A prospective nested case-control study of serum concentrations of per- and polyfluoroalkyl substances and aggressive prostate cancer risk.

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent organic pollutants detectable in the serum of most U.S. adults. Some studies of highly-exposed individuals have suggested an association between PFAS and prostate cancer, but evidence from population-based studies is limited. We investigated the association between pre-diagnostic serum PFAS concentrations and aggressive prostate cancer risk in a large prospective study. We measured pre-diagnostic serum concentrations of eight PFAS, including perfluorooctanoate (PFOA), for 750 aggressive prostate cancer cases and 750 individually matched controls within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We assessed the reproducibility of PFAS concentrations in serial samples collected up to six years apart among 60 controls using intraclass correlation coefficients (ICCs). Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with prostate cancer, adjusting for other PFAS and potential confounders. Concentrations of most PFAS were consistent (ICC>0.7) across the serial samples over time. We observed an inverse association between PFOA and aggressive prostate cancer (ORcontinuous = 0.79, 95% CI = 0.63, 0.99), but the association was limited to cases diagnosed ≤3 years after blood collection and became statistically non-significant for cases diagnosed with later follow-up (>3 years, ORcontinuous = 0.90, 95% CI = 0.79, 1.03). Other PFAS were not associated with aggressive prostate cancer risk. Although we cannot rule out an increased risk at higher levels, our findings from a population with PFAS serum concentrations comparable to the general population do not support an association with increased risk of aggressive prostate cancer.

[BCR-ABL1-positive myelodysplastic syndrome with neutropenia and anemia treated successfully with imatinib mesylate].

An 81-year-old female was referred to our hospital with progressive neutropenia and anemia of unknown etiology. We performed a bone marrow biopsy which was notable for hypercellularity, multinucleated megakaryocytes and hypo-granular neutrophils with 2.6% blasts. A diagnosis of myelodysplastic syndrome with multilineage dysplasia (MDS-MLD) was made. Karyotype analysis revealed a t (9;22)(q34;q11.2) BCR-ABL1 fusion with no additional chromosomal abnormalities. BCR-ABL1 was also detected in transcripts from peripheral blood cells as well as in polynuclear leukocytes via FISH. Within one year, her peripheral blood neutrophil count had declined to 403/µl; further analysis was notable for increasing dysplasia including enlarged platelets and hypo-granular neutrophils. Platelet counts gradually increased over time and reached 100×104/µl. A second bone marrow examination revealed similar cell morphology and the BCR-ABL1 translocation. Her condition deteriorated and blood transfusions were required. Treatment with low doses of the tyrosine kinase inhibitor (TKI), imatinib mesylate (100 mg), was initiated. Thereafter, both the neutropenia and anemia resolved gradually, platelet counts returned to normal levels, and dysplasia eventually disappeared. Detection of the BCR-ABL fusion in mRNA decreased to < 0.0007% (IS%) after 16 months of treatment. Several cases of BCR-ABL1-positive myelodysplastic syndrome treated with TKIs have been reported. Our results suggest that complete hematologic recovery in response to imatinib mesylate suggests a critical role for the BCR-ABL1 fusion in the pathogenesis of this disease.

Mutations of the glycine cleavage system genes possibly affect the negative symptoms of schizophrenia through metabolomic profile changes.

AIM: Hypofunction of N-methyl-D-aspartate receptors (NMDAR) may contribute to the pathophysiology of schizophrenia (SCZ). Recently, the glycine cleavage system (GCS) was shown to affect NMDAR function in the brain. GCS functional defects cause nonketotic hyperglycinemia, the atypical phenotype of which presents psychiatric symptoms similar to SCZ. Here, we examined the involvement of GCS in SCZ. METHODS: First, to identify the rare variants and the exonic deletions, we resequenced all the coding exons and the splice sites of four GCS genes (GLDC, AMT, GCSH, and DLD) in 474 patients with SCZ and 475 controls and performed multiplex ligation-dependent probe amplification analysis in SCZ. Next, we performed metabolome analysis using plasma of patients harboring GCS variants (n = 5) and controls (n = 5) by capillary electrophoresis time-of-flight mass spectrometry. The correlation between plasma metabolites and Positive and Negative Syndrome Scale score was further examined. RESULTS: Possibly damaging variants were observed in SCZ: A203V, S801N in GLDC, near the atypical nonketotic hyperglycinemia causative mutations (A202V, A802V); G825D in GLDC, a potential neural tube defect causative mutation; and R253X in AMT. Marked elevation of plasma 5-oxoproline (pyroglutamic acid), aspartate, and glutamate, which might affect NMDAR function, was observed in patients harboring GCS variants. The aspartate level inversely correlated with negative symptoms (r = -0.942, P = 0.0166). CONCLUSION: These results suggest that GCS rare variants possibly contribute to the pathophysiology of SCZ by affecting the negative symptoms through elevation of aspartate.

Quantification of urinary mono-hydroxylated metabolites of polycyclic aromatic hydrocarbons by on-line solid phase extraction-high performance liquid chromatography-tandem mass spectrometry.

Human exposure to polycyclic aromatic hydrocarbons (PAHs) can be assessed through monitoring of urinary mono-hydroxylated PAHs (OH-PAHs). Gas chromatography (GC) has been widely used to separate OH-PAHs before quantification by mass spectrometry in biomonitoring studies. However, because GC requires derivatization, it can be time consuming. We developed an on-line solid phase extraction coupled to isotope dilution-high performance liquid chromatography-tandem mass spectrometry (on-line-SPE-HPLC-MS/MS) method for the quantification in urine of 1-OH-naphthalene, 2-OH-naphthalene, 2-OH-fluorene, 3-OH-fluorene, 1-OH-phenanthrene, the sum of 2-OH and 3-OH-phenanthrene, 4-OH-phenanthrene, and 1-OH-pyrene. The method, which employed a 96-well plate platform and on-line SPE, showed good sensitivity (i.e., limits of detection ranged from 0.007 to 0.09 ng/mL) and used only 100 µL of urine. Accuracy, calculated from the recovery percentage at three spiking levels, varied from 94 to 113 %, depending on the analyte. The inter- and intra-day precision, calculated from 20 repeated measurements of two quality control materials, varied from 5.2 to 16.7 %. Adequate method performance was also confirmed by acceptable recovery (83-102 %) of two NIST standard reference materials (3672 and 3673). This high-throughput on-line-SPE-HPLC-MS/MS method can be applied in large-scale epidemiological studies. Graphical abstract Example LC-MS chromatogram of urinary mono-hydroxylated PAH metabolites.

Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing.

Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although there is a large genetic contribution, the genetic architecture of TS remains unclear. Exome sequencing has successfully revealed the contribution of de novo mutations in sporadic cases with neuropsychiatric disorders such as autism and schizophrenia. Here, using exome sequencing, we investigated de novo mutations in individuals with sporadic TS to identify novel risk loci and elucidate the genetic background of TS. Exome analysis was conducted for sporadic TS cases: nine trio families and one quartet family with concordant twins were investigated. Missense mutations were evaluated using functional prediction algorithms, and their population frequencies were calculated based on three public databases. Gene expression patterns in the brain were analyzed using the BrainSpan Developmental Transcriptome. Thirty de novo mutations, including four synonymous and four missense mutations, were identified. Among the missense mutations, one in the rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR)-coding gene (rs140964083: G > A, found in one proband) was predicted to be hazardous. In the three public databases analyzed, variants in the same SNP locus were absent, and variants in the same gene were either absent or present at an extremely low frequency (3/5,008), indicating the rarity of hazardous RICTOR mutations in the general population. The de novo variant of RICTOR may be implicated in the development of sporadic TS, and RICTOR is a novel candidate factor for TS etiology.

Serum concentrations of perfluorinated compounds (PFC) among selected populations of children and adults in California.

Perfluorinated compounds (PFCs) have been widely used in industrial applications and consumer products. Their persistent nature and potential health impacts are of concern. Given the high cost of collecting serum samples, this study is to understand whether we can quantify PFC serum concentrations using factors extracted from questionnaire responses and indirect measurements, and whether a single serum measurement can be used to classify an individual's exposure over a one-year period. The study population included three demographic groups: young children (2-8 years old) (N=67), parents of young children (<55 years old) (N=90), and older adults (>55 years old) (N=59). PFC serum concentrations, house dust concentrations, and questionnaires were collected. The geometric mean of perfluorooctane sulfonic acid (PFOS) was highest for the older adults. In contrast, the geometric mean of perfluorooctanoic acid (PFOA) was highest for children. Serum concentrations of the parent and the child from the same family were moderately correlated (Spearman correlation (r)=0.26-0.79, p<0.05), indicating common sources within a family. For adults, age, having occupational exposure or having used fire extinguisher, frequencies of consuming butter/margarine, pork, canned meat entrées, tuna and white fish, freshwater fish, and whether they ate microwave popcorn were significantly positively associated with serum concentrations of individual PFCs. For children, residential dust concentrations, frequency of wearing waterproof clothes, frequency of having canned fish, hotdogs, chicken nuggets, French fries, and chips, and whether they ate microwave popcorn were significant positive predictors of individual PFC serum concentrations. In addition, the serum concentrations collected in a subset of young children (N=20) and the parents (N=42) one year later were strongly correlated (r=0.68-0.98, p<0.001) with the levels measured at the first visits, but showed a decreasing trend. Children had moderate correlation (r=0.43) between serum and dust concentrations of PFOS, indicating indoor sources contribute to exposure. In conclusion, besides food intake, occupational exposure, consumer product use, and exposure to residential dust contribute to PFC exposure. The downward temporal trend of serum concentrations reflects the reduction of PFCs use in recent years while the year-to-year correlation indicates that a single serum measurement could be an estimate of exposure relative to the population for a one-year period in epidemiology studies.

Changes in serum concentrations of maternal poly- and perfluoroalkyl substances over the course of pregnancy and predictors of exposure in a multiethnic cohort of Cincinnati, Ohio pregnant women during 2003-2006.

Data on predictors of gestational exposure to poly- and perfluoroalkyl substances (PFASs) in the United States are limited. To fill in this gap, in a multiethnic cohort of Ohio pregnant women recruited in 2003-2006, we measured perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and six additional PFASs in maternal serum at ∼16 weeks gestation (N = 182) and delivery (N = 78), and in umbilical cord serum (N = 202). We used linear regression to examine associations between maternal serum PFASs concentrations and demographic, perinatal, and lifestyle factors. PFASs concentrations in maternal sera and in their infants' cord sera were highly correlated (Spearman rank correlation coefficients = 0.73-0.95). In 71 maternal-infant dyads, unadjusted geometric mean (GM) concentrations (95% confidence interval) (in µg/L) in maternal serum at delivery of PFOS [8.50 (7.01-9.58)] and PFOA [3.43 (3.01-3.90)] were significantly lower than at 16 weeks gestation [11.57 (9.90-13.53], 4.91 (4.32-5.59), respectively], but higher than in infants' cord serum [3.32 (2.84-3.89), 2.85 (2.51-3.24), respectively] (P < 0.001). Women who were parous, with a history of previous breastfeeding, black, or in the lowest income category had significantly lower PFOS and PFOA GM concentrations than other women. These data suggest transplacental transfer of PFASs during pregnancy and nursing for the first time in a U.S. birth cohort.

Exploring the potential association between brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phthalates, and bisphenol A in polycystic ovary syndrome: a case-control study.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is an endocrine-metabolic disorder that affects approximately 6-10% of women of child-bearing age. Although preliminary studies suggest that certain pollutants may act as endocrine disruptors in animals, little is known about their potential association with PCOS. The objective of this case-control pilot study is to determine whether women with PCOS have higher concentrations of specific environmental contaminants compared to women who have not developed PCOS. METHODS: Fifty-two PCOS case-patients (diagnosed using the National Institutes of Health 1990 definition) and 50 controls were recruited in 2007-2008, from an urban academic medical center in Los Angeles, CA. Brominated diphenyl ethers, polychlorinated biphenyls (PCBs), organochlorine pesticides, and perfluorinated compounds (PFCs) were measured in serum, and phthalates metabolites and bisphenol A (BPA) in urine. RESULTS: PCOS case-patients had significantly higher geometric mean (GM) serum concentrations of two PFCs: perfluorooctanoate (PFOA) (GMcases = 4.1 µg/L, GMcontrols = 2.3 µg/L; p = 0.001) and perfluorooctane sulfonate (PFOS) (GMcases = 8.2 µg/L, GMcontrols = 4.9 µg/L; p = 0.01), and lower urinary concentrations of monobenzyl phthalate (mBzP) (GMcases = 7.5 µg/g creatinine, GMcontrols = 11.7 µg/g creatinine; p = 0.02). Logistic regression, controlling for body mass index, age and race, identified an increased likelihood of PCOS in subjects with higher serum concentrations of PFOA and PFOS (adjusted-ORs = 5.8-6.9, p < 0.05), and with lower urine concentrations of mBzP and mono-n-butyl phthalate (mBP) (aORs = 0.14-0.25, p < 0.05). CONCLUSIONS: Our data suggest that PCOS case-patients may differ from controls in their environmental contaminant profile. PCOS subjects had higher serum concentrations of two PFCs, PFOA and PFOS, and lower urine concentrations of mBP and mBzP. Future studies are needed to confirm these preliminary findings and determine if these chemicals or their precursors may have a role in the pathogenesis of PCOS.

Reductions in serum lipids with a 4-year decline in serum perfluorooctanoic acid and perfluorooctanesulfonic acid.

BACKGROUND: Several epidemiological cross-sectional studies have found positive associations between serum concentrations of lipids and perfluorooctanoic acid (PFOA, or C8). A longitudinal study should be less susceptible to biases from uncontrolled confounding or reverse causality. METHODS: We investigated the association between within-individual changes in serum PFOA and perfluorooctanesulfonic acid (PFOS) and changes in serum lipid levels (low-density lipoprotein [LDL] cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglycerides) over a 4.4-year period. The study population consisted of 560 adults living in parts of Ohio and West Virginia where public drinking water had been contaminated with PFOA. They had participated in a cross-sectional study in 2005-2006, and were followed up in 2010, by which time exposure to PFOA had been substantially reduced. RESULTS: Overall serum concentrations of PFOA and PFOS fell by half from initial geometric means of 74.8 and 18.5 ng/mL, respectively, with little corresponding change in LDL cholesterol (mean increase 1.8%, standard deviation 26.6%). However, there was a tendency for people with greater declines in serum PFOA or PFOS to have greater LDL decrease. For a person whose serum PFOA fell by half, the predicted fall in LDL cholesterol was 3.6% (95% confidence interval = 1.5-5.7%). The association with a decline in PFOS was even stronger, with a 5% decrease in LDL (2.5-7.4%). CONCLUSIONS: Our findings from this longitudinal study support previous evidence from cross-sectional studies of positive associations between PFOA and PFOS in serum and LDL cholesterol.

Polyfluorinated compounds in serum linked to indoor air in office environments.

We aimed to investigate the role of indoor office air on exposure to polyfluorinated compounds (PFCs) among office workers. Week-long, active air sampling was conducted during the winter of 2009 in 31 offices in Boston, MA. Air samples were analyzed for fluorotelomer alcohols (FTOHs), sulfonamides (FOSAs), and sulfonamidoethanols (FOSEs). Serum was collected from each participant (n = 31) and analyzed for 12 PFCs including PFOA and PFOS. In air, FTOHs were present in the highest concentrations, particularly 8:2-FTOH (GM = 9920 pg/m(3)). FTOHs varied significantly by building with the highest levels observed in a newly constructed building. PFOA in serum was significantly correlated with air levels of 6:2-FTOH (r = 0.43), 8:2-FTOH (r = 0.60), and 10:2-FTOH (r = 0.62). Collectively, FTOHs in air significantly predicted PFOA in serum (p < 0.001) and explained approximately 36% of the variation in serum PFOA concentrations. PFOS in serum was not associated with air levels of FOSAs/FOSEs. In conclusion, FTOH concentrations in office air significantly predict serum PFOA concentrations in office workers. Variation in PFC air concentrations by building is likely due to differences in the number, type, and age of potential sources such as carpeting, furniture, and/or paint.

A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia.

Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10-8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.

Genome-wide association study of idiopathic hypersomnia in a Japanese population.

Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In contrast to narcolepsy type 1, which is a well-recognized hypersomnia, the etiology of IH remains poorly understood. No susceptibility loci for IH have been identified, although familial aggregations have been observed among patients with IH. Narcolepsy type 1 is strongly associated with human leukocyte antigen (HLA)-DQB1*06:02; however, no significant associations between IH and HLA alleles have been reported. To identify genetic variants that affect susceptibility to IH, we performed a genome-wide association study (GWAS) and two replication studies involving a total of 414 Japanese patients with IH and 6587 healthy Japanese individuals. A meta-analysis of the three studies found no single-nucleotide polymorphisms (SNPs) that reached the genome-wide significance level. However, we identified several candidate SNPs for IH. For instance, a common genetic variant (rs2250870) within an intron of PDE9A was suggestively associated with IH. rs2250870 was significantly associated with expression levels of PDE9A in not only whole blood but also brain tissues. The leading SNP in the PDE9A region was the same in associations with both IH and PDE9A expression. PDE9A is a potential target in the treatment of several brain diseases, such as depression, schizophrenia, and Alzheimer's disease. It will be necessary to examine whether PDE9A inhibitors that have demonstrated effects on neurophysiologic and cognitive function can contribute to the development of new treatments for IH, as higher expression levels of PDE9A were observed with regard to the risk allele of rs2250870. The present study constitutes the first GWAS of genetic variants associated with IH. A larger replication study will be required to confirm these associations. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-021-00349-2.

Trends in exposure to polyfluoroalkyl chemicals in the U.S. Population: 1999-2008.

Since 2002, practices in manufacturing polyfluoroalkyl chemicals (PFCs) in the United States have changed. Previous results from the National Health and Nutrition Examination Survey (NHANES) documented a significant decrease in serum concentrations of some PFCs during 1999-2004. To further assess concentration trends of perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA), we analyzed 7876 serum samples collected from a representative sample of the general U.S. population ≥12 years of age during NHANES 1999-2008. We detected PFOS, PFOA, PFNA, and PFHxS in more than 95% of participants. Concentrations differed by sex regardless of age and we observed some differences by race/ethnicity. Since 1999-2000, PFOS concentrations showed a significant downward trend, because of discontinuing industrial production of PFOS, but PFNA concentrations showed a significant upward trend. PFOA concentrations during 1999-2000 were significantly higher than during any other time period examined, but PFOA concentrations have remained essentially unchanged during 2003-2008. PFHxS concentrations showed a downward trend from 1999 to 2006, but concentrations increased during 2007-2008. Additional research is needed to identify the environmental sources contributing to human exposure to PFCs. Nonetheless, these NHANES data suggest that sociodemographic factors may influence exposure and also provide unique information on temporal trends of exposure.

Determination of perfluorinated alkyl acid concentrations in human serum and milk standard reference materials.

Standard Reference Materials (SRMs) are certified reference materials produced by the National Institute of Standards and Technology that are homogeneous materials well characterized with values for specified properties, such as environmental contaminant concentrations. They can be used to validate measurement methods and are critical in improving data quality. Disagreements in perfluorinated alkyl acid (PFAA) concentrations measured in environmental matrices during past interlaboratory comparisons emphasized the need for SRMs with values assigned for PFAAs. We performed a new interlaboratory comparison among six laboratories and provided, for the first time, value assignment of PFAAs in SRMs. Concentrations for perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and other PFAAs in two human serum and two human milk SRMs are reported. PFAA concentration measurements agreed for serum SRM 1957 using different analytical methods in six laboratories and for milk SRM 1954 in three laboratories. The interlaboratory relative standard deviation for PFOS in SRM 1957 was 7%, which is an improvement over past interlaboratory studies. Matrix interferences are discussed, as well as temporal trends and the percentage of branched vs. linear isomers. The concentrations in these SRMs are similar to the present-day average concentrations measured in human serum and milk, resulting in representative and useful control materials for PFAA human monitoring studies.

Polyfluoroalkyl chemicals in house dust.

We developed a high throughput analytical method using on-line solid phase extraction coupled with isotope dilution high-performance liquid chromatography-tandem mass spectrometry (on-line SPE-HPLC-MS/MS) to simultaneously determine the concentrations of 17 polyfluoroalkyl chemicals (PFCs) in house dust. The sample preparation includes dispersion of the dust samples in 0.1 M formic acid:MeOH (1:1), followed by agitation and filtration, addition of the isotope-labeled internal standard solution to the filtrate, and analysis by on-line SPE-HPLC-MS/MS. The limits of quantitation were <4.0 ng/g. The method accuracies ranged between 73.2% and 100.2% for the different analytes at two spike levels. We confirmed the validity of the method by analyzing 39 household dust samples collected in 2004. Of the 17 PFCs measured, 6 of them--perfluorobutane sulfonate (PFBuS), N-ethyl-perfluorooctane sulfonamide, 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid (Et-PFOSA-AcOH), 2-(N-methyl-perfluorooctane sulfonamido) ethanol (Me-PFOSA-EtOH), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS)--had detection frequencies >70%. We detected PFOS, PFBuS, and PFHxS at the highest median concentration, followed by Et-PFOSA-AcOH and Me-PFOSA-EtOH.

Legacy and alternative per- and polyfluoroalkyl substances in the U.S. general population: Paired serum-urine data from the 2013-2014 National Health and Nutrition Examination Survey.

Concerns are heightened from detecting environmentally persistent man-made per- and polyfluoroalkyl substances (PFAS) in drinking water systems around the world. Many PFAS, including perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), remain in the human body for years. Since 1999-2000, assessment of exposure to PFOS, PFOA, and other select PFAS in the U.S. general population has relied on measuring PFAS serum concentrations in participants of the National Health and Nutrition Examination Survey (NHANES). Manufacturers have replaced select chemistries ("legacy" PFAS) with PFAS with shorter biological half-lives (e.g., GenX, perfluorobutanoate [PFBA]) which may efficiently eliminate in urine. However, knowledge regarding exposure to these compounds is limited. We analyzed 2682 urine samples for 17 legacy and alternative PFAS in 2013-2014 NHANES participants ≥6 years of age. Concentrations of some of these PFAS, measured previously in paired serum samples from the same NHANES participants, suggested universal exposure to PFOS and PFOA, and infrequent or no exposure to two short-chain PFAS, perfluorobutane sulfonate and perfluoroheptanoate. Yet, in urine, PFAS were seldom detected; the frequency of not having detectable concentrations of any of the 17 PFAS was 67.5%. Only two were detected in >1.5% of the population: PFBA (13.3%) and perfluorohexanoate (PFHxA, 22.6%); the 90th percentile urine concentrations were 0.1 µg/L (PFBA), and 0.3 µg/L (PFHxA). These results suggest that exposures to short-chain PFAS are infrequent or at levels below those that would result in detectable concentrations in urine. As such, these findings do not support biomonitoring of short-chain PFAS or fluorinated alternatives in the general population using urine, and highlight the importance of selecting the adequate biomonitoring matrix.

Maternal serum concentrations of perfluoroalkyl substances during pregnancy and gestational weight gain: The Avon Longitudinal Study of Parents and Children.

Perfluoroalkyl substances (PFAS) are chemicals used in the manufacture of consumer products. PFAS may act as endocrine disruptors, influencing metabolic pathways and weight-related outcomes. Previous studies observed an association between perfluorooctane sulfonic acid (PFOS) and higher gestational weight gain among under-/normal weight mothers. We analyzed associations of maternal serum pregnancy concentrations of PFAS with gestational weight gain (GWG) using data from 905 women in a subsample of the Avon Longitudinal Study of Parents and Children. Women were routinely weighed in antenatal check-ups; absolute GWG was determined by subtracting the first weight measurement from the last. Linear regression was used to explore associations of maternal PFAS concentrations with absolute GWG, stratified by prepregnancy body mass index. Associations of maternal PFOS, perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid (PFHxS) concentrations with absolute GWG were null; 10% higher PFOS was associated with GWG of -0.03 kg (95% CI: -0.11, 0.06) among under-/normal weight mothers. Ten percent higher perfluorononanoic acid (PFNA) was associated with a higher GWG of 0.09 kg (95% CI: 0.02, 0.16) among under-/normal weight mothers. Overall, findings suggest no association between maternal PFOA, PFOS, and PFHxS concentrations and GWG, and a weak positive association between maternal PFNA and GWG.

Maternal serum concentrations of perfluoroalkyl substances and birth size in British boys.

Per- and polyfluoroalkyl substances (PFAS) have been widely used in commercial and industrial manufacturing processes since the 1950s. Inverse associations between prenatal exposure to PFAS and birth size have been found in populations around the globe. This study examined the association of prenatal maternal serum concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) and birth size in British boys. The study included 457 mother-son dyads participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Birth weight (g), crown to heel length (cm), and head circumference (cm) were collected at delivery. PFAS were detected in all maternal serum samples during pregnancy (median: 30 weeks gestation (interquartile range: 12-33)). Median concentrations (interquartile range) were 13.8 ng/mL (11.0, 17.7), 3.0 ng/mL (2.3, 3.8), 1.9 ng/mL (1.4, 2.5), and 0.4 ng/mL (0.3, 0.5) for PFOS, PFOA, PFHxS, and PFNA, respectively. In multivariable linear regression models, inverse associations were detected between PFOS (continuous) and birth weight (ß = -8.50 g, 95% CI = -15.93, -1.07 g), crown to heel length (ß = -0.04 cm, 95% CI = -0.08, -0.01 cm), and head circumference (ß = -0.02 cm, 95% CI = -0.04, -0.002 cm). In conclusion, prenatal exposure to high levels of PFOS may be associated with reduced birth size in male infants.

Per- and polyfluoroalkyl substances and fluorinated alternatives in urine and serum by on-line solid phase extraction-liquid chromatography-tandem mass spectrometry.

Per- and polyfluoroalkyl substances (PFAS), man-made chemicals with variable length carbon chains containing the perfluoroalkyl moiety (CnF2n+1-), are used in many commercial applications. Since 1999-2000, several long-chain PFAS, including perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), have been detected at trace levels in the blood of most participants of the National Health and Nutrition Examination Survey (NHANES)-representative samples of the U.S. general population-while short-chain PFAS have not. Lower detection frequencies and concentration ranges may reflect lower exposure to short-chain PFAS than to PFOS or PFOA or that, in humans, short-chain PFAS efficiently eliminate in urine. We developed on-line solid phase extraction-HPLC-isotope dilution-MS/MS methods for the quantification in 50 µL of urine or serum of 15 C3-C11 PFAS (C3 only in urine), and three fluorinated alternatives used as PFOA or PFOS replacements: GenX (ammonium salt of 2,3,3,3,-tetrafluoro-2-(1,1,2,2,3,3,3-heptafluoropropoxy)-propanoate, also known as HFPO-DA), ADONA (ammonium salt of 4,8-dioxa-3H-perfluorononanoate), and 9Cl-PF3ONS (9-chlorohexadecafluoro-3-oxanonane-1-sulfonate), main component of F53-B. Limit of detection for all analytes was 0.1 ng/mL. To validate the method, we analyzed 50 commercial urine/serum paired samples collected in 2016 from U.S. volunteers with no known exposure to the chemicals. In serum, detection frequency and concentration patterns agreed well with those from NHANES. By contrast, except for perfluorobutanoate, we did not detect long-chain or short-chain PFAS in urine. Also, we did not detect fluorinated alternatives in either urine or serum. Together, these results suggest limited exposure to both short-chain PFAS and select fluorinated alternatives in this convenience population.

Per- and polyfluoroalkyl substances in sera from children 3 to 11 years of age participating in the National Health and Nutrition Examination Survey 2013-2014.

Several per- and polyfluoroalkyl substances (PFAS) have been measured in U.S. National Health and Nutrition Examination Survey (NHANES) participants 12 years of age and older since 1999-2000, but PFAS data using NHANES individual samples among children younger than 12 years do not exist. To obtain the first nationally representative PFAS exposure data in U.S. children, we quantified serum concentrations of 14 PFAS including perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA), in a nationally representative subsample of 639 3-11year old participants in NHANES 2013-2014. We used on-line solid-phase extraction coupled to isotope dilution-high performance liquid chromatography-tandem mass spectrometry; limits of detection were 0.1ng/mL for all analytes. We calculated geometric mean concentrations, determined weighted Pearson correlations, and used linear regression to evaluate associations of sex, age (3-5 vs 6-11 years), race/ethnicity (Hispanic vs non-Hispanic), household income, and body mass index with concentrations of PFAS detected in more than 60% of participants. We detected PFOS, PFOA, PFHxS, and PFNA in all children at concentrations similar to those of NHANES 2013-2014 adolescents and adults, suggesting prevalent exposure to these PFAS or their precursors among U.S. 3-11year old children, most of whom were born after the phase out of PFOS in the United States in 2002. PFAS concentration differences by sex, race/ethnicity, and age suggest lifestyle differences that may impact exposure, and highlight the importance of identifying exposure sources and of studying the environmental fate and transport of PFAS.