Publications by authors named "Philippe Grandjean"

284 Publications

Plasma concentrations of perfluoroalkyl substances and risk of inflammatory bowel diseases in women: A nested case control analysis in the Nurses' Health Study cohorts.

Environ Res 2021 Oct 16:112222. Epub 2021 Oct 16.

Clinical and Translational Epidemiology Unit, Massachusetts Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Perfluoroalkyl substances (PFASs) are synthetic compounds used in a wide variety of industrial and consumer applications. An association between PFAS exposure and risk of ulcerative colitis (UC) has been reported in a highly exposed population. However, data are limited on risk of inflammatory bowel diseases (IBD) among individuals with background population levels of PFAS exposure.

Objectives: We set out to examine the association between plasma PFAS concentrations and risk of IBD among women in two population-based, prospective cohort studies in which pre-diagnostic blood specimens were available.

Methods: We conducted a nested case-control study in the Nurses' Health Study and Nurses' Health Study II cohorts. We identified 73 participants with incident Crohn's disease (CD) and 80 participants with incident UC who had provided blood samples before diagnosis. Cases were matched 1:2 to IBD-free controls. Plasma concentrations of five major PFASs were measured by liquid chromatography and tandem mass spectrometry. We used conditional logistic models to estimated odds ratios for risk of IBD according to log-transformed PFAS concentrations, adjusting for potential confounders.

Results: In multivariable models, we observed inverse associations between plasma concentrations of three PFASs and risk of CD (all P ≤ 0.012 for a standard deviation increase in logPFAS). The inverse association with CD was strongest for perfluorodecanoate, where, compared to the lowest tertile, the odds ratio (OR) for the highest tertile was 0.39 (95% confidence interval, 0.17-0.92). No associations were observed between PFAS concentrations and UC risk.

Discussion: Our results do not support the hypothesis that elevated PFAS exposure is associated with higher risk of UC. Contrary to expectation, our data suggest that circulating concentrations of some PFASs may be inversely associated with CD development.
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http://dx.doi.org/10.1016/j.envres.2021.112222DOI Listing
October 2021

No association between maternal and child PFAS concentrations and repeated measures of ADHD symptoms at age 2½ and 5 years in children from the Odense Child Cohort.

Neurotoxicol Teratol 2021 Sep 24;88:107031. Epub 2021 Sep 24.

Department of Clinical Pharmacology, Pharmacy and Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark.

Introduction: The potential impact of exposure to perfluoroalkyl substances (PFAS) on childhood Attention-Deficit Hyperactivity-Disorder (ADHD) is unclear and deserves scrutiny. The majority of previously conducted longitudinal studies found no association between maternal serum-PFAS concentrations and ADHD symptoms in the offspring, but some studies observed possible associations with postnatal PFAS exposures, mainly in girls.

Objective: To investigate the association between maternal and child serum concentrations of five PFAS and symptoms of ADHD at ages 2½ and 5 years.

Methods: In the Odense Child Cohort (OCC) women were recruited in early pregnancy in 2010-12 and their children are being prospectively followed. Mothers donated serum samples in the first trimester and children at age 18 months to be analyzed for perfluorohexane sulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA). Parents completed the Child Behavior Check List for ages 1.5-5 years (CBCL/1½-5), including a 6-item ADHD symptom scale at age 2½ years and again at 5 years. Negative binomial and logistic regression models taking account of repeated measures were used to investigate the association between maternal and child serum-PFAS concentrations and the ADHD symptom score. Effect modification by child sex was investigated as well.

Results: A total of 1138 mother-child pairs were included. At age 2½ years, 17.4% of the children had an ADHD scale score ≥ 5 (equivalent to the 90th percentile), whereas the proportion was 15.8% at age 5. We found no association between either maternal or child PFAS concentrations in serum and symptoms of ADHD at age 2½ or 5 years, and no evidence of effect modification by sex.

Conclusion: We found no evidence of an association between early-life PFAS exposure and the risk of developing symptoms of ADHD.
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http://dx.doi.org/10.1016/j.ntt.2021.107031DOI Listing
September 2021

Pregnancy exposure to perfluoroalkyl substances, prolactin concentrations and breastfeeding in the Odense Child Cohort.

J Clin Endocrinol Metab 2021 Sep 16. Epub 2021 Sep 16.

Research Unit of Clinical Pharmacology, Pharmacy and Environmental Medicine, University of Southern Denmark, Denmark.

Context: Human exposure to perfluoroalkyl substances (PFAS) has been associated with reduced duration of breastfeeding, though not consistently so, and mechanisms by which PFAS might affect breastfeeding are unknown.

Objective: To examine the association between early pregnancy serum-PFAS concentrations and breastfeeding termination and elucidate the potential role of serum-prolactin concentrations in pregnancy.

Materials And Methods: Pregnant women from the Odense Child Cohort provided blood samples for analysis of five major PFAS (n=1300) and prolactin concentrations (n=924). They subsequently provided information about the duration of breastfeeding in questionnaires at three and eighteen months postpartum, and a subgroup also provided breastfeeding information via weekly cell phone text messages. Associations between serum-PFAS concentrations and breastfeeding termination were analyzed using Cox regressions, while linear regression was used to assess associations between serum-PFAS and prolactin concentrations.

Results: Increased serum concentrations of PFOS, PFOA, PFNA and ∑PFAS were associated with a 16% (95% CI: 4-30%), 14% (95% CI: 2-26%), 14% (95% CI: 3-27%), and 20% (95% CI: 6-36%), respectively, increased risk of terminating breastfeeding at any given time after childbirth. Serum-PFAS concentrations were not associated with serum-prolactin concentrations.

Conclusions: These findings are of public health importance due to the global exposures to PFAS. Because breastfeeding is crucial to promote both child health and maternal health, adverse PFAS effects on the ability to breastfeed may have long-term health consequences.
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http://dx.doi.org/10.1210/clinem/dgab638DOI Listing
September 2021

Early-life exposure to perfluoroalkyl substances in relation to serum adipokines in a longitudinal birth cohort.

Environ Res 2021 Aug 19;204(Pt A):111905. Epub 2021 Aug 19.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA; Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark. Electronic address:

Background: Per- and polyfluoroalkyl substances (PFAS) exposure has been linked to metabolic health outcomes such as obesity, and changes in adipokine hormones may be one of the underlying biological mechanisms. We prospectively evaluated the associations between prenatal and early childhood exposures to PFASs and adipokines in children.

Material And Methods: PFAS concentrations were measured in serum samples collected at birth, 18 months, and 5 and 9 years, and adiponectin, leptin, leptin receptor, and resistin were measured in serum samples collected at birth and 9 years. We used multivariable linear regression models to estimate the percent change in serum-adipokine concentrations for a doubling in serum-PFAS concentrations. The potential sex-specific effect of PFAS was assessed by including an interaction term between PFAS and sex in each model. Bayesian kernel machine regression (BKMR) was implemented to evaluate the overall effect of PFAS mixtures.

Results: Significant associations with leptin, leptin receptor, and resistin at age 9 years were observed for serum-PFAS concentrations at 18 months and 5 and 9 years, whereas associations for PFAS concentrations at birth were mostly null. However, we observed a positive association between serum-PFHxS at birth and leptin receptor at birth. We found limited evidence regarding modification effect of sex on serum-PFAS concentrations. BKMR findings were consistent and suggested some significant effects of the overall PFAS mixtures at 18 months and 5 and 9 years on adipokine concentrations at 9 years.

Conclusions: Given the associations of PFAS exposure with both adipokine hormones and metabolic functions, future studies should include assessment of adipokine hormones when examining PFAS-associated metabolic alterations.
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http://dx.doi.org/10.1016/j.envres.2021.111905DOI Listing
August 2021

Environmental epidemiology in a crossfire.

Environ Health 2021 08 19;20(1):91. Epub 2021 Aug 19.

Department of Environmental Health, Boston University School of Public Health, Boston, USA.

Two tendencies have emerged in environmental epidemiology that hamper the translation of research findings into prevention of environmental hazards. One is the increased focus on highlighting weaknesses of epidemiology research that is clearly meant to explain away the research conclusions and weaken their possible implications for interventions to control environmental hazards. Another is the voluminous amount of information sharing that involves a substantial amount of misinformation, as part of the ongoing infodemic. In this light, the appearance of the catalogue of doubt-raising strategies, indeed the worst practices of scientific inference, is good news. Collected under the auspices of the International Network for Epidemiology in Policy, it serves to illustrate the range of possible (and impossible) forms of critique that may be raised on behalf of vested interests or other groups who for some reason disagree with the epidemiological conclusions. We believe that this systematic list will be useful in our field and help to identify critiques of policy options that are hidden and sometimes suppressed in weighing the epidemiological evidence.
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http://dx.doi.org/10.1186/s12940-021-00776-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375458PMC
August 2021

Reference intervals for trace elements in the general Danish population and their dependence on serum proteins.

Scand J Clin Lab Invest 2021 Aug 8:1-9. Epub 2021 Aug 8.

Department of Public Health, University of Southern Denmark, Odense, Denmark.

Reference intervals that indicate the anticipated results of clinical chemistry parameters in a healthy background population are essential for the proper interpretation of laboratory data. In the present study, we analysed major trace elements in blood samples from 400 randomly selected members of the general Danish population. Reference intervals were established for trace elements in both whole blood and serum, and associations with major plasma transport proteins were investigated. In the case of a statistically significant correlation, a corresponding protein-adjusted reference interval was established for comparison with the unadjusted interval. While several trace elements correlated with albumin, ferritin and transferrin, the overall impact of transport proteins was minor and resulted in only marginal changes in the reference intervals. In conclusion, the updated reference intervals for trace elements can be employed without adjusting for plasma protein concentrations.
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http://dx.doi.org/10.1080/00365513.2021.1959050DOI Listing
August 2021

Concentrations of tetanus and diphtheria antibodies in vaccinated Greenlandic children aged 7-12 years exposed to marine pollutants, a cross sectional study.

Environ Res 2021 Jul 31;203:111712. Epub 2021 Jul 31.

Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Previous studies have shown immunotoxic effects of environmental chemicals, and the European Food Safety Authority (EFSA) recently identified a need for more studies on PFAS immunotoxicity in different populations. In the Arctic, populations are exposed to several environmental chemicals through marine diet, and the objective of this study was therefore to examine the association between Greenlandic children's exposure to major environmental chemicals and their concentrations of diphtheria and tetanus vaccine antibodies after vaccination. The study includes cross-sectional data from Greenlandic children aged 7-12 years examined during 2012-2015. A total of 338 children were eligible for the study, and 175 of these had available vaccination records. A parent or guardian participated in a structured interview, and a blood sample from the child was analyzed for specific antibodies against diphtheria and tetanus as well as perfluoroalkyl substances (PFASs), polychlorinated biphenyls (PCBs) and total mercury. Furthermore, for a subgroup, blood samples from pregnancy were available and analyzed for environmental contaminants. The associations between the environmental exposures and antibody concentrations and odds of having antibody concentrations below the protective level were examined in linear and logistic regression models. In crude analyses, elevated concentrations of some of the contaminants were associated with higher concentrations of diphtheria and tetanus antibodies, but the associations were reversed when adjusting for area of residence, and duration of being breastfed and including children with a known vaccination date only. Each 1 ng/mL increase in serum concentrations of perfluorohexane sulfonic acid (PFHxS) and perfluorooctane sulfonic acid (PFOS) was associated with decreases of 78 % (95 % CI: 25-94 %) and 9 % (95 % CI: 2-16 %), respectively, in diphtheria antibody concentrations. Exposure to PCBs and all PFASs was associated with markedly increased odds of having diphtheria antibody concentrations below the protective level. For each 1 ng/mL increase in serum concentrations of PFHxS, PFOS, perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), odds of not having protective levels of diphtheria antibodies were increased 6.44 times (95 % CI: 1.51-27.36), 1.14 times (95 % CI: 1.04-1.26), 1.96 times (95 % CI: 1.07-3.60), and 5.08 times (95 % CI: 1.32-19.51, respectively. No consistent associations were seen between maternal contaminant concentrations and vaccine antibody concentrations. In conclusion, we found that increased exposure to environmental chemicals among children in this Arctic population were associated with a decrease in post-vaccination antibody concentrations and with increased odds of not being protected against diphtheria despite appropriate vaccination. These findings emphasize the risk of environmental chemical exposures also in this Arctic population.
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http://dx.doi.org/10.1016/j.envres.2021.111712DOI Listing
July 2021

Serum vaccine antibody concentrations in adults exposed to per- and polyfluoroalkyl substances: A birth cohort in the Faroe Islands.

J Immunotoxicol 2021 12;18(1):85-92

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Cambridge, MA, USA.

Per- and polyfluoroalkyl substances (PFASs) are highly persistent in the environment and may cause depressed immune function. Previous studies have linked PFAS exposure to lower vaccine responses in children, but research in adults is limited. Therefore, the present study evaluated the associations between exposure to PFASs and serum antibody concentrations in adults vaccinated at age 28 years in the Faroe Islands. PFAS concentrations were determined from cord-blood collected at birth and serum samples collected at ages 7, 14, 22, and 28 years. Serum antibody concentrations against hepatitis type A and B, diphtheria, and tetanus were analyzed from blood samples collected about 6 mo after the first vaccine inoculation at age 28 years. Linear regression models were used to estimate changes in antibody concentration for each doubling of PFAS concentration. Potential effect modification by sex was assessed by including an interaction term between PFAS and sex. Although the 95% confidence intervals contain the null value, inverse trends were observed between serum perfluorooctanoate (PFOA) at ages 14 and 28 years and hepatitis type A antibody (anti-HAV) concentrations, as revealed by an estimated decrease of 0.71 (95% CI: -1.52, 0.09) and 0.24 (95% CI: -0.59, 0.10) signal-to-cutoff ratio for each doubling of exposure, respectively. Inverse trends were also observed between serum PFOA at ages 22 and 28 years and hepatitis type B antibody (anti-HBs) concentration, with an estimated decrease of 21% (95% CI: -42.20%, 7.34%) and of 17% (95% CI: -35.47%, 7.35%) in anti-HBs for each doubling of exposure, respectively. Sex-specific associations with anti-HAV were observed for cord-blood PFASs and serum PFAS concentrations at ages 7 and 14 years. No inverse associations of PFAS exposure were found with diphtheria and tetanus antibody concentrations. Future studies are needed to confirm these findings and further investigate the effects of PFASs on adult immune function.
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http://dx.doi.org/10.1080/1547691X.2021.1922957DOI Listing
December 2021

A Benchmark Dose Analysis for Maternal Pregnancy Urine-Fluoride and IQ in Children.

Risk Anal 2021 Jun 8. Epub 2021 Jun 8.

Department of Biostatistics, University of Copenhagen, Denmark.

As a guide to establishing a safe exposure level for fluoride exposure in pregnancy, we applied benchmark dose modeling to data from two prospective birth cohort studies. We included mother-child pairs from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort in Mexico and the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort in Canada. Maternal urinary fluoride concentrations (U-F, in mg/L, creatinine-adjusted) were measured in urine samples obtained during pregnancy. Children were assessed for intelligence quotient (IQ) at age 4 (n = 211) and between six and 12 years (n = 287) in the ELEMENT cohort, and three to four years (n = 407) in the MIREC cohort. We calculated covariate-adjusted regression coefficients and their standard errors to assess the association of maternal U-F concentrations with children's IQ measures. Assuming a benchmark response of 1 IQ point, we derived benchmark concentrations (BMCs) and benchmark concentration levels (BMCLs). No deviation from linearity was detected in the dose-response relationships, but boys showed lower BMC values than girls. Using a linear slope for the joint cohort data, the BMC for maternal U-F associated with a 1-point decrease in IQ scores was 0.31 mg/L (BMCL, 0.19 mg/L) for the youngest boys and girls in the two cohorts, and 0.33 mg/L (BMCL, 0.20 mg/L) for the MIREC cohort and the older ELEMENT children. Thus, the joint data show a BMCL in terms of the adjusted U-F concentrations in the pregnant women of approximately 0.2 mg/L. These results can be used to guide decisions on preventing excess fluoride exposure in pregnant women.
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http://dx.doi.org/10.1111/risa.13767DOI Listing
June 2021

Early-life associations between per- and polyfluoroalkyl substances and serum lipids in a longitudinal birth cohort.

Environ Res 2021 09 31;200:111400. Epub 2021 May 31.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark.

Background: Exposures to per- and polyfluoroalkyl substances (PFASs) may affect metabolic outcomes, including lipid concentrations in the blood. However, few studies have evaluated potential associations between PFASs and lipids longitudinally.

Objectives: We estimated associations between PFAS and lipid concentrations at birth and at several points in childhood.

Methods: We measured concentrations of five major PFASs in cord serum and in serum collected at 18 months, five years and nine years in 490 children from a prospective cohort in the Faroe Islands. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations were measured at birth, 18 months and nine years. We estimated associations between PFAS and lipid concentrations and evaluated possible effect modification by sex. We also tested whether PFAS associations with age-nine lipids varied by exposure period.

Results: Serum PFAS concentrations at ages five and nine were positively associated with lipid concentrations at age nine. Cross-sectional associations between PFASs and lipids at age nine were the strongest, with increases in serum concentrations of perfluorodecanoic acid (PFDA), perfluorononanoic acid (PFNA) and perfluorooctanesulfonic acid (PFOS) associated with increases in TC, HDL-C and LDL-C. We found statistically significant differences in estimated PFAS effects by sex, where girls had stronger positive associations between PFASs and TC and LDL-C and boys had stronger positive associations with HDL-C. In repeated measure models, exposure period was a significant modifier of PFAS effects.

Conclusions: Our findings suggest that childhood PFAS exposures may be associated with elevated serum lipid concentrations. This is a public health concern, as a detrimental lipid profile in childhood is a risk factor for later development of hyperlipidemia and cardiovascular disease.
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http://dx.doi.org/10.1016/j.envres.2021.111400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403652PMC
September 2021

Prenatal exposure to pyrethroid and organophosphate insecticides and language development at age 20-36 months among children in the Odense Child Cohort.

Int J Hyg Environ Health 2021 06 5;235:113755. Epub 2021 May 5.

Department of Public Health, University of Southern Denmark, Odense, J.B. Winsløws Vej 17A, 5000, Odense, Denmark; Hans Christian Andersen Children's Hospital, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.

Background: Prenatal exposure to organophosphate and pyrethroid insecticides has been associated with impaired neurodevelopment. Few longitudinal studies have investigated associations with early language development in populations with mainly low dietary exposure.

Objective: To investigate associations between biomarkers of maternal gestational exposure to organophosphate and pyrethroid insecticides and the child's language development at age 20-36 months in the prospective Odense Child Cohort.

Methods: Metabolites of organophosphate and pyrethroid insecticides were measured in maternal urine samples collected at gestational week 28. Language development was assessed among 755 singletons at age 20-36 months using the Vocabulary and Complexity scores of the MacArthur-Bates Communicative Development Inventories, standardized into age and sex specific percentile scores according to a Danish reference study. Multiple logistic regression models were used to estimate the odds of scoring below the 15th percentile scores in relation to maternal urinary insecticide metabolite concentrations after adjustment for confounders.

Results: The generic pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA) and the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCPY) were detectable in more than 90% of the urine samples analyzed. Likewise, 82.2% had detectable concentrations of diethyl phosphates (DE) and 58.4% of dimethyl phosphates (DM), both of which are common metabolites of organophosphate insecticides. None of the metabolites was associated with higher odds of delayed results below the 15th percentile language scores. In contrast, reduced probability for scoring below the 15th percentile Vocabulary score was seen for the highest tertile of 3-PBA in boys and for the upper tertile of TCPY and DE in girls.

Conclusion: In this prospective cohort, with predominantly dietary insecticide exposure, we found no evidence that gestational exposure to organophosphate or pyrethroid insecticides adversely affected early language development in the children. The observed indication of a positive effect of insecticides on language development may be explained by residual and unmeasured confounding from socioeconomic factors and dietary habits. Follow-up of these children should include assessment of more complex cognitive functions in later childhood, as well as associations with their own postnatal insecticide exposure.
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http://dx.doi.org/10.1016/j.ijheh.2021.113755DOI Listing
June 2021

Life-course Exposure to Perfluoroalkyl Substances in Relation to Markers of Glucose Homeostasis in Early Adulthood.

J Clin Endocrinol Metab 2021 07;106(8):2495-2504

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Objective: To investigate the prospective associations of life-course perfluoroalkyl substances (PFASs) exposure with glucose homeostasis at adulthood.

Methods: We calculated insulin sensitivity and beta-cell function indices based on 2-h oral glucose tolerance tests at age 28 in 699 Faroese born in 1986-1987. Five major PFASs were measured in cord whole blood and in serum from ages 7, 14, 22, and 28 years. We evaluated the associations with glucose homeostasis measures by PFAS exposures at different ages using multiple informant models fitting generalized estimating equations and by life-course PFAS exposures using structural equation models.

Results: Associations were stronger for perfluorooctane sulfonate (PFOS) and suggested decreased insulin sensitivity and increased beta-cell function-for example, β (95% CI) for log-insulinogenic index per PFOS doubling = 0.12 (0.02, 0.22) for prenatal exposures, 0.04 (-0.10, 0.19) at age 7, 0.07 (-0.07, 0.21) at age 14, 0.05 (-0.04, 0.15) at age 22, and 0.04 (-0.03, 0.11) at age 28. Associations were consistent across ages (P for age interaction > 0.10 for all PFASs) and sex (P for sex interaction > 0.10 for all PFASs, except perfluorodecanoic acid). The overall life-course PFOS exposure was also associated with altered glucose homeostasis (P = 0.04). Associations for other life-course PFAS exposures were nonsignificant.

Conclusions: Life-course PFAS exposure is associated with decreased insulin sensitivity and increased pancreatic beta-cell function in young adults.
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http://dx.doi.org/10.1210/clinem/dgab267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277200PMC
July 2021

Human milk extracellular vesicle miRNA expression and associations with maternal characteristics in a population-based cohort from the Faroe Islands.

Sci Rep 2021 Mar 12;11(1):5840. Epub 2021 Mar 12.

Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, 10023, USA.

Human milk plays a critical role in infant development and health, particularly in cognitive, immune, and cardiometabolic functions. Milk contains extracellular vesicles (EVs) that can transport biologically relevant cargo from mother to infant, including microRNAs (miRNAs). We aimed to characterize milk EV-miRNA profiles in a human population cohort, assess potential pathways and ontology, and investigate associations with maternal characteristics. We conducted the first study to describe the EV miRNA profile of human milk in 364 mothers from a population-based mother-infant cohort in the Faroe Islands using small RNA sequencing. We detected 1523 miRNAs with ≥ one read in 70% of samples. Using hierarchical clustering, we determined five EV-miRNA clusters, the top three consisting of 15, 27 and 67 miRNAs. Correlation coefficients indicated that the expression of many miRNAs within the top three clusters was highly correlated. Top-cluster human milk EV-miRNAs were involved in pathways enriched for the endocrine system, cellular community, neurodevelopment, and cancers. miRNA expression was associated with time to milk collection post-delivery, maternal body mass index, and maternal smoking, but not maternal parity. Future studies investigating determinants of human EV-miRNAs and associated health outcomes are needed to elucidate the role of human milk EV-miRNAs in health and disease.
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http://dx.doi.org/10.1038/s41598-021-84809-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970999PMC
March 2021

Exposure to perfluoroalkyl substances and blood pressure in pregnancy among 1436 women from the Odense Child Cohort.

Environ Int 2021 06 17;151:106442. Epub 2021 Feb 17.

Department of Clinical Pharmacology, Pharmacy and Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark; Odense Child Cohort, Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark; OPEN Patient Data Explorative Network, Odense University Hospital, Odense, Denmark. Electronic address:

Background: Previous studies of association between exposure to poly- and perfluoroalkyl substances (PFAS) and gestational hypertension (GH) and preeclampsia (PE) have shown conflicting results, but most dichotomized outcome and did not study continuous blood pressure (BP) changes.

Objectives: To study the association between PFAS exposure in early pregnancy and maternal BP trajectories in pregnancy, gestational hypertension and preeclampsia.

Methods: 1436 women were enrolled in the Odense Child Cohort in early pregnancy and had a serum sample drawn, from which perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) were measured using LC-MS/MS. Repeated BP measurements through pregnancy and information on PE were obtained from hospital files. Adjusted linear mixed models were used to investigate association between PFAS exposure and BP trajectory. Associations between PFAS and PE and GH were assessed by Cox proportional hazards model.

Results: All women had measurable concentrations of PFAS. In all of many comparisons higher PFAS exposure (apart from PFHxS) was associated with higher systolic (SBP) and diastolic (DBP) blood pressures, although not all were significant, which is unlikely to be due to chance. After adjustment, each doubling in PFOS or PFOA exposure was associated with 0.47 mmHg (95% CI: -0.13; 1.08) and 0.36 mmHg (-0.19; 0.92) higher SBP; and 0.58 mmHg (0.13; 1.04) and 0.37 mmHg (-0.05; 0.79) higher DBP. No clear associations between PFAS exposure and PE or GH were found.

Discussion: The magnitude of the association between PFAS exposure and BP might appear small, statistically non-significant and the possible clinical importance low. However, at a population level this may slightly shift the distribution of BP towards an increased incidence of GH. If BP increases in pregnancy, it may have long-term impact on health not only of the pregnant woman but also of her offspring.
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http://dx.doi.org/10.1016/j.envint.2021.106442DOI Listing
June 2021

Public-health risks from tea drinking: Fluoride exposure.

Scand J Public Health 2021 Feb 8:1403494821990284. Epub 2021 Feb 8.

Environmental Medicine, University of Southern Denmark, Denmark.

Aims: Due to new evidence on fluoride neurotoxicity during early life, this study examined maternal exposure to fluoride through tea consumption in a low-fluoride region and measured fluoride releases from commercially available teas (tea bags and loose teas) to determine the need to limit fluoride exposure.

Methods: Maternal urine fluoride (MUF) concentrations were measured in spot urine samples (=118) from first-trimester pregnant women and in prepared tea infusions made with deionised water from 33 brand teas and 57 loose-tea products, as determined by the direct method of using a fluoride-selective electrode.

Results: The fluoride concentration in the local drinking water supplies ranged from 0.10 to 0.18 mg/L, and the creatinine-adjusted MUF ranged from 0.09 to 1.57 mg/L. Seventeen per cent of the women were daily tea drinkers, and their MUFs were higher than those with no consumption (=0.002). The fluoride concentration from tea bags ranged from 0.34 to 2.67 mg/L, while loose teas showed 0.72-4.50 mg/L (black), 0.56-1.58 mg/L (oolong), 1.28-1.50 mg/L (green), and 0.33-1.17 mg/L (white tea).

Conclusions:
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http://dx.doi.org/10.1177/1403494821990284DOI Listing
February 2021

Exposure to perfluoroalkyl substances during fetal life and hospitalization for infectious disease in childhood: A study among 1,503 children from the Odense Child Cohort.

Environ Int 2021 04 25;149:106395. Epub 2021 Jan 25.

Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark.

Introduction: The immunosuppressive properties of PFASs are widely recognized. Early-life exposure to PFAS has been linked to reduced immune response to childhood vaccinations and increased rates of common infectious diseases, but implications for hospitalizations are unclear.

Objectives: To investigate the association between maternal serum concentrations of five PFASs during pregnancy and the child's rate of hospitalization due to common infectious diseases between birth and 4 years of age.

Methods: Serum samples from first trimester pregnant women from the Odense Child Cohort (OCC) collected in 2010-2012 were analyzed for concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and three other PFASs. Data on child hospitalizations with an ICD-10 code for infectious disease was obtained from the Danish National Patient Register. The following were identified: upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), gastrointestinal infections (GI), and other infections. The Andersen-Gill Cox proportional hazard model for recurrent events was used to investigate the association between PFAS exposure and hospitalizations. The resulting estimates were hazard ratios (HRs), which express the relative change in the instantaneous risk of hospitalization with a doubling in maternal PFAS concentration.

Results: A total of 1,503 mother-child pairs were included, and 26% of the children were hospitalized at least once for infectious disease. A doubling in maternal PFOS concentration was associated with a 23% increase in the risk of hospitalization due to any infection (HR: 1.23 (95% CI: 1.05, 1.44). There was indication of an interaction between child sex and PFOS (p = 0.07) and PFDA (p = 0.06), although in opposite directions. Further, every doubling of PFOA or PFOS increased the risk of LRTI by 27% (HR: 1.27 (1.01, 1.59)) and 54% (HR: 1.54 (1.11, 2.15)), respectively. Similar tendencies were seen for URTI and the group of other infections. For GIs, the opposite pattern of association was seen as HR's were consistently below 1 (PFOA, HR: 0.55 (0.32, 0.95)).

Discussion: We found an association between PFOS and the overall risk of infectious disease, and between PFOS and PFOA exposures and the risk of LRTI's. These results are in agreement with previous findings from the OCC, in which maternal PFOS and PFOA concentrations were positively associated with the number of days that the children experienced fever, thereby suggesting that PFOS and PFOA may affect the prevalence of both mild and more severe infectious diseases even in a rather low-exposed population.
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April 2021

Severity of COVID-19 at elevated exposure to perfluorinated alkylates.

PLoS One 2020 31;15(12):e0244815. Epub 2020 Dec 31.

The Department of Epidemiology, Statens Serum Institut, Copenhagen, Denmark.

Background: The course of coronavirus disease 2019 (COVID-19) seems to be aggravated by air pollution, and some industrial chemicals, such as the perfluorinated alkylate substances (PFASs), are immunotoxic and may contribute to an association with disease severity.

Methods: From Danish biobanks, we obtained plasma samples from 323 subjects aged 30-70 years with known SARS-CoV-2 infection. The PFAS concentrations measured at the background exposures included five PFASs known to be immunotoxic. Register data was obtained to classify disease status, other health information, and demographic variables. We used ordered logistic regression analyses to determine associations between PFAS concentrations and disease outcome.

Results: Plasma-PFAS concentrations were higher in males, in subjects with Western European background, and tended to increase with age, but were not associated with the presence of chronic disease. Of the study population, 108 (33%) had not been hospitalized, and of those hospitalized, 53 (16%) had been in intensive care or were deceased. Among the five PFASs considered, perfluorobutanoic acid (PFBA) showed an unadjusted odds ratio (OR) of 2.19 (95% confidence interval, CI, 1.39-3.46) for increasing severities of the disease. Among those hospitalized, the fully adjusted OR for getting into intensive care or expiring was 5.18 (1.29, 20.72) when based on plasma samples obtained at the time of diagnosis or up to one week before.

Conclusions: Measures of individual exposures to immunotoxic PFASs included short-chain PFBA known to accumulate in the lungs. Elevated plasma-PFBA concentrations were associated with an increased risk of a more severe course of COVID-19. Given the low background exposure levels in this study, the role of exposure to PFASs in COVID-19 needs to be ascertained in populations with elevated exposures.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774856PMC
January 2021

Human Health and Ocean Pollution.

Ann Glob Health 2020 12 3;86(1):151. Epub 2020 Dec 3.

Nigerian Institute for Medical Research, Lagos, NG.

Background: Pollution - unwanted waste released to air, water, and land by human activity - is the largest environmental cause of disease in the world today. It is responsible for an estimated nine million premature deaths per year, enormous economic losses, erosion of human capital, and degradation of ecosystems. Ocean pollution is an important, but insufficiently recognized and inadequately controlled component of global pollution. It poses serious threats to human health and well-being. The nature and magnitude of these impacts are only beginning to be understood.

Goals: (1) Broadly examine the known and potential impacts of ocean pollution on human health. (2) Inform policy makers, government leaders, international organizations, civil society, and the global public of these threats. (3) Propose priorities for interventions to control and prevent pollution of the seas and safeguard human health.

Methods: Topic-focused reviews that examine the effects of ocean pollution on human health, identify gaps in knowledge, project future trends, and offer evidence-based guidance for effective intervention.

Environmental Findings: Pollution of the oceans is widespread, worsening, and in most countries poorly controlled. It is a complex mixture of toxic metals, plastics, manufactured chemicals, petroleum, urban and industrial wastes, pesticides, fertilizers, pharmaceutical chemicals, agricultural runoff, and sewage. More than 80% arises from land-based sources. It reaches the oceans through rivers, runoff, atmospheric deposition and direct discharges. It is often heaviest near the coasts and most highly concentrated along the coasts of low- and middle-income countries. Plastic is a rapidly increasing and highly visible component of ocean pollution, and an estimated 10 million metric tons of plastic waste enter the seas each year. Mercury is the metal pollutant of greatest concern in the oceans; it is released from two main sources - coal combustion and small-scale gold mining. Global spread of industrialized agriculture with increasing use of chemical fertilizer leads to extension of Harmful Algal Blooms (HABs) to previously unaffected regions. Chemical pollutants are ubiquitous and contaminate seas and marine organisms from the high Arctic to the abyssal depths.

Ecosystem Findings: Ocean pollution has multiple negative impacts on marine ecosystems, and these impacts are exacerbated by global climate change. Petroleum-based pollutants reduce photosynthesis in marine microorganisms that generate oxygen. Increasing absorption of carbon dioxide into the seas causes ocean acidification, which destroys coral reefs, impairs shellfish development, dissolves calcium-containing microorganisms at the base of the marine food web, and increases the toxicity of some pollutants. Plastic pollution threatens marine mammals, fish, and seabirds and accumulates in large mid-ocean gyres. It breaks down into microplastic and nanoplastic particles containing multiple manufactured chemicals that can enter the tissues of marine organisms, including species consumed by humans. Industrial releases, runoff, and sewage increase frequency and severity of HABs, bacterial pollution, and anti-microbial resistance. Pollution and sea surface warming are triggering poleward migration of dangerous pathogens such as the species. Industrial discharges, pharmaceutical wastes, pesticides, and sewage contribute to global declines in fish stocks.

Human Health Findings: Methylmercury and PCBs are the ocean pollutants whose human health effects are best understood. Exposures of infants to these pollutants through maternal consumption of contaminated seafood can damage developing brains, reduce IQ and increase children's risks for autism, ADHD and learning disorders. Adult exposures to methylmercury increase risks for cardiovascular disease and dementia. Manufactured chemicals - phthalates, bisphenol A, flame retardants, and perfluorinated chemicals, many of them released into the seas from plastic waste - can disrupt endocrine signaling, reduce male fertility, damage the nervous system, and increase risk of cancer. HABs produce potent toxins that accumulate in fish and shellfish. When ingested, these toxins can cause severe neurological impairment and rapid death. HAB toxins can also become airborne and cause respiratory disease. Pathogenic marine bacteria cause gastrointestinal diseases and deep wound infections. With climate change and increasing pollution, risk is high that infections, including cholera, will increase in frequency and extend to new areas. All of the health impacts of ocean pollution fall disproportionately on vulnerable populations in the Global South - environmental injustice on a planetary scale.

Conclusions: Ocean pollution is a global problem. It arises from multiple sources and crosses national boundaries. It is the consequence of reckless, shortsighted, and unsustainable exploitation of the earth's resources. It endangers marine ecosystems. It impedes the production of atmospheric oxygen. Its threats to human health are great and growing, but still incompletely understood. Its economic costs are only beginning to be counted.Ocean pollution can be prevented. Like all forms of pollution, ocean pollution can be controlled by deploying data-driven strategies based on law, policy, technology, and enforcement that target priority pollution sources. Many countries have used these tools to control air and water pollution and are now applying them to ocean pollution. Successes achieved to date demonstrate that broader control is feasible. Heavily polluted harbors have been cleaned, estuaries rejuvenated, and coral reefs restored.Prevention of ocean pollution creates many benefits. It boosts economies, increases tourism, helps restore fisheries, and improves human health and well-being. It advances the Sustainable Development Goals (SDG). These benefits will last for centuries.

Recommendations: World leaders who recognize the gravity of ocean pollution, acknowledge its growing dangers, engage civil society and the global public, and take bold, evidence-based action to stop pollution at source will be critical to preventing ocean pollution and safeguarding human health.Prevention of pollution from land-based sources is key. Eliminating coal combustion and banning all uses of mercury will reduce mercury pollution. Bans on single-use plastic and better management of plastic waste reduce plastic pollution. Bans on persistent organic pollutants (POPs) have reduced pollution by PCBs and DDT. Control of industrial discharges, treatment of sewage, and reduced applications of fertilizers have mitigated coastal pollution and are reducing frequency of HABs. National, regional and international marine pollution control programs that are adequately funded and backed by strong enforcement have been shown to be effective. Robust monitoring is essential to track progress.Further interventions that hold great promise include wide-scale transition to renewable fuels; transition to a circular economy that creates little waste and focuses on equity rather than on endless growth; embracing the principles of green chemistry; and building scientific capacity in all countries.Designation of Marine Protected Areas (MPAs) will safeguard critical ecosystems, protect vulnerable fish stocks, and enhance human health and well-being. Creation of MPAs is an important manifestation of national and international commitment to protecting the health of the seas.
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http://dx.doi.org/10.5334/aogh.2831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731724PMC
December 2020

Endocrine disrupting chemicals and COVID-19 relationships: A computational systems biology approach.

Environ Int 2021 12 30;157:106232. Epub 2020 Oct 30.

Université de Paris, T3S, Inserm UMR S-1124, F-75006 Paris, France. Electronic address:

Background: Patients at high risk of severe forms of COVID-19 frequently suffer from chronic diseases, but other risk factors may also play a role. Environmental stressors, such as endocrine disrupting chemicals (EDCs), can contribute to certain chronic diseases and might aggravate the course of COVID-19.

Objectives: To explore putative links between EDCs and COVID-19 severity, an integrative systems biology approach was constructed and applied.

Methods: As a first step, relevant data sets were compiled from major data sources. Biological associations of major EDCs to proteins were extracted from the CompTox database. Associations between proteins and diseases known as important COVID-19 comorbidities were obtained from the GeneCards and DisGeNET databases. Based on these data, we developed a tripartite network (EDCs-proteins-diseases) and used it to identify proteins overlapping between the EDCs and the diseases. Signaling pathways for common proteins were then investigated by over-representation analysis.

Results: We found several statistically significant pathways that may be dysregulated by EDCs and that may also be involved in COVID-19 severity. The Th17 and the AGE/RAGE signaling pathways were particularly promising.

Conclusions: Pathways were identified as possible targets of EDCs and as contributors to COVID-19 severity, thereby highlighting possible links between exposure to environmental chemicals and disease development. This study also documents the application of computational systems biology methods as a relevant approach to increase the understanding of molecular mechanisms linking EDCs and human diseases, thereby contributing to toxicology prediction.
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http://dx.doi.org/10.1016/j.envint.2020.106232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831776PMC
December 2021

A Benchmark Dose Analysis for Maternal Pregnancy Urine-Fluoride and IQ in Children.

medRxiv 2020 Nov 4. Epub 2020 Nov 4.

Department of Biostatistics, University of Copenhagen, Denmark.

As a safe exposure level for fluoride in pregnancy has not been established, we used data from two prospective studies for benchmark dose modeling. We included mother-child pairs from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort in Mexico and the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort in Canada. Children were assessed for IQ at age 4 (n=211) and between 6 and 12 years (n=287) in the ELEMENT cohort and between ages 3 and 4 years (n=512) in the MIREC cohort. We calculated covariate-adjusted regression coefficients and their standard errors to explore the concentration-effect function for maternal urinary fluoride with children's IQ, including possible sex-dependence. Assuming a benchmark response of 1 IQ point, we derived benchmark concentrations (BMCs) of maternal urinary fluoride and benchmark concentration levels (BMCLs). No deviation from linearity was detected from the results of the two studies. Using a linear slope, the BMC for maternal urinary fluoride associated with a 1-point decrease in IQ scores of preschool-aged boys and girls was 0.29 mg/L (BMCL, 0.18 mg/L). The BMC was 0.30 mg/L (BMCL, 0.19 mg/L) when pooling the IQ scores from the older ELEMENT children and the MIREC cohort. Boys showed slightly lower BMC values compared with girls. Relying on two prospective studies, maternal urine-fluoride exposure at levels commonly occurring in the general population, the joint data showed BMCL results about 0.2 mg/L. These results can be used to guide decisions on preventing excess fluoride exposure in vulnerable populations.
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http://dx.doi.org/10.1101/2020.10.31.20221374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654913PMC
November 2020

PFAS concentration during pregnancy in relation to cardiometabolic health and birth outcomes.

Environ Res 2021 01 8;192:110287. Epub 2020 Oct 8.

Harvard TH Chan School of Public Health, Boston, MA, USA; University of Southern Denmark, Odense, Denmark.

Introduction: Poly- and perfluoroalkyl substances (PFAS) are persistent organic pollutants with pervasive exposure and suspected associations with metabolic abnormalities and adverse pregnancy outcomes. The goal of the present study was to examine the relationship between serum-PFAS concentrations measured in late pregnancy with relevant outcomes.

Methods: The study sample included 433 pregnant women enrolled in the Vanguard Pilot Study of the National Children's Study. Six PFAS were measured in primarily third trimester serum, as well as fasting insulin, total cholesterol, and triglycerides. The PFAS were examined in quartiles in relation to serum biomarkers, gestational age at birth and birth weight standardized for gestational age using multivariable-adjusted regression models.

Results: Over 98% of the study population had detectable concentrations of four of the PFAS, and concentrations varied by race/ethnicity. Total cholesterol was positively associated with PFDA, PFNA, and PFOS, and triglycerides with PFDA, PFNA, PFOS, and PFOA, but PFAS were not associated with fasting insulin in adjusted models. Only PFNA was associated with an increased odds of birth at <37 weeks gestation. PFAS were generally not associated with birth weight, though PFHxS was associated with the first quartile of birth weight among males only.

Conclusions: This study of pregnant U.S. women supports the ubiquitous exposure to PFAS and positive associations between PFAS exposure with serum-lipid concentrations. PFAS were largely unassociated with gestational age at birth and birth weight, though PFNA was associated with preterm birth. The results support the vulnerability to PFAS exposure of pregnancy.
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http://dx.doi.org/10.1016/j.envres.2020.110287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736328PMC
January 2021

Serum Perfluoroalkyl Substances, Vaccine Responses, and Morbidity in a Cohort of Guinea-Bissau Children.

Environ Health Perspect 2020 08 10;128(8):87002. Epub 2020 Aug 10.

Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark.

Background: Perfluoroalkyl substances (PFAS) are a group of widely used persistent chemicals with suspected immunotoxic effects.

Objectives: The present study aimed to examine the association between infant PFAS exposure and antibody responses to measles vaccination as well as morbidity in a low-income country.

Methods: In a randomized controlled trial, children from Guinea-Bissau, West Africa, were followed from inclusion (4-7 months of age) through 2 years of age. Half the children received two measles vaccinations (at inclusion and at 9 months of age), and the other half received only one (at 9 months of age). In a subset of 237 children, six PFAS were quantified in serum at inclusion, and measles antibody concentrations were assessed at inclusion and at approximately 9 months and 2 years of age. At inclusion and at the 9-month visit, mothers were interviewed about infant morbidity.

Results: All but one child had detectable serum concentrations of all six PFAS, although levels were lower than seen elsewhere. A doubling in perfluorooctane sulfonic acid (PFOS) and perfluorodecanoic acid (PFDA) were associated with 21% (95% CI: 2, 37%) and 25% (95% CI: 1, 43%), respectively, lower measles antibody concentrations at the 9-month visit among the children who had received a measles vaccine at inclusion. Elevated serum PFAS concentrations were also associated with reduced prevaccination measles antibody concentrations and increased morbidity.

Discussion: The present study documents that PFAS exposure has reached West Africa and that infants show PFAS-associated increases in morbidity and decreases in measles-specific antibody concentrations before and after vaccination. These findings support the evidence on PFAS immunotoxicity at comparatively low serum concentrations. https://doi.org/10.1289/EHP6517.
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http://dx.doi.org/10.1289/EHP6517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416537PMC
August 2020

Endocrine disrupting chemicals and COVID-19 relationships: a computational systems biology approach.

medRxiv 2020 Jul 15. Epub 2020 Jul 15.

Université de Paris, T3S, Inserm UMR S-1124, F-75006 Paris, France.

Background: Patients at high risk of severe forms of COVID-19 frequently suffer from chronic diseases, but other risk factors may also play a role. Environmental stressors, such as endocrine disrupting chemicals (EDCs), can contribute to certain chronic diseases and might aggravate the course of COVID-19.

Objectives: To explore putative links between EDCs and COVID-19 severity, an integrative systems biology approach was constructed and applied.

Methods: As a first step, relevant data sets were compiled from major data sources. Biological associations of major EDCs to proteins were extracted from the CompTox database. Associations between proteins and diseases known as important COVID-19 comorbidities were obtained from the GeneCards and DisGeNET databases. Based on these data, we developed a tripartite network (EDCs-proteins-diseases) and used it to identify proteins overlapping between the EDCs and the diseases. Signaling pathways for common proteins were then investigated by over-representation analysis.

Results: We found several statistically significant pathways that may be dysregulated by EDCs and that may also be involved in COVID-19 severity. The Th17 and the AGE/RAGE signaling pathways were particularly promising.

Conclusions: Pathways were identified as possible targets of EDCs and as contributors to COVID-19 severity, thereby highlighting possible links between exposure to environmental chemicals and disease development. This study also documents the application of computational systems biology methods as a relevant approach to increase the understanding of molecular mechanisms linking EDCs and human diseases, thereby contributing to toxicology prediction.
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http://dx.doi.org/10.1101/2020.07.10.20150714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373141PMC
July 2020

Correction to: Response to Juberg et al.

Environ Health 2020 Jul 8;19(1):76. Epub 2020 Jul 8.

Department of Public Health, University of Southern Denmark, Odense, Denmark.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12940-020-00633-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341632PMC
July 2020

Prenatal Exposures to Perfluoroalkyl Acids and Associations with Markers of Adiposity and Plasma Lipids in Infancy: An Odense Child Cohort Study.

Environ Health Perspect 2020 07 6;128(7):77001. Epub 2020 Jul 6.

Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark.

Background: Perfluoroalkyl acids (PFAA) are repellants that cross the placental barrier, enabling interference with fetal programming. Maternal PFAA concentrations have been associated with offspring obesity and dyslipidemia in childhood and adulthood, but this association has not been studied in infancy.

Objectives: We investigated associations between maternal PFAA concentrations and repeated markers of adiposity and lipid metabolism in infancy.

Methods: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAA: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured in 649 women. Offspring were examined at birth () and at 3 months () and 18 months () of age. Total cholesterol, LDL, HDL, and triglyceride were evaluated at 3 months () and 18 months () of age. Mixed effects linear regression models estimated associations between PFAA and standardized (SDS) body mass index (BMI), ponderal index, and waist circumference. Associations between PFAA and body fat% (BF%) and plasma lipids SDS at 3 months and 18 months of age were investigated with linear regression models.

Results: PFNA and PFDA were associated with higher BMI SDS [adjusted ; 95% confidence interval (CI): 0.03, 0.49 and ; 95% CI: , 1.19, respectively, for increases] and ponderal index SDS (; 95% CI: 0.13, 0.59 and ; 95% CI: 0.40, 1.64, respectively) at 3 and 18 months of age (pooled) in girls. Corresponding estimates for boys were closer to the null but not significantly different from estimates for girls. In boys and girls (combined), PFNA and PFDA were associated with BF% at age 3 months (for PFDA, ; 95% CI: 0.04, 0.75), and PFDA was associated with total cholesterol SDS at 18 months (; 95% CI: 0.08, 2.03) ().

Discussion: Prenatal PFAA were positively associated with longitudinal markers of adiposity and higher total cholesterol in infancy. These findings deserve attention in light of rising rates of childhood overweight conditions and dyslipidemia. https://doi.org/10.1289/EHP5184.
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http://dx.doi.org/10.1289/EHP5184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338787PMC
July 2020

Reducing exposure to high levels of perfluorinated compounds in drinking water improves reproductive outcomes: evidence from an intervention in Minnesota.

Environ Health 2020 04 22;19(1):42. Epub 2020 Apr 22.

Department of Agricultural and Resource Economics, University of California Berkeley, Berkeley, CA, 94720, USA.

Background: Per- and polyfluoroalkyl substances (PFASs) have been detected in drinking water supplies around the world and are the subject of intense regulatory debate. While they have been associated with several illnesses, their effects on reproductive outcomes remains uncertain.

Methods: We analyzed birth outcomes in the east Minneapolis-St. Paul metropolitan area from 2002 to 2011, where a portion of the population faced elevated exposure to PFASs due to long-term contamination of drinking water supplies from industrial waste disposal. Installation of a water filtration facility in the highly contaminated city of Oakdale, MN at the end of 2006 resulted in a sharp decrease in exposure to PFASs, creating a "natural experiment". Using a difference-in-differences approach, we compare the changes in birth outcomes before and after water filtration in Oakdale to the changes over the same period in neighboring communities where the treatment of municipal water remained constant.

Results: Average birth weight and average gestational age were statistically significantly lower in the highly exposed population than in the control area prior to filtration of municipal water supply. The highly exposed population faced increased odds of low birth weight (adjusted odds ratio 1.36, 95% CI 1.25-1.48) and pre-term birth (adjusted odds ratio 1.14, 95% CI 1.09-1.19) relative to the control before filtration, and these differences moderated after filtration. The general fertility rate was also significantly lower in the exposed population (incidence rate ratio 0.73, 95% CI 0.69-0.77) prior to filtration and appeared to be rebounding post-2006.

Conclusions: Our findings provide evidence of a causal relationship between filtration of drinking water containing high levels of exposure to PFASs and improved reproductive outcomes.
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http://dx.doi.org/10.1186/s12940-020-00591-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178962PMC
April 2020

Prenatal exposure to perfluorodecanoic acid is associated with lower circulating concentration of adrenal steroid metabolites during mini puberty in human female infants. The Odense Child Cohort.

Environ Res 2020 03 31;182:109101. Epub 2019 Dec 31.

Department of Environmental Medicine, University of Southern Denmark, J.B. Winsløws Vej 17A, 5000, Odense C, Denmark; Odense Child Cohort, Hans Christian Andersen Children's Hospital, Odense University Hospital, Søndre Blvd. 29, 5000, Odense C, Denmark; Odense Patient Data Explorative Network (OPEN), University of Southern, J. B. Winsløws Vej 9a, Odense C, Denmark.

Background: Fetal programming of the endocrine system may be affected by exposure to perfluoroalkyl substances (PFAAs), as they easily cross the placental barrier. In vitro studies suggest that PFAAs may disrupt steroidogenesis. "Mini puberty" refers to a transient surge in circulating androgens, androgen precursors, and gonadotropins in infant girls and boys within the first postnatal months. We hypothesize that prenatal PFAA exposure may decrease the concentrations of androgens in mini puberty.

Objectives: To investigate associations between maternal serum PFAA concentrations in early pregnancy and serum concentrations of androgens, their precursors, and gonadotropins during mini puberty in infancy.

Methods: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAAs: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured at median gestational week 12 (IQR: 10, 15) in 1628 women. Among these, offspring serum concentrations of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), androstenedione, 17-hydroxyprogesterone (17-OHP), testosterone, luteinizing (LH) and follicle stimulating hormones (FSH) were measured in 373 children (44% girls; 56% boys) at a mean age of 3.9 (±0.9 SD) months. Multivariate linear regression models were performed to estimate associations.

Results: A two-fold increase in maternal PFDA concentration was associated with a reduction in DHEA concentration by -19.6% (95% CI: -32.9%, -3.8%) in girls. In girls, also, the androstenedione and DHEAS concentrations were decreased, albeit non-significantly (p < 0.11), with a two-fold increase in maternal PFDA concentration. In boys, no significant association was found between PFAAs and concentrations of androgens, their precursors, and gonadotropins during mini puberty.

Conclusion: Prenatal PFDA exposure was associated with significantly lower serum DHEA concentrations and possibly also with lower androstenedione and DHEAS concentrations in female infants at mini puberty. The clinical significance of these findings remains to be elucidated.
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http://dx.doi.org/10.1016/j.envres.2019.109101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117803PMC
March 2020

Joint and independent neurotoxic effects of early life exposures to a chemical mixture: A multi-pollutant approach combining ensemble learning and g-computation.

Environ Epidemiol 2019 Oct;3(5)

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Background: Exposure to mercury (Hg) is associated with adverse developmental effects. However, Hg occurs with a multitude of chemicals. We assessed the associations of developmental exposure to multiple pollutants with children's neurodevelopment using a novel approach.

Methods: Hg, polychlorinated biphenyls (PCBs), and perfluoroalkyl substances were measured in maternal and children's blood at 5-years (n=449 and 419). At 7-years, children were administered Boston Naming Test (BNT) and the Strengths and Difficulties Questionnaire (SDQ). We used the G-formula combined with SuperLearner to estimate independent and joint effects of chemicals at both ages. We constructed flexible exposure-response relationships and assessed interactions.

Results: Most chemicals showed negative relationships with BNT scores. An inter-quartile range (IQR) increase in maternal Hg and perfluorooctanoic acid (PFOA) was associated with 0.15 standard deviation [SD] (95% Confidence Interval [CI]: -0.29,-0.03) and 0.14 SD (95%CI: -0.26,-0.05) lower scores in BNT, whereas a joint IQR increase in the mixture of chemicals was associated with 0.48 SD (95%CI: -0.69,-0.25) lower scores in BNT. An IQR increase in PFOA was associated with 0.11 SD (95%CI: 0.02,0.26) higher total SDQ difficulties scores. Maternal ∑PCBs concentrations were associated with lower SDQ scores (β=-0.09 SD; 95%CI: -0.19,0), whereas 5-years ∑PCBs showed a negative association (β=-0.09 SD; 95%CI: -0.21,0). Finally, a joint IQR increase in the mixture was associated with 0.22 SD (95%CI: 0.04,0.4) higher SDQ scores.

Conclusions: Using a novel statistical approach, we confirmed associations between prenatal mercury exposure and lower cognitive function. The potential developmental effects of PFASs need additional attention.
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http://dx.doi.org/10.1097/ee9.0000000000000063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015154PMC
October 2019

Associations of Perfluoroalkyl substances with blood lipids and Apolipoproteins in lipoprotein subspecies: the POUNDS-lost study.

Environ Health 2020 01 13;19(1). Epub 2020 Jan 13.

Department of Nutrition, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA, 02115, USA.

Background: The associations of perfluoroalkyl substance (PFAS) exposure with blood lipids and lipoproteins are inconsistent, and existing studies did not account for metabolic heterogeneity of lipoprotein subspecies. This study aimed to examine the associations between plasma PFAS concentrations and lipoprotein and apolipoprotein subspecies.

Methods: The study included 326 men and women from the 2-year Prevention of Obesity Using Novel Dietary Strategies (POUNDS) Lost randomized trial. Five PFASs, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), were measured in plasma at baseline. For lipoprotein and apolipoprotein subspecies, total plasma was fractionated first by apolipoprotein (apo) C-III content and then by density. Each subfraction was then measured for apoB, apoC-III, and apoE concentrations, as well as triglyceride and cholesterol contents, both at baseline and at 2 years.

Results: For lipids and apolipoproteins in total plasma at baseline, elevated plasma PFAS concentrations were significantly associated with higher apoB and apoC-III concentrations, but not with total cholesterol or triglycerides. After multivariate adjustment of lifestyle factors, lipid-lowering medication use, and dietary intervention groups, PFAS concentrations were primarily associated with lipids or apolipoprotein concentrations in intermediate-to-low density lipoprotein (IDL + LDL) and high-density lipoprotein (HDL) that contain apoC-III. Comparing the highest and lowest tertiles of PFOA, the least-square means (SE) (mg/dl) were 4.16 (0.4) vs 3.47 (0.4) for apoB (P trend = 0.04), 2.03 (0.2) vs 1.66 (0.2) for apoC-III (P trend = 0.04), and 8.4 (0.8) vs 6.8 (0.8) for triglycerides (P trend = 0.03) in IDL + LDL fraction that contains apoC-III. For HDL that contains apoC-III, comparing the highest and lowest tertiles of PFOA, the least-square means (SE) (mg/dl) of apoC-III were 11.9 (0.7) vs 10.4 (0.7) (P trend = 0.01). In addition, elevated PFNA and PFDA concentrations were also significantly associated with higher concentrations of apoE in HDL that contains apoC-III (P trend< 0.01). Similar patterns of associations were demonstrated between baseline PFAS concentrations and lipoprotein subspecies measured at 2 years. Baseline PFAS levels were not associated with changes in lipoprotein subspecies during the intervention.

Conclusions: Our results suggest that plasma PFAS concentrations are primarily associated with blood lipids and apolipoproteins in subspecies of IDL, LDL, and HDL that contain apoC-III, which are associated with elevated cardiovascular risk in epidemiological studies. Future studies of PFAS-associated cardiovascular risk should focus on lipid subfractions.
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http://dx.doi.org/10.1186/s12940-020-0561-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958662PMC
January 2020

What is useful research? The good, the bad, and the stable.

Environ Health 2020 01 7;19(1). Epub 2020 Jan 7.

Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark.

A scientific journal like Environmental Health strives to publish research that is useful within the field covered by the journal's scope, in this case, public health. Useful research is more likely to make a difference. However, in many, if not most cases, the usefulness of an article can be difficult to ascertain until after its publication. Although replication is often thought of as a requirement for research to be considered valid, this criterion is retrospective and has resulted in a tendency toward inertia in environmental health research. An alternative viewpoint is that useful work is "stable", i.e., not likely to be soon contradicted. We present this alternative view, which still relies on science being consensual, although pointing out that it is not the same as replicability, while not in contradiction. We believe that viewing potential usefulness of research reports through the lens of stability is a valuable perspective.
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http://dx.doi.org/10.1186/s12940-019-0556-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945512PMC
January 2020
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