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Is Bisphenol A (BPA) a Threat to Children's Behavior?

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Vicente Mustieles at Granada Biosanitary Research Institute
Vicente Mustieles
  • Granada Biosanitary Research Institute
Carmen Messerlian at Harvard University
Carmen Messerlian
Iris Reina-Pérez at University of Granada
Iris Reina-Pérez
Andrea Rodríguez-Carrillo at Vlaamse Instelling voor Technologisch Onderzoek (VITO)
Andrea Rodríguez-Carrillo
  • Vlaamse Instelling voor Technologisch Onderzoek (VITO)
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Abstract

In 2015 we reviewed the state of knowledge regarding the potential impact of bisphenol A (BPA) exposure on child neurobehavior. At that time, we expressed concern about the effects of BPA on children’s behavior, especially when exposure takes place in utero. Since then, the number of human studies addressing the BPA-neurobehavior hypothesis has doubled, most of them reinforcing previous prenatal associations and frequently showing differences between boys and girls. An increasing number of studies have also shown an association between postnatal BPA exposure and diverse neurobehavioral impairments, including attention-deficit and hyperactivity disorder (ADHD). It may never be possible to establish a causal link between this specific endocrine disruptor and a particular neurobehavioral endpoint; however, research data on the relationship between human BPA exposure and children’s behavior has revealed a relatively consistent pattern that cannot be ignored. The mounting experimental and epidemiologic evidence on neurobehavioral effects support more than ever the need to apply the precautionary principle during development, especially in relation to pregnant women and children. It seems that the time to act has arrived.
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Mustieles V, Messerlian C, Reina I, Rodríguez-Carrillo A, Olea N, Fernández MF. J Mental Health
& Clin Psychology (2018) 2(1): 6-9
Mini Review Open Access
Page 6 of 9
www.mentalhealthjournal.org
JOURNAL OF MENTAL HEALTH
AND CLINICAL PSYCHOLOGY
Is Bisphenol A (BPA) a Threat to Children’s Behavior?
Vicente Mustieles1, Carmen Messerlian2, Iris Reina1, Andrea Rodríguez-Carrillo1, Nicolás Olea1, and Mariana F.
Fernández1*
*1University of Granada, Center for Biomedical Research (CIBM); Biosanitary Research Institute of Granada (ibs.GRANADA), Spain; Consortium for Biomedical
Research in Epidemiology & Public Health (CIBERESP), Spain.
2Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Article Info
Article Notes
Received: February 02, 2018
Accepted: March 05, 2018
*Correspondence:
Dr. Mariana F. Fernández Universidad de Granada. Instituto
de Investigación Biosanitaria ibs. GRANADA, Spain; Tel.
Phone: +34 958241000 ext 20367
E-mail address: marieta@ugr.es
© 2018 Fernández MF. This article is distributed under the
terms of the Creative Commons Attribution 4.0 International
License.
Keywords
Bisphenol A
Bisphenol S
Bisphenol F
Behavior
Neurodevelopment
Endocrine Disruption
Risk Assessment
Precautionary Principle
ABSTRACT
In 2015 we reviewed the state of knowledge regarding the potenal
impact of bisphenol A (BPA) exposure on child neurobehavior. At that me, we
expressed concern about the eects of BPA on children’s behavior, especially
when exposure takes place in utero. Since then, the number of human studies
addressing the BPA-neurobehavior hypothesis has doubled, most of them
reinforcing previous prenatal associaons and frequently showing dierences
between boys and girls. An increasing number of studies have also shown an
associaon between postnatal BPA exposure and diverse neurobehavioral
impairments, including aenon-decit and hyperacvity disorder (ADHD). It
may never be possible to establish a causal link between this specic endocrine
disruptor and a parcular neurobehavioral endpoint; however, research data
on the relaonship between human BPA exposure and children’s behavior has
revealed a relavely consistent paern that cannot be ignored. The mounng
experimental and epidemiologic evidence on neurobehavioral eects
support more than ever the need to apply the precauonary principle during
development, especially in relaon to pregnant women and children. It seems
that the me to act has arrived.
Neurobehavioral disabilities affect millions of children worldwide,
and the prevalence of some neurodevelopmental disorders appears
to be increasing. Subclinical symptoms are even more frequent
and also contribute to a poorer quality of life and lower academic
achievement1. Epidemiologic and animal studies have demonstrated
that exposure to several families of endocrine-disrupting chemicals
(EDCs) contribute to the risk of neurodevelopmental impairment1,2.
Bisphenol A (BPA) is a well-known EDC that can interfere with
hormonal balance, even at low doses, via multiple steroid hormone
receptors that mediate a myriad of cellular effects3. The mechanistic
understanding of its effects is particularly complex: BPA can bind
not only to nuclear and membrane estrogen receptors but also to
thyroid, glucocorticoid, and peroxisome proliferator-activated
receptors, and it can also interact with steroidogenic enzymes,
among other molecular targets4,5. This biological promiscuity
might explain the pleiotropic effects exerted by BPA on behavior,
reproduction, and metabolism6,7. The developing brain is a key target
for this compound, and pre-, peri- and post-natal BPA exposure has
been linked to a variety of altered behaviors, as demonstrated in
multiple experimental models3.
In 2015 we reviewed the state of knowledge on the relationship
between human BPA exposure and neurobehavior5. We expressed
Mustieles V, Messerlian C, Reina I, Rodríguez-Carrillo A, Olea N, Fernández MF. J Mental Health
& Clin Psychology (2018) 2(1): 7-9
Journal of Mental Health Care
Page 7 of 9
concern about the effects of BPA on children’s behavior,
especially when exposure takes place in utero. Although
only 12 epidemiologic studies were available at that time,

studies, suggesting a negative impact of prenatal BPA
exposure on children’s neurobehavioral functioning in
a sex-dependent manner5. The results suggested that
male fetuses were more frequently affected by prenatal
BPA exposure than females, in line with the current
hypothesis of environmental intrauterine sex-dependent
vulnerability8.
Since March 2015, the number of human studies
addressing the BPA-neurobehavior hypothesis has
doubled9–19, most of them reinforcing previous associations
and frequently showing differences between boys and
20
and Roen et al. (2015)21     
(2016)13, showing a consistent longitudinal pattern of
internalizing problems, including anxiety and depression
symptoms, among boys from childhood to adolescence
in a birth cohort from the U.S.. More recently, Casas et
al. (2015)9 in Spain, Philippat et al. (2017)15 in France,
and Braun et al. (2017)14 in Canada all supported the
        22 in
California and by Evans et al. (2014)23 in a multicenter
U.S. cohort. These reported more frequent behavior
problems related to prenatal BPA exposure in the males
than in the females. Notably, Braun and colleagues
(2017)14 studied 812 mother-child pairs belonging to the
Maternal–Infant Research on Environmental Chemicals
       
     
frequent internalizing problems among three-year-old
boys and with poorer executive function and higher social
impairments. In contrast, two birth cohorts observed more
behavior problems24 and social impairments17 related
to prenatal BPA exposure in girls than in boys. Overall,
epidemiologic data support a probable negative effect of
prenatal BPA exposure on children’s behavior in a sex-
dependent manner.
An increasing number of studies show that postnatal BPA
exposure is also associated with diverse neurobehavioral
impairments among both boys and girls10,11,16,21,22. For
example, some studies, including two representative
national surveys, have reported associations with
     
        
(2015)10 observed positive cross-sectional associations

in 2730 Canadian children/youths aged 6-17, while Tewar
et al. (2016)12 found a positive cross-sectional association
   
North American children/youths aged 8-15 years. A more
recent case-control study in China also reported a stepwise

urinary BPA concentrations19. These associations reinforce
data from some previous prospective studies that found

concentrations9,15,24. These associations are also supported
by experimental data25,26.
The human brain is a sexually dimorphic organ, and
major morphological differences are permanently shaped
      
steroid hormones, especially estrogen and aromatizable
androgens27,28       
structural and behavioral patterns in experimental animals,
including non-human primates, increasing, decreasing,
and/or eliminating sex differences29–32. It is possible that

related to the estrogen-androgen balance, given evidence
that BPA affects the gene expression of several estrogen
 
 29  in utero BPA exposure
could predetermine later responses of certain brain areas
to steroid hormones. Moreover, a recent high-quality
experimental study by the Consortium Linking Academic
and Regulatory Insights on BPA Toxicity (CLARITY-BPA)
demonstrated that low BPA doses in utero alter the rat brain
      
33.
More than 90% of Europeans and Americans have
detectable concentrations of BPA in their urine, and diet is
considered the main source of BPA exposure in humans34–37.
Despite the ubiquity of BPA, its non-persistence and
short biological half-life and the episodic nature of its
     
frequently producing an important degree of exposure
       
obtain null results, the so-called attenuation bias15,38.
Therefore, it is possible that we have been systematically
underestimating the effects of BPA, and researchers in the

   11,15,38 
despite these methodological limitations, the overall
picture of the relationship between human BPA exposure
and behavior is relatively consistent across studies and
populations. Moreover, the widespread nature of exposure
to BPA means that even subtle changes in behavior at the
individual level may have relevant effects at the population
level, with public health repercussions39,40.
In 2008, a National Toxicology Program assessment,
based on animal data, reported that BPA-related neural
and behavioral endpoints were a major concern for fetuses,
infants, and children41. Since then, some governments have
implemented preventive measures, such as the banning
of BPA in baby bottles by Canada and subsequently by
the European Union42,43, and the total prohibition of BPA
Mustieles V, Messerlian C, Reina I, Rodríguez-Carrillo A, Olea N, Fernández MF. J Mental Health
& Clin Psychology (2018) 2(1): 8-9
Journal of Mental Health Care
Page 8 of 9
in France44. Additionally, regulatory organizations such
as the European Food Safety Authority (EFSA) have been
progressively reducing their estimation of the tolerable
daily intake (TDI) in subsequent risk assessments. Thus,
the TDI for BPA was lowered from 50 µg/kg bw/day to
4 µg/kg bw/day in 201545. Nevertheless, recent well-
conducted experimental studies have shown that BPA can
impact the brain and behavior of rats at doses near to or
even below the current TDI33,46, and it has been suggested
that EFSA’s temporary tolerable daily intake of 4µg/kg

the general population46. EFSA’s forthcoming assessment
will be an opportunity to integrate new experimental and
epidemiologic data and provide evidence in support of
action to protect children’s behavior.
BPA is commonly found in food packaging materials,
being used in the manufacture of polycarbonate plastics
and in the epoxy resin liners of food cans. The greater
        
    47 
many of these products are manufactured using bisphenol
analogues, including bisphenol S and F (BPS and BPF),
which have been shown to be at least as hormonally active
as BPA48. Furthermore, experimental studies of bisphenol
substitutes such as BPS and BPF suggest similar and in
some cases greater adverse neurobehavioral effects than
those associated with BPA49.
It may never be possible to establish a causal link
       
endpoint50. Nevertheless, it is impossible to ignore the
consistent and accumulating human evidence on the effects
of BPA on child neurobehavior. While future research will
provide greater clarity, the mounting experimental and
epidemiologic data on its neurobehavioral effects support
more than ever the need to apply the precautionary
principle during development, especially in relation to
pregnant women and children5,51. It seems that the time to
act has arrived52.

       


This work was supported by research grants from
    
the Biomedical Research Networking Center-CIBER de
Epidemiología y Salud Pública (CIBERESP).This article
will form part of the thesis developed by Vicente Mustieles
    


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... Several in vitro and in vivo studies have shown that BPA can interfere with estrogenic pathways by binding to nuclear estrogen receptors (ERs) (Wetherill et al., 2007) as well as other membrane estrogen receptor families (Alonso-Magdalena et al., 2012). It has also been found to exert antagonistic activities after binding to the androgen receptor (Molina-Molina et al., 2013) and to alter the expression of steroidogenic enzymes, as well as interacting with glucocorticoid, PPAR-γ, and thyroid signaling pathways (Mustieles et al., 2015(Mustieles et al., , 2018b. ...
... Although most published studies have analyzed the relationship of developmental BPA exposure with the behavior of children, which has been reported to be sex-specific (Casas et al., 2015;Findlay and Kohen, 2015;Mustieles et al., 2015Mustieles et al., , 2018bPerera et al., 2012;Roen et al., 2015), much less is known about its relationship with their cognitive functions. Therefore, the objective of this study was to explore the relationship of urinary BPA concentrations with cognitive functioning in a group of Spanish boys aged 9-11 years. ...
... Although epidemiologic evidence on the impact of BPA exposure in children has been strengthened over the past few years, most researchers have assessed behavior rather than cognitive function. Moreover, the few studies on cognitive function have published less consistent results than those obtained for children's behavior (Ejaredar et al., 2017;Mustieles et al., 2015Mustieles et al., , 2018b. Thus, in the EDEN birth cohort, Philippat et al. (2017) reported the association of prenatal urinary BPA concentrations with relationship problems and hyperactivity-inattention in children at 3 and 5 years of age (Philippat et al., 2017). ...
Bisphenol A and cognitive function in school-age boys: Is BPA predominantly related to behavior?
Article
  • Jun 2019
  • NEUROTOXICOLOGY
Background: Bisphenol A (BPA) has been associated with impairments in children’s behavior, but few studies have investigated its relationship with cognitive function. Objective: To investigate the association of urinary BPA concentrations with cognitive domains and intelligence quotient (IQ) in Spanish boys. Methods: BPA levels were quantified by liquid chromatography-tandem mass spectrometry (LC-MS-MS) in one spot urine sample from 269 boys of the INMA-Granada cohort, in their follow-up at 9-11 years of age. Cognitive function was evaluated by a trained psychologist using a comprehensive neuropsychological test battery (including general intelligence, language skills, working memory, attention, impulsivity, visual-motor coordination, processing speed and executive function, among others). Cross-sectional associations between BPA levels and neuropsychological standardized scores were analyzed by adjusted linear and logistic regression models. Results: Median (P25, P75) BPA concentrations were 4.76 (2.77, 9.03) μg/L and 4.75 (2.75, 10.2) μg/g of creatinine (Cr). Boys in the third and fourth quartile of volume-based BPA concentrations showed better processing speed scores than boys in the first quartile (β = 5.47; 95%CI: 1.4, 9.4 and β = 3.57; 95%CI: -0.4, 7.5, respectively); and boys in the third quartile showed better inhibitory control (β = 1.6; 95%CI: -0.3, 3.5) and impulsivity (β= -4.2; 95%CI: -9.0, 0.0). In contrast, boys in the fourth quartile showed poorer working memory scores than those in the first quartile (β= -1.0; 95%CI: -2.1, -0.1). All these associations were attenuated when (Cr)-standardized BPA concentrations were considered. Cr-based BPA concentrations were also associated with a higher risk of being below the 20th percentile of working memory scores [ORa = 1.51; 95%CI: 1.01, 2.25]. Discussion: Our findings do not support an association between urinary BPA concentrations and cognitive function or IQ among boys, except for working memory. BPA was previously found to be associated with behavior problems in the same study population, suggesting that BPA may predominantly affect the behavior of children rather than their cognitive function, in line with previous epidemiologic studies.
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... Consequently, human exposure is widespread as suggested by the fact that more than 90% of the US population has detectable BPA concentrations in their urine . Well-conducted experimental and a small but growing number of epidemiologic studies show that BPA can interfere with several aspects of hormone action, and may produce pleiotropic effects on reproduction, behavior and metabolism (Peretz et al., 2014;Giulivo et al., 2016;Mustieles et al., 2015Mustieles et al., , 2018. Increasing concern over BPA has prompted its substitution in some consumer products often labeled as 'BPA-free'. ...
... To date, the study has recruited~800 women ages 18-46 years and 500 men ages 18-55 years. Details of the study have been described elsewhere (Messerlian et al., 2018). Briefly, participants enroll independently or as a couple and are followed from study entry and throughout their fertility care, pregnancy and delivery. ...
... Republished from Messerlian et al. (2018). ...
Maternal and paternal preconception exposure to bisphenols and size at birth
Article
  • Jul 2018
  • HUM REPROD
Study question: Are maternal and paternal preconception urinary bisphenol A (BPA) or bisphenol S (BPS) concentrations associated with offspring birth size? Summary answer: Maternal-but not paternal-preconception urinary BPA concentrations were associated with lower birth size among couples seeking fertility evaluation. What is known already: Prenatal BPA exposure has been previously associated with reduced birth size in some but not all epidemiologic studies. However, the potential effect of BPA exposure before conception in either parent is unknown. Data on BPS is practically absent. Study design, size, duration: Ongoing prospective preconception cohort of women and men seeking fertility evaluation between 2005 and 2016 in a large fertility center in an academic hospital in Boston, MA, USA. Participants/materials, setting, methods: We examined the association between maternal and paternal preconception, as well as maternal prenatal urinary BPA and BPS concentrations, and size at birth among 346 singletons from couples recruited in the Environment and Reproductive Health (EARTH) Study using multivariable linear regression. Infant birth weight and head circumference were abstracted from delivery records. Mean preconception and prenatal exposures were estimated by averaging urinary ln-BPA and ln-BPS concentrations in multiple maternal and paternal urine samples collected before pregnancy, and maternal pregnancy samples collected in each trimester. Main results and the role of chance: Maternal preconception urinary BPA concentrations were inversely associated with birth weight and head circumference in adjusted models: each ln-unit increase was associated with a decrease in birth weight of 119 g (95% CI: -212, -27), and a head circumference decrease of 0.72 cm (95% CI: -1.3, -0.1). Additional adjustment by gestational age or prenatal BPA exposure modestly attenuated results. Women with higher prenatal BPA concentrations had infants with lower mean birth weight (-75 g, 95% CI: -153, 2) although this did not achieve statistical significance. Paternal preconception urinary BPA concentrations were not associated with either birth weight or head circumference. No consistent patterns emerged for BPS concentrations measured in either parent. Limitations, reasons for caution: We observed a strong negative association between maternal-but not paternal-preconception BPA concentrations and offspring birth size among a subfertile population. Although these results are overall consistent with prior studies on prenatal BPA exposure, these findings may not be generalizable to women without fertility concerns. Wider implications of the findings: This study suggests that the unexplored maternal preconception period may be a sensitive window for BPA effects on birth outcomes. Study funding/competing interest(s): Work supported by Grants (ES R01 009718, ES 022955 and ES 000002) from the National Institute of Environmental Health Sciences (NIEHS). C.M. was supported by a post-doctoral fellowship award from the Canadian Institutes of Health Research. There are no competing interests to declare.
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... BPA may interact with a variety of hormonal systems that affect growth, metabolism, and neurodevelopment. The existing studies, including several reviews, have concluded that BPA exposure might be related to neuro-behavioral problems in children [6][7][8][9][10][11]. However, the results from the existing publications are not fully consistent. ...
... BPA interference with hormonal and genomic regulation is, however, pointed out. BPA can bind not only to nuclear and membrane estrogen receptors but also to thyroid, glucocorticoid and peroxisome proliferator-activated receptors, and it can also interact with steroidogenic enzymes [7,[9][10][11]. The developing brain is a key target for this compound and thus both prenatal and childhood are sensitive periods of exposure. ...
Human-Biomonitoring derived exposure and Daily Intakes of Bisphenol A and their associations with neurodevelopmental outcomes among children of the Polish Mother and Child Cohort Study
Article
Full-text available
  • Aug 2021
  • ENVIRON HEALTH-GLOB
Background Bisphenol A (BPA) is an industrial chemical mostly used in the manufacture of plastics, resins and thermal paper. Several studies have reported adverse health effects with BPA exposures, namely metabolic disorders and altered neurodevelopment in children, among others. The aim of this study was to explore BPA exposure, its socio-demographic and life-style related determinants, and its association with neurodevelopmental outcomes in early school age children from Poland. Methods A total of 250 urine samples of 7 year-old children from the Polish Mother and Child Cohort Study (REPRO_PL) were analyzed for BPA concentrations using high performance liquid chromatography with online sample clean-up coupled to tandem mass spectrometry (online-SPE-LC-MS/MS). Socio-demographic and lifestyle-related data was collected by questionnaires or additional biomarker measurements. Emotional and behavioral symptoms in children were assessed using mother-reported Strengths and Difficulties Questionnaire (SDQ). Cognitive and psychomotor development was evaluated by Polish adaptation of the Intelligence and Development Scales (IDS) performed by trained psychologists. Results Urinary BPA concentrations and back-calculated daily intakes (medians of 1.8 μg/l and 46.3 ng/kg bw/day, respectively) were similar to other European studies. Urinary cotinine levels and body mass index, together with maternal educational level and socio-economic status, were the main determinants of BPA levels in Polish children. After adjusting for confounding factors, BPA has been found to be positively associated with emotional symptoms (β: 0.14, 95% CI: 0.022; 0.27). Cognitive and psychomotor development were not found to be related to BPA levels. Conclusions This study represents the first report of BPA levels and their determinants in school age children in Poland. The exposure level was found to be related to child emotional condition, which can have long-term consequences including social functioning and scholastic achievements. Further monitoring of this population in terms of overall chemical exposure is required.
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... Its mechanisms of action are particularly complex since BPA can bind not only to nuclear and membrane estrogen receptors but also to thyroid, glucocorticoid, and peroxisome proliferator-activated receptors. It can also interact with steroidogenic enzymes, among other molecular targets (Acconcia et al., 2015;Mustieles et al., 2018a;Rubin, 2011;Wetherill et al., 2007). Additionally, BPA has been shown to exert epigenetic modifications (e.g. ...
... Although associations found in human populations cannot demonstrate causality, BPA effects on different systems and organs are supported by an extensive body of experimental evidence. For some endpoints such as reproduction and behavior, the epidemiological findings are also increasingly consistent (Mustieles et al., 2018a(Mustieles et al., , 2015Peretz et al., 2014). ...
Bisphenol A and its analogues: A comprehensive review to identify and prioritize effect biomarkers for human biomonitoring
Article
Full-text available
  • Nov 2020
  • ENVIRON INT
Human biomonitoring (HBM) studies have demonstrated widespread and daily exposure to bisphenol A (BPA). Moreover, BPA structural analogues (e.g. BPS, BPF, BPAF), used as BPA replacements, are being increasingly detected in human biological matrices. BPA and some of its analogues are classified as endocrine disruptors suspected of contributing to adverse health outcomes such as altered reproduction and neurodevelopment, obesity, and metabolic disorders among other developmental and chronic impairments. One of the aims of the H2020 European Human Biomonitoring Initiative (HBM4EU) is the implementation of effect biomarkers at large scales in future HBM studies in a systematic and standardized way, in order to complement exposure data with mechanistically-based biomarkers of early adverse effects. This review aimed to identify and prioritize existing biomarkers of effect for BPA, as well as to provide relevant mechanistic and adverse outcome pathway (AOP) information in order to cover knowledge gaps and better interpret effect biomarker data. A comprehensive literature search was performed in PubMed to identify all the epidemiologic studies published in the last 10 years addressing the potential relationship between bisphenols exposure and alterations in biological parameters. A total of 5716 references were screened, out of which, 119 full-text articles were analyzed and tabulated in detail. This work provides first an overview of all epigenetics, gene transcription, oxidative stress, reproductive, glucocorticoid and thyroid hormones, metabolic and allergy/immune biomarkers previously studied. Then, promising effect biomarkers related to altered neurodevelopmental and reproductive outcomes including brain-derived neurotrophic factor (BDNF), kisspeptin (KiSS), and gene expression of nuclear receptors are prioritized, providing mechanistic insights based on in vitro, animal studies and AOP information. Finally, the potential of omics technologies for biomarker discovery and its implications for risk assessment are discussed. To the best of our knowledge, this is the first effort to comprehensively identify bisphenol-related biomarkers of effect for HBM purposes.
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... Additionally, in 2015 EFSA brought into effect a tolerable daily intake of 4 μg/kg bw/day for BPA consumption ( EFSA, 2015 ). Extensive research has been conducted to find out the adverse health effects of BPA even at low doses, and it has been reported that BPA possesses binding affinity with receptors against estrogen, thyroid hormone, glucocorticoids, and peroxisome proliferators ( Acconcia et al., 2015 ;Mustieles et al., 2018 ;Rubin, 2011 ) and observed to have a relationship with various lifestyle diseases, like diabetes ( Bi et al., 2016 ;Wahby et al., 2017 ), obesity and cardiovascular and reproductive disorders, at low doses (below the NOAEL given by USFDA) ( Bansal et al., 2018 ;Murata and Kang, 2018 ). BPA is also known to cause oxidative stress-mediated damage to the neurons ( Tiwari et al., 2015 ), hepatocytes, nephrons, and testicular sperm ( Gassman, 2017 ), carcinogenesis ( Prins et al., 2014 ), and potential estrogenic disruption ( Skledar and Ma š i č, 2016 ;Vandenberg et al., 2012 ). ...
Quantification of Bisphenol A in Swiss albino mice following topical exposure
Article
Full-text available
  • Nov 2022
Bisphenol A (BPA) is an industrial chemical used in plastics, resin-based food packaging, and thermal papers etc. BPA is reported as an endocrine disruptor and implicated in many disorders including infertility, diabetes, neurological, obesity, and cancer. The populace comes in contact with BPA through oral, inhalation, and dermal routes as it leaches out of the finished products. The present study is aimed to determine the levels of absorption through the skin as well as the penetration rate of BPA into the circulation following dermal exposure in Swiss albino mice. We used ultra-performance liquid chromatography with fluorescence detector to quantify the unconjugated BPA in the serum and skin samples collected at 6 h, 12 h, 24 h, 48 h, 72 h, and 168 h from Swiss albino mice exposed to 250 mg/kg bw BPA through a single dermal application. Mean serum unconjugated BPA Cmax of 745 ng/mL was observed at 24 h. Unconjugated BPA appeared in serum 562 ng/mL within 6 h and was detected till 72 h at concentrations near the LOD (3.9 ng/mL) while those in skin samples unconjugated BPA is detectable at all the time points and displayed a gradual decrease in BPA concentration with progressing duration post dermal exposure. Our study showed a slow absorption rate of BPA through the skin into the circulation and greater bioavailability of unconjugated BPA as it bypasses the first-pass metabolism, resulting in prolonged retention in the system with delayed elimination on dermal exposure.
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... The mounting experimental and epidemiological evidence on its neurobehavioral effects emphasizes more than ever the need to apply the precautionary principle during development, especially in relation to pregnant women and children. It appears that the time for action t has arrived [paper #5: (Mustieles et al., 2018a)]. ...
Exposure to bisphenol A: Effects on reproduction, neurodevelopment and obesity/metabolism
Thesis
Full-text available
  • Oct 2018
Bisphenol A (BPA) is a well-known endocrine disruptor able to interfere with hormonal homeostasis even at low doses. BPA is a high-production man-made chemical used worldwide in the manufacture of polycarbonate plastics, epoxy resin liners of canned food, some dental sealants, medical devices, and thermal receipts, among many other applications. Available data from biomonitoring studies clearly indicate that the general population is ubiquitously exposed to BPA. There is also growing evidence that BPA is harmful in laboratory animals and may adversely affect human health, especially during development. BPA has become a target of current risk assessments and policy regulations, mainly due to concerns about its possible adverse effects on children’s reproductive health, neurodevelopment, and obesity/metabolism. Hence, there is an urgent need to advance our knowledge on the potential effects of BPA exposure in human populations, with a special emphasis on different critical periods of development. Cite as: Mustieles Miralles, Vicente. Exposición a bisfenol-A: efectos sobre la reproducción, neurodesarrollo y obesidad/metabolismo. Granada: Universidad de Granada, 2019. [http://hdl.handle.net/10481/54773]
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... Bisphenol A (BPA) is a well-known EDC capable of disturbing hormonal homeostasis at low doses in experimental studies (Vandenberg et al., 2012). Apart from its ability to interfere with reproduction and neurodevelopment (Mustieles et al., 2018a(Mustieles et al., , 2015Peretz et al., 2014), BPA is a suspected obesogen found to increase adiposity and alter (Valentino et al., 2016;Wassenaar et al., 2017). Despite not being biologically inert, BPA is extensively used in the manufacture of polycarbonate plastics, epoxy resin liners of canned food, some dental composite resins, medical devices, and thermal-paper receipts (Molina-Molina et al., 2019), among many other technological applications (Vandenberg et al., 2007). ...
Bisphenol A and adiposity measures in peripubertal boys from the INMA- Granada cohort
Article
  • Apr 2019
Introduction: Childhood obesity is one of the most serious public health challenges of our times. Although an important body of experimental evidence highlights the obesogenic potential of endocrine disruptors such as bisphenol A (BPA), the epidemiological evidence remains inconclusive and limited. Objective: To assess associations between urinary BPA concentrations and several adiposity measures in peri-pubertal boys from the Environment and Childhood (INMA) cohort in Granada, Spain. Material and methods: BPA concentrations were determined in spot urine samples from 298 boys aged 9-11, and their weight, height, waist circumference, and percentage body fat mass were measured. Overweight/obesity was defined as BMI z-score ≥85th percentile and abdominal obesity as waist-to-height ratio (WHtR) ≥0.5. Associations were assessed using multivariable linear and logistic regression models. Results: In adjusted models, each natural log-unit increase in urinary BPA concentrations was associated with higher BMI z-score (β = 0.22; 95%CI = 0.03, 0.41) and increased odds of overweight/obesity (OR = 1.46; 95%CI = 1.05, 2.05). Children with higher BPA concentrations had higher WHtR values (β = 0.007; 95%CI = −0.001, 0.015), and BPA was associated with a greater risk of abdominal obesity (OR = 1.45; 95%CI = 1.03, 2.06). No associations were found with % body fat mass. Conclusions: BPA may exert an obesogenic effect in peripubertal boys, potentially increasing the risk of over-weight/obesity, especially abdominal obesity. However, these results should be interpreted with caution given the modest sample size and the possibilities of reverse causality and residual confounding by diet and lifestyle patterns.
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Prenatal Exposure to Nonpersistent Endocrine Disruptors and Behavior in Boys at 3 and 5 Years
Article
Full-text available
  • Sep 2017
Background: Sex-specific associations have been reported between phthalates, bisphenol A (BPA), and child behavior. No data on large study populations are available for other phenols with possible endocrine-disrupting properties. Objectives: We aimed to study associations between prenatal exposure to phthalates and several phenols on behavior among male infants. Methods: We quantified 11 phthalate metabolites and nine phenols (four parabens, benzophenone-3, BPA, two dichlorophenols, triclosan) in spot urine samples collected during pregnancy among EDEN cohort mothers who delivered a boy. Mothers completed the Strength and Difficulties Questionnaire (SDQ) when their children were 3.1 (n=529) and 5.6 (n=464) y old. Results: BPA was positively associated with the relationship problems subscale at 3 y [incidence rate ratio (IRR): 1.11; 95% confidence interval (CI): 1.03, 1.20] and the hyperactivity-inattention subscale scores at 5 y (IRR: 1.08; 95% CI: 1.01, 1.14). Mono-n-butyl phthalate (MnBP) was positively associated with internalizing behavior, relationship problem, and emotional symptom scores at 3 y. Monobenzyl phthalate (MBzP) was positively associated with internalizing behavior and relationship problems scores at 3 y. After dichotomizing SDQ scores, triclosan tended to be positively associated with emotional symptom subscales at both 3 and 5 y. Conclusions: The observed associations between BPA, MnBP, and behavior in boys are consistent with previous findings. Further health impact assessment studies based on dose-response functions corrected for exposure misclassification are required to quantify the public health burden possibly entailed by such associations. https://doi.org/10.1289/EHP1314.
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Prenatal and postnatal bisphenol A exposure and social impairment in 4-year-old children
Article
Full-text available
  • Jul 2017
  • ENVIRON HEALTH-GLOB
Background Prenatal and postnatal exposure to bisphenol A (BPA) may affect early brain development. Rodent studies suggest that prenatal and postnatal neurodevelopmental toxicity from BPA exposure may manifest as social deficits in offspring. We investigated the association between prenatal and postnatal exposure to BPA and social impairments in a sample of 4-year-old children. Methods We recruited second-trimester pregnant women between 2008 and 2011, and measured their creatinine-adjusted prenatal urine BPA levels. In 2014-2015, a subset of 4-year-old children born to these women underwent neurobehavioral assessment and physical examination. We collected urine and blood from the children and assessed social impairments, including deficits in social interaction, social communication, and other behavior patterns using the Korean version of the Social Communication Questionnaire (K-SCQ) (n = 304). We examined social impairments associated with prenatal exposure at mid-term pregnancy and postnatal exposure to BPA at 4 years of age, using linear and piecewise linear regression models. ResultsThe relationship between prenatal BPA exposure and social communication was non-linear and statistically significant at or above the flexion point for BPA levels of 3.0 μg/g creatinine in girls (58.4%, 95% confidence interval [CI], 6.5% to 135.8%). Each 2-fold increase in postnatal BPA exposure was significantly associated with an 11.8% (95% CI, 0.6% to 24.3%) increase in impairment in social communication in 4-year old girls, as indicated by the linear regression model. Conclusion Prenatal and postnatal BPA exposure is associated with social impairment at 4 years of age, particularly in girls.
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Associations of Prenatal Urinary Bisphenol A Concentrations with Child Behaviors and Cognitive Abilities
Article
Full-text available
  • Jun 2017
Background: Prenatal bisphenol A (BPA) exposure has been associated with adverse neurodevelopment in epidemiological studies. However, prior studies had limited statistical power to examine sex-specific effects, and few examined child cognition. Objectives: We estimated the association between prenatal BPA exposure and child neurobehavior at 3 y of age in a prospective cohort of 812 mothers and their children. Methods: We measured BPA concentration in urine samples collected at ∼12 wk gestation among women enrolled in a 10-city Canadian cohort study. At approximately 3 y of age, we assessed children’s cognitive abilities with the Wechsler Primary and Preschool Scale of Intelligence(TM)–III (WPPSI-III) and two scales of the Behavior Rating Inventory of Executive Function–Preschool (BRIEF-P). Parents reported children’s behavior using the Behavior Assessment System for Children–2 (BASC-2) and the Social Responsiveness Scale(TM)–2 (SRS-2). We estimated covariate-adjusted differences in neurobehavioral outcomes with a doubling in BPA concentration and sex-specific associations. Results: BPA was not associated with WPPSI-III scores; child sex did not modify these associations. The association between BPA and BRIEF-P scores was modified by child sex (BPA×sex p -values≤0.03). For example, a doubling of BPA concentration was associated with 1-point (95% CI: 0.3, 1.7) poorer working memory in boys and 0.5-point (95% CI: −1.1, 0.1) better scores in girls. BPA was not associated with most BASC-2 scales; however, it was associated with more internalizing and somatizing behaviors in boys, but not in girls (BPA×sex p -values≤0.08). A doubling of BPA concentration was associated with poorer SRS-2 scores [β=0.3 ( 95% CI: 0, 0.7)]; this association was not modified by sex. Conclusion: Prenatal urinary BPA concentration was associated with some aspects of child behavior in this cohort, and some associations were stronger among boys. https://doi.org/10.1289/EHP984.
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Relationship between Bisphenol A exposure and Attention-deficit/ hyperactivity disorder: A case-control study for primary school children in Guangzhou, China.
Article
  • Dec 2017
Bisphenol A (BPA) is an endocrine-disrupting chemical. Studies have shown that the exposure to BPA is associated with attention-deficit/hyperactivity disorder (ADHD) during adolescent development. However the direct clinical evidence is limited. To investigate the possible association between environmental BPA exposure and the altered behavior of children, a case-control study was conducted with children aged 6e12 years in Guangzhou, China. Two hundred fifteen children diagnosed with ADHD and 253 healthy children from Guangzhou were recruited as the case and control groups, respectively. Uri-nary BPA and 8-hydroxy-2 0-deoxyguanosine (8-OHdG, a biomarker of oxidative DNA damage) concentrations were determined by high-performance liquid chromatography/tandem spectrometry. The results showed that concentrations of urinary BPA for the case group were significantly higher than those for the control group (3.44 vs 1.70 mg/L; 4.63 vs 1.71 mg/g Crt. p < .001). A stepwise increase in the odds ratios for ADHD was observed with the increasing quartiles of children's urinary BPA (first quartile: reference category; second quartile adjusted OR: 1.79, 95% CI: 0.95e3.37; third quartile adjusted OR: 7.44, 95% CI: 3.91e14.1; fourth quartile adjusted OR: 9.41, 95% CI: 4.91e18.1). When the BPA levels were stratified by gender, the odds of ADHD among boys and girls increased significantly with urinary BPA concentrations (adjusted OR: 4.58, 95% CI: 2.84e7.37; adjusted OR: 2.83, 95% CI: 1.17e6.84). Urinary 8-OHdG concentrations in the ADHD children were significantly higher than those in the control group. Furthermore, the linear regression analysis results indicated that a significant relationship existed between BPA exposure and 8-OHdG levels (R ¼ 0.257, p < .001). Our findings provide direct evidence that childhood BPA exposure may be related to ADHD and 8-OHdG concentrations for children. Moreover, BPA exposure could increase the higher occurrence of ADHD for boy than for girls.
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Opening the black box of endocrine disruption of brain development: Lessons from the characterization of Bisphenol A
Article
  • Dec 2017
  • HORM BEHAV
Bisphenol A (BPA) is among the best-studied endocrine disrupting chemicals, known to act via multiple steroid hormone receptors to mediate a myriad of cellular effects. Pre-, peri-, and postnatal BPA exposure have been linked to a variety of altered behaviors in multiple model organisms, ranging from zebrafish to frogs to mammalian models. Given that BPA can cross the human placental barrier and has been found in the serum of human fetuses during gestation, BPA has been postulated to adversely affect ongoing neurodevelopment, ultimately leading to behavioral disorders later in life. Indeed, the brain has been identified as a key developmental target for BPA disruption. Despite these known associations between gestational BPA exposure and adverse developmental outcomes, as well as an extensive body of evidence existing in the literature, the mechanisms by which BPA induces its cellular- and tissue-specific effects on neurodevelopmental processes still remains poorly understood at a mechanistic level. In this review we will briefly summarize the effects of gestational BPA exposure on neural developmental mechanisms and resulting behaviors, and then present suggestions for how we might address gaps in our knowledge to develop a fuller understanding of endocrine neurodevelopmental disruption to better inform governmental policy against the use of BPA or other endocrine disruptors.
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Bisphenol A and reproductive hormones and cortisol in peripubertal boys: The INMA-Granada cohort
Article
  • Oct 2017
Introduction: Bisphenol A (BPA) is a well-known endocrine disrupting compound. Although several studies have investigated the effect of BPA exposure and reproductive hormones in humans, results have been inconsistent. Objective: To explore the cross-sectional relationship between bisphenol A (BPA) exposure and reproductive hormones/cortisol among peripubertal boys. Material and methods: Urinary BPA and serum hormones were assessed in 172 boys belonging to the INMA "Environment and Childhood" Granada birth cohort in their follow-up at 9-11years of age. BPA concentrations were quantified by liquid chromatography-mass spectrometry, and levels of serum total testosterone (TT), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and cortisol were measured by electrochemiluminescence immunoassay. Result(s): After adjustment for confounders, linear regression models showed that each natural-log unit increase in urinary BPA concentrations was associated with a 19% increase in geometric mean (GM) serum TT levels, and a 16% decrease in GM serum cortisol levels. When urinary BPA concentrations were categorized in tertiles, boys in the 3rd tertile showed 49% higher TT levels and 23% lower cortisol concentrations compared to boys in the 1st tertile. Additionally, urinary BPA concentrations were also significantly associated with higher TT:LH and TT:cortisol ratios, but not with serum LH or FSH levels. Conclusion(s): Our results suggest the possible endocrine disrupting potential of BPA during this important period of development. Although action at the testis or pituitary cannot be ruled out, our findings are compatible with a possible involvement of BPA at the adrenal gland, resulting in a differential production of androgens/cortisol. However, given the cross-sectional design of our study, the heterogeneous results reported in the literature, and the scant experimental research on BPA effects at the adrenal gland, the present findings should be interpreted with caution.
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Neuroendocrine Disruption in Animal Models Due to Exposure to Bisphenol A Analogues
Article
  • Aug 2017
Animal and human studies provide evidence that exposure to the endocrine disrupting chemical (EDC), bisphenol A (BPA), can lead to neurobehavioral disorders. Consequently, there is an impetus to identify safer alternatives to BPA. Three bisphenol compounds proposed as potential safer alternatives to BPA are bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF). However, it is not clear whether these other compounds are safer in terms of inducing less endocrine disrupting effects in animals and humans who are now increasingly coming into contact with these BPA-substitutes. In the past few years, several animal studies have shown exposure to these other bisphenols induce similar neurobehavioral disruption as BPA. We will explore in this review article the current studies suggesting these other bisphenols result in neuroendocrine disruptions that may be estrogen receptor-dependent. Current work may aide in designing future studies to test further whether these BPA-substitutes can act as neuroendocrine disruptors.
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Early life bisphenol A exposure and neurobehavior at 8 years of age: Identifying windows of heightened vulnerability
Article
  • Jul 2017
Background: Early life BPA exposure could affect neurobehavior, but few studies have investigated whether there are developmental periods when the fetus or child is more vulnerable to these potential effects. Objectives: We explored windows of vulnerability to BPA exposure in a multiethnic cohort of 228 mothers and their children from Cincinnati, Ohio. Methods: We measured urinary BPA concentrations at up to two prenatal and six postnatal time points from the 2nd trimester of pregnancy until the child was age 8years. At age 8years, we administered the Behavioral Assessment System for Children-2 (BASC-2), Behavior Rating Inventory of Executive Function, and Wechsler Intelligence Scale for Children-IV. We estimated covariate-adjusted differences in composite scores from each instrument using a multiple informant model designed to identify heightened windows of vulnerability. Results: Among all children, there was not strong evidence that the associations between BPA and neurobehavior varied by the timing of exposure (Visit x BPA p-values≥0.16). However, child sex modified the associations of repeated BPA measures with BASC-2 scores (Visit x Sex x BPA p-values=0.02-0.23). For example, each 10-fold increase in prenatal BPA was associated with more externalizing behaviors in girls (β=6.2, 95% CI: 0.8, 11.6), but not boys (β=-0.8, 95% CI: -5.0, 3.4). In contrast, a 10-fold increase in 8-year BPA was associated with more externalizing behaviors in boys (β=3.9, 95% CI: 0.6, 7.2), but not girls (β=0.3, 95% CI: -3.5, 4.1). Conclusions: We found that sex-dependent associations between BPA and child neurobehavior may depend on the timing of BPA exposure.
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Early-life exposure to EDCs: role in childhood obesity and neurodevelopment
Article
  • Nov 2016
  • NAT REV ENDOCRINOL
Endocrine-disrupting chemicals (EDCs) might increase the risk of childhood diseases by disrupting hormone-mediated processes that are critical for growth and development during gestation, infancy and childhood. The fetus, infant and child might have enhanced sensitivity to environmental stressors such as EDCs due to their rapid development and increased exposure to some EDCs as a consequence of development-specific behaviour, anatomy and physiology. In this Review, I discuss epidemiological studies examining the relationship between early-life exposure to bisphenol A (BPA), phthalates, triclosan and perfluoroalkyl substances (PFAS) with childhood neurobehavioural disorders and obesity. The available epidemiological evidence suggest that prenatal exposure to several of these ubiquitous EDCs is associated with adverse neurobehaviour (BPA and phthalates) and excess adiposity or increased risk of obesity and/or overweight (PFAS). Quantifying the effects of EDC mixtures, improving EDC exposure assessment, reducing bias from confounding, identifying periods of heightened vulnerability and elucidating the presence and nature of sexually dimorphic EDC effects would enable stronger inferences to be made from epidemiological studies than currently possible. Ultimately, improved estimates of the causal effects of EDC exposures on child health could help identify susceptible subpopulations and lead to public health interventions to reduce these exposures.
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