Emerging evidence suggests that perfluoroalkyl substances (PFASs) are endocrine disruptors and may contribute to the etiology of type 2 diabetes (T2D), but this hypothesis needs to be clarified in ...prospective human studies.
Our objective was to examine the associations between PFAS exposures and subsequent incidence of T2D in the Nurses' Health Study II (NHSII). In addition, we aimed to evaluate potential demographic and lifestyle determinants of plasma PFAS concentrations.
A prospective nested case-control study of T2D was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in 1995-2000 (mean±SD): 45.3±4.4 y) of age. We identified and ascertained 793 incident T2D cases through 2011 (mean±SD) years of follow-up: 6.7±3.7 y). Each case was individually matched to a control (on age, month and fasting status at sample collection, and menopausal status and hormone replacement therapy). Plasma concentrations of five major PFASs, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonate, perfluorononanoic acid, and perfluorodecanoic acid were measured. Odds ratios (ORs) of T2D by PFAS tertiles were estimated by conditional logistic regression.
Shorter breastfeeding duration and higher intake of certain foods, such as seafood and popcorn, were significantly associated with higher plasma concentrations of PFASs among controls. After multivariate adjustment for T2D risk factors, including body mass index, family history, physical activity, and other covariates, higher plasma concentrations of PFOS and PFOA were associated with an elevated risk of T2D. Comparing extreme tertiles of PFOS or PFOA, ORs were 1.62 (95% CI: 1.09, 2.41;
=0.02) and 1.54 (95% CI: 1.04, 2.28;
=0.03), respectively. Other PFASs were not clearly associated with T2D risk.
Background exposures to PFASs in the late 1990s were associated with higher T2D risk during the following years in a prospective case-control study of women from the NHSII. These findings support a potential diabetogenic effect of PFAS exposures. https://doi.org/10.1289/EHP2619.
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.
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.
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.
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.
Per- and polyfluoroalkyl substances (PFASs) are a growing public health concern. Some longer chain PFASs bioaccumulate and many compounds persist in the environment for long time periods. Recent ...studies have established their ability to pass through placenta, yet data on the transplacental transfer efficiency and partitioning of short and long chain PFASs in blood matrices are limited.
To assess predictors of the partitioning of 17 PFAS compounds detected in the maternal serum, umbilical cord serum and whole cord blood samples from matched mother-newborn pairs from two Faroe Islands cohorts.
We examined 151 mother-newborn pairs from two successive Faroese birth cohorts. Cord:maternal serum (transplacental transfer) and serum:whole cord blood (blood partitioning) ratios were estimated for 17 PFAS compounds. We also examined the relationships of these ratios with maternal, newborns', and physico-chemical properties using multivariable regression analyses.
Moderate to high correlations were observed between maternal and cord serum PFAS concentrations (ρ: 0.41 to 0.95), indicating significant transfer of these compounds from the mother to the fetus. Median transplacental transfer ratios were generally below 1, except for perfluorooctane sulfonamide (FOSA), and ranged between 0.36 for perfluorodecanoate (PFDA) and perfluoroundecanoate (PFUnDA) and 1.21 for FOSA. Most PFASs exhibited a preference to the serum component of the blood, except FOSA and perfluoroheptanoate (PFHpA), with blood partitioning ratios ranging from 0.36 for FOSA to 2.75 for PFUnDA. Both the functional groups and carbon chain length of different PFASs were important predictors of transplacental transfer and blood partitioning. We observed a U-shaped relationship between transplacental transfer ratios and carbon chain length for perfluorocarboxylates and perfluorosulfonates. Importantly, gestational diabetes was also a strong predictor of transplacental transfer ratios, with significantly higher transfer in mothers with gestational diabetes.
Our findings provide a better understanding of the transplacental transfer and blood partitioning of a large number of PFAS compounds. Results elucidate the importance of chemical structure for future risk assessments and choice of appropriate blood matrices for measurement of PFAS compounds.
•Per- and polyfluoroalkyl substances (PFASs) are a growing public health concern and can cross the placenta•Data on transplacental transfer efficiency and partitioning of short and long chain PFASs in blood matrices are limited.•We investigated predictors of transplacental transfer and blood partitioning of 17 PFAS in 151 mother-newborn pairs.•We observed significantly higher transfer in mothers with gestational diabetes.•Functional groups and carbon chain length were important predictors of transplacental transfer and blood partitioning.
CONTEXT Perfluorinated compounds (PFCs) have emerged as important food contaminants. They cause immune suppression in a rodent model at serum concentrations similar to those occurring in the US ...population, but adverse health effects of PFC exposure are poorly understood. OBJECTIVE To determine whether PFC exposure is associated with antibody response to childhood vaccinations. DESIGN, SETTING, AND PARTICIPANTS Prospective study of a birth cohort from the National Hospital in the Faroe Islands. A total of 656 consecutive singleton births were recruited during 1997-2000, and 587 participated in follow-up through 2008. MAIN OUTCOME MEASURES Serum antibody concentrations against tetanus and diphtheria toxoids at ages 5 and 7 years. RESULTS Similar to results of prior studies in the United States, the PFCs with the highest serum concentrations were perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Among PFCs in maternal pregnancy serum, PFOS showed the strongest negative correlations with antibody concentrations at age 5 years, for which a 2-fold greater concentration of exposure was associated with a difference of −39% (95% CI, −55% to −17%) in the diphtheria antibody concentration. PFCs in the child's serum at age 5 years showed uniformly negative associations with antibody levels, especially at age 7 years, except that the tetanus antibody level following PFOS exposure was not statistically significant. In a structural equation model, a 2-fold greater concentration of major PFCs in child serum was associated with a difference of −49% (95% CI, −67% to −23%) in the overall antibody concentration. A 2-fold increase in PFOS and PFOA concentrations at age 5 years was associated with odds ratios between 2.38 (95% CI, 0.89 to 6.35) and 4.20 (95% CI, 1.54 to 11.44) for falling below a clinically protective level of 0.1 IU/mL for tetanus and diphtheria antibodies at age 7 years. CONCLUSION Elevated exposures to PFCs were associated with reduced humoral immune response to routine childhood immunizations in children aged 5 and 7 years.
•PFAS exposure associated with systolic and diastolic blood pressure in pregnancy.•No clear associations between PFAS exposure and PE or GH were found.•Blood pressure increase was small but at a ...population level this may increase hypertension.•This has potential long term health implications for both the mother and the child.
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.
To study the association between PFAS exposure in early pregnancy and maternal BP trajectories in pregnancy, gestational hypertension and preeclampsia.
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.
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.
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.
The aim of this study was to evaluate the effect of genetic variations in OCT1, OCT2, MATE1, MATE 2, and PMAT on the trough steady-state plasma concentration of metformin and hemoglobin A1c (Hb1Ac).
...The South Danish Diabetes Study was a 2 x 2 x 2 factorial, prospective, randomized, double-blind, placebo-controlled, multicentre study. One hundred and fifty-nine patients received 1 g of metformin, twice daily continuously, and 415 repeated plasma metformin measurements were obtained after 3, 6, and 9 months of treatment.
The mean trough steady-state metformin plasma concentration was estimated to be 576 ng/ml (range, 54–4133 ng/ml, p = 0.55) and correlated to the number of reduced function alleles in OCT1 (none, one or two: 642, 542, 397 ng/ml; P = 0.001). The absolute decrease in Hb1Ac both initially and long term was also correlated to the number of reduced function alleles in OCT1 resulting in diminished pharmacodynamic effect of metformin after 6 and 24 months.
In a large cohort of type 2 diabetics, we either confirm or show for the first time: (a) an enormous (80-fold) variability in trough steady-state metformin plasma concentration, (b) OCT1 activity affects metformin steady-state pharmacokinetics, and (c) OCT1 genotype has a bearing on HbA1c during metformin treatment.
To evaluate whether clinical, radiographic or MRI findings are associated with long term risk for total knee arthroplasty (TKA) in persons with knee osteoarthritis.
We performed a follow-up analysis ...of 100 persons with knee osteoarthritis who participated in a clinical trial between 2000 and 2002. Clinical data as well as radiography and MRI of the inclusion knee were obtained in all participants. Data on TKA procedures were extracted from The Danish National Patient Register. Clinical, radiographic and MRI findings were analyzed for associations with subsequent TKA.
During a mean follow-up period of 15 years, 66% received a TKA in the included knee (target knee); 37% also received a TKA in the other knee. The degree of joint space narrowing was highly associated with subsequent TKA (adjusted odds ratio (OR) 5.0 (95% confidence interval (95% CI) 2.6 - 9.9)) as was a radiological sum score comprising joint space narrowing, osteophytes, subchondral sclerosis and cysts (adjusted OR 1.7 (95% CI 1.3 - 2.1)). MRI detected bone marrow lesions, synovitis and effusion were similarly associated with subsequent TKA with an adjusted OR of 2.3 (95% CI 1.3 - 4.0), 2.8 (95% CI 1.5 - 5.2) and 1.9 (95% CI 1.2 - 3.1), respectively. Increased body mass index (BMI) was not associated with subsequent TKA in the target knee but was associated with TKA in the other knee (OR 2.3 (95% CI 1.2 - 4.3).
Radiographic findings including joint space narrowing and MRI detected bone marrow lesions, synovitis and effusion were all significantly associated with the long term risk of TKA in persons with knee osteoarthritis.
•Prenatal perfluoroalkyl acid (PFAS) exposure increases the risk of hospitalization.•Maternal PFOS concentration was associated with higher risk of any infection.•Maternal PFOS and PFOA increased the ...risk of lower respiratory tract infections.
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.
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.
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.
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)).
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.
Abstract
The developmental toxicity of perfluorohexane sulfonate (PFHxS) is largely unknown despite widespread environmental contamination and presence in human serum, tissues and milk. To thoroughly ...investigate PFHxS toxicity in developing rats and to mimic a realistic human exposure situation, we examined a low dose close to human relevant PFHxS exposure, and combined the dose-response studies of PFHxS with a fixed dose of 12 environmentally relevant endocrine disrupting chemicals (EDmix). Two reproductive toxicity studies in time-mated Wistar rats exposed throughout gestation and lactation were performed. Study 1 included control, two doses of PFHxS, and two doses of PFHxS + EDmix (n = 5–7). Study 2 included control, 0.05, 5, or 25 mg/kg body weight/day PFHxS, EDmix-only, 0.05, 5, or 25 mg PFHxS/kg plus EDmix (n = 13–20). PFHxS caused no overt toxicity in dams and offspring but decreased male pup birth weight and slightly increased liver weights at high doses and in combination with the EDmix. A marked effect on T4 levels was seen in both dams and offspring, with significant reductions from 5 mg/kg/day. The EDmix caused antiandrogenic effects in male offspring, manifested as slight decreases in anogenital distance, increased nipple retention and reductions of the weight of epididymides, ventral prostrate, and vesicular seminalis. PFHxS can induce developmental toxicity and in addition results of the co-exposure studies indicated that PFHxS and the EDmix potentiate the effect of each other on various endpoints, despite their different modes of action. Hence, risk assessment may underestimate toxicity when mixture toxicity and background exposures are not taken into account.
Perfluorinated alkylate substances (PFASs) are highly persistent and may cause immunotoxic effects. PFAS-associated attenuated antibody responses to childhood vaccines may be affected by PFAS ...exposures during infancy, where breastfeeding adds to PFAS exposures. Of 490 members of a Faroese birth cohort, 275 and 349 participated in clinical examinations and provided blood samples at ages 18 months and 5 years. PFAS concentrations were measured at birth and at the clinical examinations. Using information on duration of breastfeeding, serum-PFAS concentration profiles during infancy were estimated. As outcomes, serum concentrations of antibodies against tetanus and diphtheria vaccines were determined at age 5. Data from a previous cohort born eight years earlier were available for pooled analyses. Pre-natal exposure showed inverse associations with the antibody concentrations five years later, with decreases by up to about 20% for each two-fold higher exposure, while associations for serum concentrations at ages 18 months and 5 years were weaker. Modeling of serum-PFAS concentration showed levels for age 18 months that were similar to those measured. Concentrations estimated for ages 3 and 6 months showed the strongest inverse associations with antibody concentrations at age 5 years, particularly for tetanus. Joint analyses showed statistically significant decreases in tetanus antibody concentrations by 19-29% at age 5 for each doubling of the PFAS exposure in early infancy. These findings support the notion that the developing adaptive immune system is particularly vulnerable to immunotoxicity during infancy. This vulnerability appears to be the greatest during the first 6 months after birth, where PFAS exposures are affected by breast-feeding.
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