBzP (mono-benzyl ph hala e), and he ollowing
ou DEHP (di(2-e hylhexyl) ph hala e) me aboli es: MEHP (mono-(2-
e hylhexyl) ph hala e), MEHHP (mono-(2-e hyl-5-hyd oxyhexyl)
ph hala e), MEOHP (mono-(2-e hyl-5-oxohexyl) ph hala e), and MECPP
(mono-(2-e hyl-5-ca boxy-pen yl) ph hala e). Ph hala e me aboli es o
he Gipuzkoa and Valencia coho s we e measu ed a he Depa men o
En i onmen al Exposu e and Epidemiology a he No wegian Ins i u e
o Public Heal h (NIPH) (Oslo, No way), using pooled samples (1s and
3 d imes e s) wi h ul a-high pe o mance liquid ch oma og aphy
coupled o andem mass spec ome y de ec ion (UHPLC-MS/MS)
(Saba edzo ic e al., 2015). The limi s o de ec ion (LOD) anged be-
ween 0.07 and 0.7 ng/ml. Ph hala e me aboli es o he Sabadell coho
we e measu ed a he Bioanalysis Resea ch G oup a he Hospi al del
Ma Medical Resea ch Ins i u e (Ba celona, Spain) using samples sepa-
a ely om he 1s and 3 d imes e s also wi h UHPLC-MS/MS, as
desc ibed in (Val i e al., 2015a). LODs anged om 0.5 o 1 ng/ml. We
calcula ed he mola sums o indi idual me aboli es (in µmol/l) o DEHP
because hey occu om he same pa en ph hala e and hus, hey we e
highly co ela ed ( >0.90).
Phenols o his analysis included ou pa abens (MEPA (me hyl
pa aben), ETPA (e hyl pa aben), PRPA (p opyl pa aben), and BUPA
(bu yl pa aben)), BP3, and BPA. Phenols in samples om he Gipuzkoa
coho we e measu ed a Ins i u o de In es igaci´
on Biosani a ia ibs.
GRANADA (G anada, Spain) using pooled samples (1s and 3 d i-
mes e s) wi h dispe si e liquid–liquid mic oex ac ion and UHPLC-MS/
MS (Vela-So ia e al., 2014); LODs anged om 0.04 o 0.12 ng/ml.
Samples om he 1s and 3 d imes e s om Sabadell and Valencia
we e analyzed sepa a ely a NIPH wi h online solid-phase ex ac ion
p io o UHPLC-MS/MS (Sakhi e al., 2018); LODs anged om 0.03 o
0.07 ng/ml. BPA o he Sabadell coho was measu ed a he Depa -
men o Analy ical Chemis y labo a o y a he Uni e si y o Co doba
(Spain) using LC-MS/MS (Casas e al., 2013). LOD was 0.10 ng/ml.
In all coho s, c ea inine u ine concen a ions a each imes e (1s
and 3 d) we e de e mined using he Ja ´
e me hod (kine ic wi h a ge
measu emen , compensa ed me hod). Chemical concen a ions we e
co ec ed o u ine c ea inine concen a ions o adjus o u ine dilu ion
and we e exp essed in
μ
g/g o c ea inine. Fo pooled samples, we
applied he mean o he wo indi idual c ea inine measu emen s; we
e i ied in 20 u ine samples om Valencia ha measu ing c ea inine
le els in he pool was highly co ela ed wi h he c ea inine le els es i-
ma ed by a e aging he c ea inine le els quan i ied in he wo inde-
penden u ine samples ( =0.97). Due o he sho biological hal -li e o
he non-pe sis en chemicals, we used he a e age o he non-pooled
c ea inine-adjus ed concen a ions measu ed in he 1s and 3 d i-
mes e s o p o ide a be e es ima ion o exposu e h oughou p eg-
nancy. Because he ph hala es and phenols c ea inine-adjus ed
concen a ions we e igh -skewed, hey we e log
2
- ans o med o ob ain
no mal dis ibu ions.
2.3. BMI and BP ou comes
Child weigh and heigh we e measu ed a 11 yea s o age using
s anda d p o ocols, wi hou shoes and in ligh clo hing. We calcula ed
BMI (weigh in kg/heigh in m
2
) and age- and sex-speci ic BMI z-sco es
using he Wo ld Heal h O ganiza ion e e ence and de ined o e weigh
as a BMI z-sco e ≥85 h pe cen ile (De Onis e al., 2007). INMA nu ses
used a digi al au oma ic moni o (OMRON 705IT) o measu e sys olic
and dias olic BP a 11 yea s in Gipuzkoa and Sabadell, and 9 yea s in
Valencia. A e 5 min o es , 3 consecu i e measu emen s we e aken
wi h one-minu e ime in e als be ween hem. We de i ed a e age BP a
each age as he mean o he sys olic and dias olic BP alues.
2.4. S a is ical analysis
Concen a ions o ph hala es and phenols abo e 4 imes hei SD
(<1%) we e emo ed since BKMR is highly sensi i e o ou lying alues.
Concen a ions below he LOD we e impu ed using dis ibu ion-based
mul iple impu a ions by assuming a log-no mal dis ibu ion o he
chemicals and condi ioning he impu a ion o he ange om 0 o he
LOD (Table S1). Then, hey we e adjus ed by c ea inine and log
2
-
ans o med. We pe o med mul iple impu a ions by chained equa ions
o missing alues in exposu e (<11%) and co a ia e da a (<2%) o a oid
he loss o pa icipan s in he s udy (Table S2). We gene a ed en com-
ple e da a se s by using he ice package o S a a (Roys on, 2005). A
de ailed desc ip ion o his p ocedu e is p o ided in Table S3. Dis i-
bu ions o co a ia es and chemical concen a ions in impu ed da ase s
we e simila o he o iginal da ase (Table S2). Pea son co ela ion co-
e icien s we e calcula ed o es ima e he bi a ia e co ela ions be ween
chemicals (log
2
- ans o med).
Fi s , we assessed po en ial non-linea ela ionships be ween expo-
su es and ou comes o in e es (BMI z-sco e, sys olic and dias olic BP)
using gene alized addi i e mixed models (GAMMs; R package ‘mgc ’). I
he e ec i e deg ees o eedom we e equal o 1, he ela ionship was
close o linea . GAMM models showed e idence o linea i y (Fig. S2-S4)
wi h ew excep ions indica ing non-linea i y: BUPA and BP3 wi h BMI z-
sco e (Fig. S2), BP3 wi h sys olic BP (Fig. S3), and PRPA and BP3 wi h
dias olic BP (Fig. S4). The e o e, we modelled chemical concen a ions
as bo h con inuous and ca ego ical a iables using qua ile cu -o s.
Second, we assess single exposu e e ec s wi h linea mixed models
using he impu ed da a, and he esul s we e combined using Rubin’s
combina ion ules (Li le and Rubin, 2014). All models (GAMMs and
linea mixed models) we e adjus ed o he egion o esidence (Gipuz-
koa, Sabadell, Valencia) as a andom in e cep o accoun o wi hin-
coho and be ween-coho e ec s.
Thi d, we conduc ed BKMR o assess he join e ec o he exposu es
on BMI z-sco e and BP. BKMR is a non-pa ame ic me hod in which he
heal h ou come is eg essed on a lexible ke nel unc ion o he mix u e
componen s (Bobb e al., 2014). I accommoda es non-linea i y, non-
addi i e e ec s, and in e ac ions (Bobb e al., 2014). We used a hie -
a chical a iable selec ion me hod o iden i y impo an chemicals in he
mix u e managing he high co ela ion be ween exposu es wi hin
chemical g oups (Bobb e al., 2014). Based on Pea son co ela ion co-
e icien s and also conside ing hei common exposu e sou ces, we
classi ied he chemicals in o wo g oups: (1) Ph hala e me aboli es
(MEP, MiBP, MnBP, MBzP, and ∑DEHP), and 2) Phenols (MEPA, ETPA,
PRPA, BUPA, and BP3) (Fig. 2). Ini ially, because o he mild o null
co ela ions o BPA wi h o he chemicals (0.02–0.19) (Fig. 2) (Bobb
e al., 2014), BPA was included alone in a hi d g oup showing a small
con ibu ion o he o e all model. Thus, in a e inemen s ep, we an he
models wi hou BPA. Chemicals we e scaled o hei SD. We calcula ed
he g oup pos e io inclusion p obabili y (g oupPIP) and condi ional
pos e io inclusion p obabili y (condPIP), which ep esen he p oba-
bili y ( om 0 o 1) ha a chemical wi hin he g oup is included in he
model (Bobb e al., 2014). We also assessed (i) he shape and di ec ion o
he exposu e– esponse associa ion o each chemical in ela ion o he
heal h ou come when holding he o he chemicals in he mix u e a hei
median concen a ions, (ii) he o e all mix u e e ec s a di e en pe -
cen iles, and (iii) wo-way chemical in e ac ions while holding he o he
exposu es a hei median alues. Model con e gence was assessed
isually using ace plo s. BKMR was i ed wi h he R package “bkm ”
using he Ma ko chain Mon e Ca lo algo i hm wi h 10,000 i e a ions.
We only used he i s impu ed da ase as i is no cu en ly possible o
use mul iple impu ed da ase s wi h he BKMR unc ion. BKMR models
also included egion o esidence as a andom in e cep .
N. Güil-Oum ai e al.
En i onmen In e na ional 169 (2022) 107527
4
Po en ial co a ia es o model adjus men we e selec ed based on a
p io i knowledge (Casas e al., 2013; Val i e al., 2015b) and a di ec ed
acyclic g aph app oach (Fig. S5). These we e ob ained h ough
in e iewe -adminis e ed ques ionnai es answe ed by mo he s a
ec ui men and included: ma e nal age a p egnancy (in yea s), p e-
p egnancy BMI (kg/ m
2
), educa ional le el (low, middle, high), and
smoking in p egnancy (“yes” i hey smoke a he momen o ec ui -
men /no). We addi ionally examined i he Medi e anean die adhe -
ence sco e con ounded he associa ions since i is an indica o o
ma e nal quali y die ha conside s nu ien s ha may a ec he heal h
ou comes and can in e ac wi h p ena al ph hala es and phenols con-
cen a ions (Fe n´
andez-Ba ´
es e al., 2016). Passi e smoking du ing
p egnancy (yes/no) was also assessed since p e ious s udies ha e shown
ha i can in luence le els o non-pe sis en chemicals in p egnan
women (Casas e al., 2013; Da ishmo e alli e al., 2019; Wang e al.,
2020) and childhood obesi y (V ijheid e al., 2020). As coe icien es i-
ma es did no change, hese a iables we e no e ained (da a no
shown). Ges a ional age (in weeks) and bi h weigh (in g ams),
collec ed by clinical eco ds, may be media ing ac o s in he associa ion
o p ena al ph hala es and phenols exposu es and BMI/BP a p eado-
lescence (Fig. S5). The e o e, we did no adjus associa ions o hese
a iables as we we e in e es ed in he o al e ec o p ena al ph hala es
and phenols exposu es on BMI and BP ou comes (Vande Weele, 2009).
Models wi h sys olic and dias olic BP ou comes we e addi ionally
adjus ed o he child’s age (yea s), sex (male/ emale), and heigh (cm).
Since ph hala es and phenols can in e e e wi h sex ho mones (B aun,
2017), hei po en ial heal h e ec s may be sex-dependen . The e o e,
we s a i ied all models (linea mixed models and BKMR) by sex. In he
linea mixed models, we es ed sex-in e ac ion by inse ing c oss-
p oduc e ms (exposu e*sex using a p- alue h eshold o 0.10). In he
BKMR, sepa a e models we e un o gi ls and boys.
In sensi i i y analyses, we epea ed all he models wi h BP z-sco es
s anda dized by age, sex and heigh in he o e all s udy popula ion and
s a i ied by sex. We also epea ed all models by using he comple e-case
da ase (n =773). Mul ipollu an models adjus ed o he 10 exposu e
a iables we e also pe o med o compa e he esul s wi h he BKMR
ones. Because mos o he p eadolescen s eached pube y onse a 11
yea s, we s a i ied ou analyses by pube y s a us (p epube y/pu-
be y), which was a ed by hei pa en s using he Pube al De elopmen
Scale (Ca skadon and Acebo, 1993). Fu he mo e, we s a i ied by sex
a e excluding pa icipan s in he p epube y s age (app oxima ely one-
hi d) o assess i sex-speci ic associa ions emained he same in p e-
adolescen s who eached pube y.
Da a cleaning, mul iple impu a ions, and mixed models we e pe -
o med using S a a e sion 16 (S a a Co po a ion, College S a ion, TX,
USA). Pea son co ela ions, GAMMs, and BKMR we e conduc ed in R
e sion 4.1.0 (R Founda ion, Vienna, Aus ia).
3. Resul s
3.1. S udy popula ion cha ac e is ics
Comple e de ails o he cha ac e is ics o he s udy popula ion (N =
1,015) a e shown in Table 1. A 11 yea s, 42% o child en we e ei he
o e weigh o obese. Mo he s included in he analyses we e sligh ly
olde , had a highe educa ional le el, and we e less likely o smoke
du ing p egnancy (Table S4). The log
2
- ans o med c ea inine-adjus ed
p ena al non-pe sis en chemical concen a ions a e p esen ed in Fig. 1.
MEP and MEPA we e he chemicals wi h he highes le els (median =
225.90; in e qua ile ange (IQR) =363.20 and median =204.34; IQR
=366.10 µg/g c ea inine, espec i ely), and BUPA and BPA we e hose
wi h he lowes le els (median =2.77; IQR =8.94 and median =2.82;
IQR =2.91 µg/g c ea inine, espec i ely) (Table S1). Pea son’s co e-
la ions hea map e ealed low o mode a e co ela ions wi hin he
ph hala e me aboli es ( =0.12–0.45), and low o high ( =0.16–0.83)
wi hin-g oup co ela ions o pa abens and BP3 (Fig. 2). BPA showed
low o null co ela ion coe icien s wi h he o he chemicals ( =
0.02–0.19) (Fig. 2).
3.2. P ena al non-pe sis en chemicals in associa ion wi h BMI in
p eadolescen s
Table 2 shows esul s om he linea mixed models o BMI z-sco e.
All he associa ions we e null excep o BP3 ha in he second and hi d
qua ile was associa ed wi h a highe BMI z-sco e (Qua ile (Q) 2: β =
0.22 [95% CI =0.01, 0.42]; Q3: β =0.23 [95% CI =0.03, 0.44])
(Table 2). Fig. 3 shows esul s om he BKMR model o he BMI z-sco e.
Holding all o he chemicals a hei medians, BP3 was associa ed wi h a
highe BMI z-sco e, con i ming he di ec ion o he coe icien es ima es
ound in he single-exposu e models (Fig. 3A). We did no obse e any
associa ion be ween he whole chemical mix u e and BMI z-sco e
(Fig. 3C) no any bi a ia e in e ac ions among he chemicals.
A e s a i ying by sex, he nonmono onic associa ion epo ed in
he mixed models be ween BP3 and BMI z-sco e was only clea ly
obse ed among gi ls in he BKMR uni a ia e plo s (Fig. S6 A1, B1). BP3
was also he mos con ibu ing compound in he phenols g oup in gi ls
(Fig. S6 B1). The join e ec o he chemical mix u e showed a sligh ly
inc easing end o gi ls and dec easing o boys, when all he chemicals
we e a hei 60 h pe cen ile o abo e, compa ed o hei 50 h pe cen-
ile; howe e , c edible in e als con ained he null (Fig. 6A). No in-
e ac ions be ween chemicals we e obse ed in gi ls o boys.
3.3. P ena al non-pe sis en chemicals in associa ion wi h BP in
p eadolescen s
The single-exposu e models e ealed null associa ions be ween he
non-pe sis en chemicals and sys olic BP, excep o a nega i e
Table 1
Ma e nal and o sp ing cha ac e is ics o he s udy popula ion.
Ma e nal cha ac e is ics N =1,015
Region o esidence – n (%)
Gipuzkoa 262 (25.81%)
Sabadell 424 (41.77%)
Valencia 329 (32.41%)
Educa ion comple ed – n (%)
P ima y 224 (21.99%)
Seconda y 411 (40.46%)
Uni e si y 380 (37.55%)
Smoking du ing p egnancy – n (%)
None 722 (70.99%)
Yes* 293 (29.01%)
Age a p egnancy (yea s) – mean (SD) 30.93 (3.83)
P e-p egnancy BMI (kg/m
2
) – mean (SD) 23.52 (4.21)
O sp ing cha ac e is ics
Sex – n (%)
Gi ls 500 (49.26%)
Boys 515 (50.74%)
Pube y – n (%)
P epube y 295 (29.06%)
In pube y 720 (70.94%)
Ges a ional age (weeks) – mean (SD) 39.74 (1.37)
Bi h weigh (g) – mean (SD) 3271.10 (435.27)
Age a BMI z-sco e assessmen (yea s) – mean (SD) 11.02 (0.44)
BMI (kg/m
2
) – mean (SD) 19.46 (3.56)
BMI z-sco e – mean (SD) 0.71 (1.21)
O e weigh – n (%)
Yes 398 (41.72%)
No 556 (58.28%)
Age a BP assessmen (yea s) – mean (SD) 10.41 (0.98)
Sys olic BP (mmHg) - mean (SD) 103.54 (9.46)
Dias olic BP (mmHg) - mean (SD) 59.60 (7.47)
Abb e ia ions: SD (s anda d de ia ion), BMI (body mass index), BP (blood
p essu e),
*
Includes women who qui smoking du ing cu en p egnancy.
N. Güil-Oum ai e al.
En i onmen In e na ional 169 (2022) 107527
5
associa ion wi h MEPA in he highes qua ile (Q4: β =-1.67 [95% CI =
-3.31, −0.04] mmHg s Q1) (Table 2). Consis en ly, he BKMR showed
an in e se associa ion be ween MEPA and sys olic BP when he o he
chemicals we e ixed a hei median (Fig. 4A). We did no obse e any
e ec o he o e all chemical mix u e wi h sys olic BP (Fig. 4C); also, no
in e ac ions be ween chemicals we e obse ed.
The nega i e associa ion obse ed in he o e all popula ion be ween
MEPA and sys olic BP was only obse ed in boys and in he BKMR model
(Fig. S7 A2), bu his phenol p esen ed a low condPIP (0.17) (Fig. S7 B2).
In boys, ∑DEHP was also associa ed wi h a dec ease in sys olic BP (p-
in e ac ion =0.10) (Table S5), which was con i med in he BKMR uni-
a ia e plo s (Fig. S7 A2) and by being he exposu e wi h he highes
in luence in he mix u e (condPIP =0.63) (Fig. S7 B2). Fo boys, no
e ec o he o e all mix u e was obse ed (Fig. 6B). In gi ls, he single-
exposu e models e ealed a dec ease in sys olic BP linked o BUPA (p-
in e ac ion =0.05) (Table S5). This was suppo ed by he BKMR model
wi h BUPA showing a sha p linea dec ease in sys olic BP when holding
all o he chemicals a hei medians (Fig. S7 A1), i s high condPIP (0.91)
(Fig. S7 B2), and he nega i e join e ec o he mix u e, al hough no
s a is ically signi ican (Fig. 6B). No in e ac ions be ween chemicals
we e obse ed in boys and gi ls.
Wi h espec o dias olic BP and in he single-exposu e models, BP3
was he only compound associa ed wi h his ou come showing an in-
c ease in dias olic BP bu only in he second qua ile o exposu e (Q2: β
=1.27 [95% CI =0.00, 2.53] mmHg) (Table 2). This nonlinea posi i e
associa ion was also obse ed in he BKMR model when all he o he
chemicals emained a hei median (Fig. 5A); being he chemical wi h
he highes con ibu ion wi hin he mix u e (condPIP =0.74) (Fig. 5B).
No o e all mix u e e ec was ound (Fig. 5C) and no in e ac ions we e
sugges ed g aphically.
Fig. 1. Loga i hm ans o med (log
2
) c ea inine-adjus ed p ena al non-pe sis en chemical concen a ions. Abb e ia ions: MEP (mono-e hyl ph hala e), MiBP (mono-
iso-bu yl ph hala e), MnBP (mono-n-bu yl ph hala e), MBzP (mono-benzyl ph hala e), DEHP (sum o di(2-e hylhexyl) ph hala e me aboli es), MEPA (me hyl pa a-
ben), ETPA (e hyl pa aben), PRPA (p opyl pa aben), BUPA (bu yl pa aben), BP3 (benzophenone-3), BPA (bisphenol A).
Fig. 2. Co ela ion hea map using Pea son’s co ela ion coe icien s. G oups o chemicals included in he mix u e model a e squa ed in ed. Abb e ia ions: MEP
(mono-e hyl ph hala e), MiBP (mono-iso-bu yl ph hala e), MnBP (mono-n-bu yl ph hala e), MBzP (mono-benzyl ph hala e), DEHP (sum o di(2-e hylhexyl) ph hala e
me aboli es), MEPA (me hyl pa aben), ETPA (e hyl pa aben), PRPA (p opyl pa aben), BUPA (bu yl pa aben), BP3 (benzophenone-3), BPA (bisphenol A). (Fo
in e p e a ion o he e e ences o colou in his igu e legend, he eade is e e ed o he web e sion o his a icle.)
N. Güil-Oum ai e al.

En i onmen In e na ional 169 (2022) 107527
6
No sex in e ac ion was obse ed in he single-exposu e models (p >
0.10; Table S5). In hese models, BP3 was he only chemical associa ed
wi h an inc ease in dias olic BP, bu only in boys (Q2: β =1.86 [95% CI
=0.01, 3.72] mmHg) (Table S5). This associa ion was con i med in
BKMR models (Fig. S8 A2, B2). In gi ls, BP3 was he chemical wi h he
highes impo ance in he mix u e model (condPIP =0.76) (Fig. S8 B1)
and showed a nonlinea posi i e associa ion a e holding he o he
chemicals a hei medians (Fig. S8, A1). As o he o e all popula ion,
no o e all mix u e e ec was ound (Fig. 6C) and no in e ac ions be-
ween chemicals we e de ec ed.
3.4. Sensi i i y analyses
Simila indings we e obse ed using he z-sco e o BP ins ead o he
aw BP a iables (Table S6, Figu e S9, S10) and es ic ing all he
analyses o comple e cases. Mul ipollu an model showed simila es i-
ma es o BP3 and BMI z-sco e and s onge es ima es o MEPA and
sys olic BP (Table S7). Con e sely, es ima es o BP3 and dias olic BP
we e no longe s a is ically signi ican (Table S7). Among p e-
adolescen s who eached pube y s a us, he associa ions o BP3 wi h a
highe BMI z-sco e and dias olic BP we e s eng hened (e.g. BMI z-sco e
Q3: β =0.30 [95% CI =0.07, 0.54]) and dias olic BP (Q2: β =1.91 [95%
CI =0.40, 3.43] mmHg) (Table S8). Mo eo e , e ec es ima es o BP3
wi h all he ou comes we e s onge in sex-s a i ied analyses a e
excluding child en in p epube y s a us (Table S9 and Figu es S11-S13).
4. Discussion
In his Spanish popula ion o p egnan women wi h common expo-
su e o ph hala es and phenols, p ena al u ina y concen a ions o BP3
Table 2
Adjus ed associa ions
a
be ween p ena al non-pe sis en chemical concen a ions and BMI and BP a p eadolescence in single-exposu e models.
BMI z-sco e (n ¼954) Sys olic BP (n ¼982) Dias olic BP (n ¼981)
β (95 %CI) β 95 %CI β 95 %CI
Ph hala e me aboli es
MEP Pe log
2
inc ease 0.01 (-0.02, 0.05) 0.05 (-0.24, 0.35) 0.04 (-0.20, 0.23)
Q2 (110.67–225.90 µg/g) 0.05 (-0.16, 0.26) −0.24 (-1.96, 1.48) 0.91 (-0.41, 2.23)
Q3 (225.91–473.86 µg/g) 0.17 (-0.04, 0.38) 1.00 (-0.70, 2.69) 0.30 (-1.09, 1.69)
Q4 (473.87–9379.85 µg/g) 0.05 (-0.17, 0.27) 0.19 (-1.64, 2.01) 0.40 (-1.06, 1.87)
MiBP Pe log
2
inc ease −0.03 (-0.08, 0.03) −0.11 (-0.54, 0.33) 0.10 (-0.25, 0.46)
Q2 (20.37–30.22 µg/g) −0.03 (-0.24, 0.18) −0.25 (-1.84, 1.34) 0.66 (-0.67, 2.00)
Q3 (30.23–45.27 µg/g) −0.06 (-0.27, 0.15) −0.61 (-2.29, 1.08) 0.13 (-1.23, 1.49)
Q4 (45.28–486.99 µg/g) −0.11 (-0.33, 0.12) −0.96 (-2.63, 0.71) 0.37 (-1.02, 1.76)
MnBP Pe log
2
inc ease 0.01 (-0.03, 0.04) −0.17 (-0.51, 0.17) −0.21 (-0.49, 0.07)
Q2 (17.15–27.14 µg/g) 0.13 (-0.07, 0.33) 0.18 (-1.48, 1.84) 0.76 (-0.60, 2.11)
Q3 (27.15–46.66 µg/g) 0.02 (-0.18, 0.22) 0.05 (-1.74, 1.84) −0.42 (-1.93, 1.08)
Q4 (46.67–2101.18 µg/g) 0.04 (-0.17, 0.25) −0.29 (-2.19, 1.60) −0.34 (-2.02, 1.34)
MBzP Pe log
2
inc ease 0.00 (-0.04, 0.04) 0.01 (-0.36, 0.38) 0.06 (-0.23, 0.35)
Q2 (5.22–9.37 µg/g) 0.03 (-0.18, 0.24) −0.57 (-2.27, 1.12) −0.27 (-1.66, 1.11)
Q3 (9.38–16.38 µg/g) 0.01 (-0.20, 0.23) −1.13 (-2.89, 0.63) −0.48 (-1.86, 0.89)
Q4 (16.39–238.35 µg/g) 0.01 (-0.20, 0.21) −0.17 (-1.96, 1.62) 0.20 (-1.21, 1.61)
∑DEHP Pe log
2
inc ease 0.00 (-0.05, 0.06) −0.13 (-0.58, 0.33) 0.02 (-0.35, 0.40)
Q2 (55.77–88.34 µg/g) −0.02 (-0.22, 0.18) −0.44 (-2.10, 1.22) −0.19 (-1.52, 1.13)
Q3 (88.35–139.74 µg/g) −0.01 (-0.21, 0.19) −0.97 (-2.78, 0.84) −0.02 (-1.44, 1.39)
Q4 (139.75–941.59 µg/g) −0.01 (-0.23, 0.20) −0.37 (-2.13, 1.39) 0.11 (-1.34, 1.56)
Phenols
MEPA Pe log
2
inc ease −0.01 (-0.03, 0.02) −0.12 (-0.30, 0.06) −0.08 (-0.23, 0.06)
Q2 (69.54–204.34 µg/g) −0.11 (-0.32, 0.10) −0.54 (-2.14, 1.05) −0.09 (-1.39, 1.21)
Q3 (204.35–435.62 µg/g) −0.05 (-0.26, 0.16) −0.58 (-2.19, 1.03) −0.31 (-1.62, 1.00)
Q4 (435.63–45927.09 µg/g) −0.19 (-0.40, 0.02) ¡1.67 (-3.31, ¡0.04) −0.56 (-1.89, 0.78)
ETPA Pe log
2
inc ease −0.01 (-0.03, 0.01) 0.00 (-0.17, 0.16) −0.01 (-0.13, 0.12)
Q2 (4.35–13.75 µg/g) 0.09 (-0.11, 0.30) −0.47 (-2.09, 1.16) 0.60 (-0.70, 1.90)
Q3 (13.76–42.11 µg/g) −0.01 (-0.21, 0.20) −0.37 (-2.00, 1.26) 0.54 (-0.76, 1.83)
Q4 (42.12–980.02 µg/g) −0.10 (-0.31, 0.10) −0.37 (-2.01, 1.26) −0.08 (-1.37, 1.21)
PRPA Pe log
2
inc ease 0.00 (-0.02, 0.02) −0.08 (-0.24, 0.08) −0.01 (-0.14, 0.11)
Q2 (13.07–41.41 µg/g) −0.14 (-0.35, 0.07) −1.20 (-2.80, 0.39) −0.14 (-1.43, 1.16)
Q3 (41.42–114.51 µg/g) −0.15 (-0.36, 0.06) −0.32 (-1.92, 1.29) −0.59 (-1.89, 1.48)
Q4 (114.52–14132.26 µg/g) −0.03 (-0.24, 0.17) −0.89 (-2.48, 0.71) 0.19 (-1.11, 1.48)
BUPA Pe log
2
inc ease 0.00 (-0.02, 0.02) −0.07 (-0.21, 0.08) 0.01 (-0.10, 0.13)
Q2 (0.54–2.77 µg/g) 0.09 (-0.12, 0.29) −0.30 (-1.89, 1.29) −0.01 (-1.30, 1.27)
Q3 (2.78–9.47 µg/g) 0.05 (-0.16, 0.25) −0.82 (-2.43, 0.78) 0.27 (-1.01, 1.54)
Q4 (9.48–110.00 µg/g) −0.12 (-0.33, 0.09) −0.67 (-2.28, 0.94) 0.24 (-1.06, 1.55)
BP3 Pe log
2
inc ease 0.01 (-0.01, 0.02) 0.03 (-0.10, 0.16) 0.04 (-0.07, 0.15)
Q2 (1.30–4.17 µg/g) 0.22 (0.01, 0.42) 1.01 (-0.55, 2.56) 1.27 (0.00, 2.53)
Q3 (4.18–23.68 µg/g) 0.23 (0.03, 0.44) 0.14 (-1.45, 1.73) 0.53 (-0.75, 1.82)
Q4 (23.69–3115.95 µg/g) 0.13 (-0.07, 0.34) 0.77 (-0.81, 2.36) 0.94 (-0.35, 2.22)
BPA Pe log
2
inc ease −0.01 (-0.03, 0.03) −0.05 (-0.31, 0.21) −0.05 (-0.26, 0.16)
Q2 (1.69–2.82 µg/g) 0.15 (-0.05, 0.35) 0.21 (-1.40, 1.81) 0.00 (-1.37, 1.38)
Q3 (2.83–4.59 µg/g) 0.00 (-0.21, 0.20) 0.17 (-1.43 1.77) −0.14 (-1.52, 1.24)
Q4 (4.60–116.06 µg/g) 0.06 (-0.14, 0.26) −0.84 (-2.48, 0.79) −0.75 (-2.07, 0.58)
Abb e ia ions: BMI (body mass index), MEP (mono-e hyl ph hala e), MiBP (mono-iso-bu yl ph hala e), MnBP (mono-n-bu yl ph hala e), MBzP (mono-benzyl
ph hala e), ∑DEHP (sum o di(2-e hylhexyl) ph hala e me aboli es), MEPA (me hyl pa aben), ETPA (e hyl pa aben), PRPA (p opyl pa aben), BUPA (bu yl pa aben),
BP3 (benzophenone-3), BPA (bisphenol A).
a
Linea mixed models adjus ed o ma e nal age, educa ion, smoking in p egnancy and p e-p egnancy BMI. Blood p essu e models we e addi ionally adjus ed by
child’s age, sex and heigh . Region o esidence was included as andom in e cep . Second (Q2), hi d (Q3) o ou h qua ile (Q4) compa ed wi h i s . S a is ically
signi ican coe icien in e als a p <0.05 a e highligh ed in bold.
N. Güil-Oum ai e al.
En i onmen In e na ional 169 (2022) 107527
7
we e consis en ly linked wi h inc eased BMI z-sco e and dias olic BP a
11 yea s ac oss single and mix u e modelling app oaches. These e ec s
we e u he e idenced among p eadolescen s who eached pube y
s a us. We also obse ed ha MEPA was associa ed wi h a dec eased
sys olic BP, while BUPA and ∑DEHP we e associa ed wi h dec eased
sys olic BP in gi ls and boys, espec i ely; howe e , all hese associa-
ions we e no consis en ac oss single and mix u e models. Al hough no
o e all mix u e e ec no chemical in e ac ions we e de ec ed, in gi ls,
we obse ed a endency o highe BMI z-sco e and dec eased sys olic BP
o he chemical mix u e, ye non-s a is ically signi ican . Resul s om
his s udy highligh he bene i o combining wo complemen a y
models, conside ing hei ad an ages and disad an ages. Fo ins ance,
single-pollu an models may show s aigh o wa d esul s wi h in e -
p e able e ec es ima es, p o iding an impo an s ep in assessing
complex exposu e pa e ns. Howe e , ad anced app oaches able o
o e come he cons ain s o complex exposu e da a s uc u es (e.g.
co ela ion, high-dimensionali y) may be equi ed o add ess mo e
complex ques ions abou he e ec mix u es, including hei join e ec s
o iden i ica ion o in e ac ions (B aun e al., 2016).
Only wo p e ious s udies om he CHAMACOS coho in he US
ha e also assessed he associa ion be ween p ena al mix u es o ph ha-
la es and phenols wi h obesi y- ela ed ou comes in childhood (Be ge
e al., 2021; Ha ley e al., 2017). Bo h s udies combined single-exposu e
models wi h BKMR, as we did in he p esen s udy. Ha ley e al., (2017)
isually explo ed he exposu e– esponse associa ions ob ained om
BKMR be ween ph hala es and BMI a 12 yea s o age; nei he PIPs no
join mix u e e ec s we e analyzed. They obse ed ends o ph hala es
ha we e simila o ou s, and a signi ican associa ion be ween MEP and
highe BMI ha in ou s udy was only obse ed in he single-exposu e
models and in gi ls (Table S5). In Be ge e al., (2021), PRPA was
associa ed wi h highe BMI and o e weigh /obesi y isk a 5 yea s in
single pollu an models and i was he mos ele an chemical in he
mix u e. In ou s udy, PRPA showed inconsis en esul s among single-
exposu e and BKMR models and i had a low con ibu ion o he
mix u e (condPIP =0.10). In Be ge e al., (2021) BP3 was also
conside ed in he mix u e bu i ended o be associa ed wi h educed
BMI a 5 yea s in bo h single and mix u e models and i had a low
con ibu ion (PIP =0.02). Be ge e al., (2021) also epo ed a sligh ly
inc easing end o BMI linked o he o e all mix u e, which in ou s udy
was only obse ed in gi ls. The null o e all mix u e e ec obse ed in all
he s udy popula ions (i.e. CHAMACOS and INMA) could be pa ly
explained by he di e en sense o di ec ions o he chemicals, which
may ha e neu alized he join e ec . This has been obse ed in in i o
s udies whe e he es ogenic ac i i y o BPA can supp ess he adipogenic
e ec s o PPARγ ac i a o s DEHP and ibu yl in du ing adipogenesis,
o example (Biemann e al., 2014; Jeong and Yoon, 2011). We may
hypo hesize ha inconsis encies be ween he CHAMACOS and he INMA
s udies may be due o: (i) he dissimila i y o sociodemog aphic and
gene ic backg ound be ween mo he s om bo h coho s (i.e. mos o
CHAMACOS’ mo he s we e o La in e hnici y who li ed in he US<5
yea s, younge , had a low educa ional le el and household income, and
mo e han hal we e o e weigh ), which may ha e con ibu ed o di -
e ences in he use o chemical-associa ed pe sonal ca e p oduc s in
p egnancy (Pe ng e al., 2021; P es on e al., 2021); (ii) in ela ion o he
p e ious poin , he di e en concen a ions o chemicals, which we e
highe in CHAMACOS o bo h PRPA and BP3; (iii) he sample size
(~300 in CHAMACOS s ~ 1000 in INMA); (i ) he di e en chemicals
conside ed in o he mix u e which can modi y he join e ec and he
con ibu ion o each chemical (i.e. in Be ge e al., (2021) mo e ph ha-
la es and iclosan we e included whe eas BUPA and MEPA we e no
included); ) he dis inc age a ou come examina ion (5 yea s in
CHAMACOS s 11 yea s in INMA); and ( i) he di e en s a is ical ap-
p oaches used since Be ge e al., 2021 did no conside hie a chical
clus e ing o chemicals in he BKMR as we did, which allowed us o
Chemicals
G oupPIP
CondPIP
MEP
0.23
0.28
MiBP
0.23
0.24
MnBP
0.23
0.18
MBzP
0.23
0.12
∑DEHP
0.23
0.17
MEPA
0.31
0.10
ETPA
0.31
0.24
PRPA
0.31
0.10
BUPA
0.31
0.37
BP3
0.31
0.20
A) B)
C)
Fig. 3. Summa y es ima es om BKMR on he associa ion be ween mix u es o log
2
scaled non-pe sis en chemicals and BMI z-sco e in p eadolescence adjus ed by
ma e nal age, educa ion, smoking in p egnancy and p e-p egnancy BMI; egion o esidence was included as andom in e cep . (A) Exposu e- esponse associa ions o
each chemical when he o he s a e ixed a hei median. (B) G oup and condi ional pos e io inclusion p obabili ies (G oupPIP and CondPIP) o each chemical in he
mix u e- esponse unc ion o BMI z-sco e. (C) Join e ec o p ena al non-pe sis en chemicals mix u e on BMI z-sco e a p eadolescence (C edible in e als
o e lapping he null depic ed wi h he b oken line indica e no signi ican e ec s). Abb e ia ions: BMI (body mass index), BKMR (Bayesian ke nel machine
eg ession), MEP (mono-e hyl ph hala e), MiBP (mono-iso-bu yl ph hala e), MnBP (mono-n-bu yl ph hala e), MBzP (mono-benzyl ph hala e), DEHP (sum di(2-
e hylhexyl) ph hala e me aboli es), MEPA (me hyl pa aben), ETPA (e hyl pa aben), PRPA (p opyl pa aben), BUPA (bu yl pa aben), BP3 (benzophenone-3).
N. Güil-Oum ai e al.
En i onmen In e na ional 169 (2022) 107527
8
g oup he chemicals accoun ing o hei co ela ions and i can modi y
models’ pe o mance and ou pu .
To ou knowledge, he ela ionship be ween p ena al mix u es o
ph hala es and phenols wi h pos na al sys olic and dias olic BP has only
been assessed ecen ly in he INMA-Sabadell coho (Mon aze i e al.,
2022) wi h a sample o 416 pa icipan s, in which no e idence o single
o mix u e associa ions wi h BP a 11 yea s was ound. Con e sely, in
his s udy wi h a la ge sample size, we ound ha BP3, MEPA, BUPA,
and ∑DEHP we e associa ed wi h changes in dias olic BP, wi h some
sex-speci ic associa ions. The imp o emen o s a is ical powe may
ha e con ibu ed o he iden i ica ion o sex-speci ic e ec s in he p e-
sen s udy. Aside om Mon aze i e al., (2021) and Wa embou g e al.,
(2019), no p e ious s udy has assessed he indi idual associa ions o
phenols o he han BPA wi h BP (see Appendix 1). As o BMI, no o e all
mix u e e ec was ound wi h sys olic and dias olic BP. Howe e , we did
obse e a sha p downwa d end be ween he mix u e and sys olic BP,
d i en by BUPA, in gi ls. Because pa abens ha e po en ial es ogenic
ac i i y (Nowak e al., 2018), we specula e ha he dec ease in sys olic
BP only seen in gi ls could be media ed by a down egula ion o he
ennin-angio ensin-aldos e one sys em (RAAS), a majo egula o o
sys emic BP, ia es ogenic pa hways (Medina e al., 2020). Finally,
esul s o p ena al ∑DEHP and lowe sys olic BP in boys a e pa ly
consis en wi h he nega i e associa ion be ween p ena al ∑DEHP
me aboli es and lowe sys olic and dias olic BP in boys and gi ls a 4–6
yea s obse ed in he G eek Rhea coho (Bowman e al., 2019; Va eiadi
e al., 2018; Val i e al., 2015a).
In ou s udy, p ena al exposu e o BP3 was associa ed wi h highe
BMI and dias olic BP le els a p eadolescence in bo h sexes, and in single
and mix u e modelling app oaches. Only in BKMR, BP3 was also asso-
cia ed wi h highe sys olic BP. These associa ions we e u he consis-
en and s onge in p eadolescen s who eached pube y onse . Pube y
is conside ed one o he de elopmen al windows, besides e al and
neona al li e, in which endoc ine-dis up ing chemicals a e mo e likely o
ac a any le el in he “hypo halamic-pi ui a y–gonadal-pe iphe al is-
sues’ axis” (Go e e al., 2015). Epidemiological s udies assessing he
p ena al e ec s o BP3 on obesi y and BP a e sca ce. Apa om he
CHAMACOS s udy (Be ge e al., 2021), ano he s udy in he US assessed
p ena al BP3 and obesi y in 170 4–9 yea s-old child en and epo ed a
dec eased body a mass % in gi ls (Buckley e al., 2016). Likewise, in he
HELIX subcoho , p ena al BP3 was associa ed nei he wi h child BMI
no BP (V ijheid e al., 2020; Wa embou g e al., 2019). The p esen
s udy is he i s o assess and iden i y associa ions o p ena al BP3 alone
and in a mix u e o non-pe sis en chemicals in ela ion o BMI and BP a
p eadolescence in a big sample size (n ~ 1,000). Ou esul s shed ligh
on BP3 po en ial me abolic dis up ing e ec s in pube y due o e al
de elopmen exposu e. Benzophenones a e UV ligh il e s used in
sunsc eens o abso b and dissipa e he UV adia ion and in cosme ics o
p e en damage o colou and scen , being p obably he eason why
highe BP3 exposu e has been obse ed in emales in biomoni o ing
s udies (Cala a e al., 2008).
De elopmen al e ec s o BP3 exposu e on adipogenesis may be
media ed h ough i s es ogen-like and an i-and ogenic ac i i y (Blü h-
gen e al., 2012; Ke di el e al., 2013; Kim and Choi, 2014; Majhi e al.,
2020; Schlump e al., 2001; Sch eu s e al., 2005; Wang e al., 2016;
Wa anabe e al., 2015), he dec ease in hy oid ho mone balance (Lee
e al., 2018), and he up egula ion o PPARγ, a di ec ansc ip ional
egula o o human adipogenesis ha con ibu es o adipocy e di e -
en ia ion and insulin sensi iza ion (Shin e al., 2020b; Wnuk e al.,
2019). The mechanisms unde lying BP3 e ec s on blood p essu e could
be indi ec ly ia BP3 obesogen-like e ec s, o di ec ly h ough he
dis up ion o s e oid and hy oid ho mone molecula pa hways, which
may al e RAAS (Ba e o-Cha es e al., 2010). Fu he mo e, ecen
Chemicals
G oupPIP
CondPIP
MEP
0.09
0.32
MiBP 0.09 0.17
MnBP
0.09
0.16
MBzP
0.09
0.16
∑DEHP
0.09
0.19
MEPA
0.16
0.21
ETPA
0.16
0.15
PRPA 0.16 0.10
BUPA
0.16
0.15
BP3
0.16
0.39
A) B)
C)
Fig. 4. Summa y es ima es om BKMR on he associa ion be ween mix u es o log
2
scaled non-pe sis en chemicals and sys olic BP in p eadolescence adjus ed by
ma e nal age, educa ion, smoking in p egnancy, p e-p egnancy BMI, sex, heigh and age a ou come assessmen ; egion o esidence was included as andom
in e cep . (A) Exposu e- esponse associa ions o each chemical when he o he s a e ixed a hei median. (B) G oup and condi ional pos e io inclusion p obabili ies
(G oupPIP and CondPIP) o each chemical in he mix u e- esponse unc ion o sys olic BP. (C) Join e ec o p ena al non-pe sis en chemicals mix u e on sys olic BP
a p eadolescence (C edible in e als o e lapping he null depic ed wi h he b oken line indica e no signi ican e ec s). Abb e ia ions: BP (blood p essu e), BMI
(body mass index), BKMR (Bayesian ke nel machine eg ession), MEP (mono-e hyl ph hala e), MiBP (mono-iso-bu yl ph hala e), MnBP (mono-n-bu yl ph hala e),
MBzP (mono-benzyl ph hala e), DEHP (sum o di(2-e hylhexyl) ph hala e me aboli es), MEPA (me hyl pa aben), ETPA (e hyl pa aben), PRPA (p opyl pa aben),
BUPA (bu yl pa aben), BP3 (benzophenone-3).
N. Güil-Oum ai e al.
En i onmen In e na ional 169 (2022) 107527
9
s udies wi h animal models ha e epo ed BP3 exposu e o induce ee
adical p oduc ion and he down egula ion o an ioxidan enzymes (Liu
e al., 2015; Rod íguez-Fuen es e al., 2015), which may e en ually in-
luence he ea ly de elopmen o he ca dio ascula sys em (´
A ila e al.,
2015). The non-mono onic exposu e– esponse ela ionships ound in
his s udy sugges ha he heal h e ec s o BP3 can occu e en a low
doses o exposu e (Vandenbe g e al., 2012). O in e es , he magni ude
o he associa ion be ween BP3 and BMI z-sco e (e.g. Q2: β =0.22 [95%
CI =0.01, 0.42]) was e y simila o associa ions ound in adolescence
o he INMA Meno ca coho in ela ion o p ena al exposu e o hexa-
chlo obenzene and BMI z-sco e ( e ile 2: β =0.24 [95% CI: 0.01, 0.47])
(Güil-Oum ai e al., 2021). Al hough BP3 has a sho biological hal -li e
(<24 h) (Kim and Choi, 2014), i is one o he phenols wi h he lowes
in aindi idual a iabili y (Ve ne e al., 2018). Howe e , he in aclass
co ela ion coe icien o a spo u ine sample collec ed du ing p egnancy
is s ill low (be ween 0.39 (Mínguez-Ala c´
on e al., 2019) and 0.62
Chemicals
G oupPIP
CondPIP
MEP
0.08
0.28
MiBP
0.08
0.10
MnBP
0.08
0.11
MBzP
0.08
0.25
∑DEHP
0.08
0.25
MEPA
0.16
0.11
ETPA
0.16
0.08
PRPA
0.16
0.05
BUPA 0.16 0.03
BP3
0.16
0.74
A) B)
C)
Fig. 5. Summa y es ima es om BKMR on he associa ion be ween mix u es o log
2
scaled non-pe sis en chemicals and dias olic BP in p eadolescence adjus ed o
ma e nal age, educa ion, smoking in p egnancy, p e-p egnancy BMI, sex, heigh and age a ou come assessmen ; egion o esidence was included as andom
in e cep . (A) Exposu e- esponse associa ions o each chemical when he o he s a e ixed a hei median. (B) G oup and condi ional pos e io inclusion p obabili ies
(G oupPIP and CondPIP) o each chemical in he mix u e- esponse unc ion o dias olic BP. (C) Join e ec o p ena al non-pe sis en chemicals mix u e on dias olic
BP a p eadolescence (C edible in e als o e lapping he null depic ed wi h he b oken line indica e no signi ican e ec s). Abb e ia ions: BP (blood p essu e), BMI
(body mass index), BKMR (Bayesian ke nel machine eg ession), MEP (mono-e hyl ph hala e), MiBP (mono-iso-bu yl ph hala e), MnBP (mono-n-bu yl ph hala e),
MBzP (mono-benzyl ph hala e), DEHP (sum o di(2-e hylhexyl) ph hala e me aboli es), MEPA (me hyl pa aben), ETPA (e hyl pa aben), PRPA (p opyl pa aben),
BUPA (bu yl pa aben), BP3 (benzophenone-3).
Fig. 6. Sex-s a i ied analysis. Join e ec o log
2
scaled p ena al non-pe sis en chemicals mix u e on BMI z-sco e (A), sys olic BP (B), and dias olic BP (C) s a i ied
in gi ls and boys shown in black and g ey lines, espec i ely. C edible in e als o e lapping he null depic ed wi h he b oken line indica e no signi ican e ec s.
Summa y es ima es om BKMR we e adjus ed o ma e nal age, educa ion, smoking in p egnancy, p e-p egnancy BMI; egion o esidence was included as andom
in e cep . Heigh , and age a ou come assessmen we e addi ionally adjus ed in he BP models. Abb e ia ions: BP (blood p essu e), BMI (body mass index), BKMR
(Bayesian ke nel machine eg ession).
N. Güil-Oum ai e al.
En i onmen In e na ional 169 (2022) 107527
16
Appendix A. Supplemen a y da a
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