31 research outputs found
Association of preconception mixtures of phenol and phthalate metabolites with birthweight among subfertile couples
Background: Although parental preconception exposure to some phenols and phthalates have been associated with reduced
birthweight, few studies have examined these chemicals as complex mixtures.
Methods: We included 384 mothers and 211 fathers (203 couples) who gave birth to 384 singletons from a prospective cohort of
couples seeking fertility evaluation. Urinary concentrations of bisphenol A (BPA), parabens, and 11 phthalate metabolites including
those of di(2-ethylhexyl) phthalate (DEHP) were examined. Birthweight was abstracted from delivery records. We used principal
component analysis and Bayesian Kernel Machine Regression (BKMR) to examine maternal and paternal preconception mixtures in
relation to singleton birthweight. We also fit couple-based BKMR with hierarchical variable selection to assess couples’ joint mixtures
in relation to birthweight.
Results: PC scores of maternal and paternal preconception low molecular weight phthalates factor, and paternal preconception
DEHP-BPA factor were associated with reduced birthweight. In BKMR models, we found that maternal preconception monoethyl
phthalate and BPA concentrations, and paternal preconception mono-n-butyl phthalate concentrations were inversely associated
with birthweight when the remaining mixture components were held at their median concentrations. In couple-based BKMR models,
paternal preconception biomarkers contributed more to couples’ joint effect on birthweight compared with maternal preconception
biomarkers. A decreasing trend of birthweight was observed across quantiles of maternal, paternal, and couples’ total preconception
mixture concentrations, respectively.
Conclusions: Results from this preconception cohort of subfertile couples suggest a complex interplay between paternal and
maternal preconception exposure to mixtures of nonpersistent chemicals, with both parental windows of exposure jointly contributing
to reduced birthweight.United States Department of Health & Human Services
National Institutes of Health (NIH) - USA
NIH National Institute of Environmental Health Sciences (NIEHS) R01ES031657
R01ES028800
ES009718
ES00000
Concurrent Assessment of Phthalates/HEXAMOLL® DINCH Exposure and Wechsler Intelligence Scale for Children Performance in Three European Cohorts of the HBM4EU Aligned Studies
Information about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL (R) DINCH) on children's neurodevelopment is limited. The aim of the present research is to evaluate the association between phthalate /HEXAMOLL (R) DINCH exposure and child neurodevelopment in three European cohorts involved in HBM4EU Aligned Studies. Participating subjects were school-aged children belonging to the Northern Adriatic cohort II (NAC-II), Italy, Odense Child Cohort (OCC), Denmark, and PCB cohort, Slovakia. In each cohort, children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score (FSIQ) of the Wechsler Intelligence Scale of Children test using three different editions. The children's urine samples, collected for one point in time concurrently with the neurodevelopmental evaluation, were analyzed for several phthalates/HEXAMOLL (R) DINCH biomarkers. The relation between phthalates/HEXAMOLL (R) DINCH and FSIQ was explored by applying separate multiple linear regressions in each cohort. The means and standard deviations of FSIQ were 109 +/- 11 (NAC-II), 98 +/- 12 (OCC), and 81 +/- 15 (PCB cohort). In NAC-II, direct associations between FSIQ and DEHP's biomarkers were found: 50H-MEHP+5oxo-MEHP ((3 = 2.56; 95% CI 0.58-4.55; N = 270), 50H-MEHP+5cx-MEPP (beta = 2.48; 95% CI 0.47-4.49; N = 270) and 5OH-MEHP (beta = 2.58; 95% CI 0.65-4.51; N = 270). On the contrary, in the OCC the relation between DEHP's biomarkers and FSIQ tended to be inverse but imprecise (p-value >= 0.10). No associations were found in the PCB cohort. FSIQ was not associated with HEXAMOLL (R) DINCH in any cohort. In conclusion, these results do not provide evidence of an association between concurrent phthalate/DINCHHEXAMOLLR DINCH exposure and IQ in children.European Commission 733032
European Union through its Sixth Framework Program for RTD FOOD-CT-2006-016253Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy (Ministry of Health-Italy) RC 12/12CROME LIFE Project "Cross-Mediterranean Environment and Health Network" LIFE12 ENV/GR/001040Odense University Hospital, DenmarkUniversity of Southern Denmark
Mental Health Service of the Region of Southern Denmark
Odense Patient data Exploratory Network (OPEN), Denmark
Danish Center for Hormone Disrupting Chemicals MST-611-00012Det Frie Forskningsrad (DFF) 4004-00352B_FSSNovo Nordisk Foundation NNF19OC0058266
NNF17OC0029404Sygeforsikring Danmark 2021-0173Odense University HospitalHelsefonden
BeckettfondenDanish Mental Health FundHealth Insurance DenmarkVelux FondenSlovak Research and Development Agency APVV-0571-12Ministry of Health of the Slovak Republic 2014/47-SZU-11Region of Southern Denmark, The Municipality of Odense, DenmarkRigshospitale
Folate concentrations and serum perfluoroalkyl and polyfluoroalkyl substance concentrations in adolescents and adults in the USA (National Health and Nutrition Examination Study 2003–16): an observational study
Background Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a family of highly fluorinated aliphatic
compounds, which are widely used in commercial applications, including food packaging, textiles, and non-stick
cookware. Folate might counteract the effects of environmental chemical exposures. We aimed to explore the
relationship between blood folate biomarker concentrations and PFAS concentrations.
Methods This observational study pooled cross-sectional data from the National Health and Nutrition Examination
Survey (NHANES) 2003 to 2016 cycles. NHANES is a population-based national survey that measures the health and
nutritional status of the US general population every 2 years by means of questionnaires, physical examination, and
biospecimen collection. Folate concentrations in red blood cells and in serum, and perfluorooctanoic acid (PFOA),
perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS)
concentrations in serum were examined. We used multivariable regression models to assess the percentage change
in serum PFAS concentrations in relation to changes in folate biomarker concentrations. We additionally used
models with restricted cubic splines to investigate the shape of these associations.
Findings This study included 2802 adolescents and 9159 adults who had complete data on PFAS concentrations, folate
biomarkers, and covariates, were not pregnant, and had never had a cancer diagnosis at the time of the survey. The
mean age was 15·4 years (SD 2·3) for adolescents and 45·5 years (17·5) for adults. The proportion of male participants
was slightly higher in adolescents (1508 [54%] of 2802 participants) than in adults (3940 [49%] of 9159 participants). We
found negative associations between red blood cell folate concentrations and serum concentrations of PFOS (percentage
change for a 2·7 fold-increase in folate level –24·36%, 95% CI –33·21 to –14·34) and PFNA (–13·00%, –21·87 to –3·12)
in adolescents, and PFOA (–12·45%, –17·28 to –7·35), PFOS (–25·30%, –29·67 to –20·65), PFNA (–21·65%,
–26·19 to –16·82), and PFHxS (–11·70%, –17·32 to 5·70) in adults. Associations for serum folate concentrations and
PFAS were in line with those found for red blood cell folate levels, although the magnitude of the effects was lower.
Restricted cubic spline models suggested linearity of the observed associations, particularly for associations in adults.
Interpretation In this large-scale, nationally representative study, we found consistent inverse associations for most
examined serum PFAS compounds in relation to folate concentrations measured in either red blood cells or serum
among both adolescents and adults. These findings are supported by mechanistic in-vitro studies that show the
potential of PFAS to compete with folate for several transporters implicated in PFAS toxicokinetics. If confirmed in
experimental settings, these findings could have important implications for interventions to reduce the accumulated
PFAS body burden and mitigate the related adverse health effects.United States National Institute of Environmental Health Science
BDNF and KISS‑1 Levels in Maternal Serum, Umbilical Cord, and Placenta: The Potential Role of Maternal Levels as Effect Biomarker
Brain-derived neurotrophic factor (BDNF) and kisspeptin-1 (KISS-1) regulate placental development and fetal growth. The
predictive value of maternal serum BDNF and KISS-1 concentrations for placental and umbilical cord levels has not yet been
explored. The influence of prenatal lead (Pb) and cadmium (Cd) exposure and maternal iron status on BDNF and KISS-1
levels is also unclarified and of concern. In a pilot cross-sectional study with 65 mother–newborn pairs, we analyzed maternal
and cord serum levels of pro-BDNF, mature BDNF, and KISS-1, BDNF, and KISS-1 gene expression in placenta, Pb and
Cd in maternal and umbilical cord blood (erythrocytes), and placenta. We conducted a series of in vitro experiments using
human primary trophoblast cells (hTCs) and BeWo cells to verify main findings of the epidemiological analysis. Strong
and consistent correlations were observed between maternal serum levels of pro-BDNF, mature BDNF, and KISS-1 and
corresponding levels in umbilical serum and placental tissue. Maternal red blood cell Pb levels were inversely correlated
with serum and placental KISS-1 levels. Lower expression and release of KISS-1 was also observed in Pb-exposed BeWo
cells. In vitro Pb exposure also reduced cellular BDNF levels. Cd-treated BeWo cells showed increased pro-BDNF levels.
Low maternal iron status was positively associated with low BDNF levels. Iron-deficient hTCs and BeWo cells showed a
consistent decrease in the release of mature BDNF. The correlations between maternal BDNF and KISS-1 levels, placental
gene expression, and umbilical cord serum levels, respectively, indicate the strong potential of maternal serum as predictive
matrix for BDNF and KISS-1 levels in placentas and fetal sera. Pb exposure and iron status modulate BDNF and KISS-1
levels, but a clear direction of modulations was not evident. The associations need to be confirmed in a larger sample and
validated in terms of placental and neurodevelopmental function.HBM4EU Project from the
European Union's Horizon 2020 Research and Innovation Program
under Grant Agreement No. 73303
Exposure to Perflouroalkyl acids and foetal and maternal thyroid status: a review
Background Exposure to perfluorinated-alkyl-acids (PFAAs) is ubiquitous. PFAAs are hormone-disrupting compounds that are strongly suspected to affect mother-child-health such as fetal growth. Thyroid disruption is a plausible mechanism of action. We aim to summarize the epidemiological evidence for the relation between prenatal and postnatal exposure to PFAAs and disruption of thyroid homeostasis in mothers and/or infants. Method Fifteen original publications on PFAAs concentrations and thyroid hormones (TH) in pregnant women and/or infants were found upon a literature search in the PubMed database. Information on exposure to seven PFAAs congeners [Perfluorooctane sulfonate (PFOS), Perfluorooctanoate (PFOA), Perfluorohexane sulfonate (PFHxS), Perfluorononanoic acid (PFNA), Perfluorodecanoic acid (PFDA), Perfluoroundecanoic acid (PFUnA), and Perfluorododecanoic acid (PFDoA)] and thyroid stimulating hormone (TSH), free and total thyroxine (FT4 and TT4), free and total triiodothyronine (FT3 and TT3), T3RU (Free triiodothyronine resin uptake) and FT4-index (FT4I) levels were recorded. We evaluated sampling of maternal TH by trimester, and infant TH by sex stratification. Reported associations between mother or infant PFAAs and TH were not uniformly assessed in the selected studies. Results Ten out of the fifteen studies examined maternal PFAAs concentration and TSH level. Seven studies showed significant associations between TSH and exposure to six PFAAs congeners, most of them were positive. Maternal T4 and T3 were investigated in nine studies and five studies found inverse associations between exposure to six PFAAs congeners and TH (TT3, TT4, FT3, FT4 and FT4I) levels. Eight of the fifteen studies investigated PFAAs concentrations and infant TSH. Infant TSH level was significantly affected in four studies, positively in three studies. Nine studies investigated infant T4 and T3 and seven studies found significant associations with PFAAs exposure. However, both inverse and positive significant associations with infant TH were found eliciting no clear direction. Conclusion Results indicate a mainly positive relationship between maternal PFAAs concentrations and TSH levels, and suggestion of an inverse association with T4 and/or T3 levels. Associations of infant TH with PFAAs concentration were less consistent.Det Frie Forskningsrad (DFF)
30531European Unions' Horizon 2020 research and innovation Programme
733032 HBM4E
Bisphenols and Oxidative Stress Biomarkers—Associations Found in Human Studies, Evaluation of Methods Used, and Strengths and Weaknesses of the Biomarkers
We thank our other HBM4EU colleagues (mentioned as co-authors in Mustieles et al., 2020)
for their contribution to the first literature searches.Bisphenols, particularly bisphenol A (4,40
-(hexafluoroisopropylidene)-diphenol) (BPA),
are suspected of inducing oxidative stress in humans, which may be associated with adverse health
outcomes. We investigated the associations between exposure to bisphenols and biomarkers of
oxidative stress in human studies over the last 12 years (2008-2019) related to six health endpoints
and evaluated their suitability as effect biomarkers. PubMed database searches identified 27 relevant
articles that were used for data extraction. In all studies, BPA exposure was reported, whereas
some studies also reported other bisphenols. More than a dozen different biomarkers were
measured. The most frequently measured biomarkers were 8-oxo-7,8-dihydro-20
-deoxyguanosine
(8-OHdG), 8-iso-prostaglandin F2α (8-isoprostane) and malondialdehyde (MDA), which almost
always were positively associated with BPA. Methodological issues were reported for MDA, mainly
the need to handle samples with caution to avoid artefact formation and its measurements using
a chromatographic step to distinguish it from similar aldehydes, making some of the MDA results
less reliable. Urinary 8-OHdG and 8-isoprostane can be considered the most reliable biomarkers of
oxidative stress associated with BPA exposure. Although none of the biomarkers are considered BPAor organ-specific, the biomarkers can be assessed repeatedly and non-invasively in urine and could
help to understand causal relationships.HBM4EU project - European Union's Horizon 2020 research and innovation program
73303
Application of AOPs to assist regulatory assessment of chemical risks – Case studies, needs and recommendations
While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies
(NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate
chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an
invaluable role in identifying health effects associated with chemical exposures. To move towards the next
generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches,
and to establish processes for increasing mechanistically-based biological plausibility in human
studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs
but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited.
The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives
as it was discussed in a workshop organized within the European Union partnerships HBM4EU and
PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the
human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing
and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless,
several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory
community including the lack of quantitative information on response-response relationships and of efficient
ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing
initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation
of AOPs in the NGRA.European Commission 733032
857560
101057014Ministry of Education, Youth and Sports by the RECETOX Research Infrastructure LM2018121OP RDE project CETOCOEN Excellence CZ.02.1.01/0.0/0.0/17_043/0009632Japan Agency for Medical Research and Development (AMED) JP21mk0101216
JP22mk0101216Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceGrants-in-Aid for Scientific Research (KAKENHI) 21K1213
Genome‑wide distribution of histone trimethylation reveals a global impact of bisphenol A on telomeric binding proteins and histone acetyltransferase factors: a pilot study with human and in vitro data
Objective: To assess the genetic and epigenetic effects promoted by Bisphenol A (BPA) exposure in adolescent
males from the Spanish INMA-Granada birth cohort, and in human cells.
Methods: DNA methylation was analysed using MEDIP. Repeat number variation in genomic DNA was evaluated,
along with the analysis of H3K4me3 by using chromatin immunoprecipitation followed by high-throughput sequencing
(ChIP-seq). Analyses were performed with material extracted from whole blood of the adolescents, complemented
by in vitro assessments of human (HeLa) cells exposed to 10 nM BPA, specifically, immunofluorescence
evaluation of protein levels, gene expression analysis and ChIP‒qPCR analysis.
Results: Adolescents in the high urinary BPA levels group presented a higher level of Satellite A (SATA) repetitive
region copy numbers compared to those in the low BPA group and a tendency towards increase in telomere length.
We also observed decreased DNA methylation at the promoters of the imprinted genes H19, KCNQ1, and IGF2; at
LINE1 retroelements; and at the ARID2, EGFR and ESRRA and TERT genes. Genome-wide sequencing revealed increased
H3K4me3 occupancy at the promoters of genes encoding histone acetyltransferases, telomeric DNA binding factors
and DNA repair genes. Results were supported in HeLa cells exposed to 10 nM BPA in vitro. In accordance with
the data obtained in blood samples, we observed higher H3K4me3 occupancy and lower DNA methylation at some
specific targets in HeLa cells. In exposed cells, changes in the expression of genes encoding DNA repair factors (ATM,
ARID2, TRP53) were observed, and increased expression of several genes encoding telomeric DNA binding factors (SMG7, TERT, TEN1, UPF1, ZBTB48) were also found. Furthermore, an increase in ESR1/ERa was observed in the nuclei of
HeLa cells along with increased binding of ESR1 to KAT5, KMT2E and TERF2IP promoters and decreased ESR1 binding
at the RARA promoter. The DNA damage marker p53/TP53 was also increased.
Conclusion: In this pilot study, genome-wide analysis of histone trimethylation in adolescent males exposed to BPA
revealed a global impact on the expression of genes encoding telomeric binding proteins and histone acetyltransferase
factors with similar results in HeLa cells. Nevertheless, larger studies should confirm our findings.European Commission E17013NKInstitut National de la Sante et de la Recherche Medicale (Inserm)
European CommissionNational Natural Science Foundation of China (NSFC) 3180106