Spatio-temporal trends in livestock exposure to per- and polyfluoroalkyl substances (PFAS) inform risk assessment and management measures.

The migration of per- and polyfluoroalkyl substances (PFAS) onto agricultural properties has resulted in the accumulation of PFAS in livestock. The environmental determinants of PFAS accumulation in livestock from the grazing environment are poorly understood, resulting in limited capacity to manage livestock exposure and subsequent transfer of PFAS through the food chain. Analytical- (n = 978 samples of soil, water, pasture, and serum matrices), farm management/practice- and livestock physiology data were collated and interrogated from environmental PFAS investigations across ten farms, from four agro-ecological regions of Victoria (Australia). Statistical analysis identified perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) as key analytes of concern for livestock bioaccumulation. PFOS and PFHxS concentrations in livestock drinking water were positively correlated with serum concentrations while other intake pathways (pasture and soil) had weaker correlations. Seasonal trends in PFAS body burden (serum concentrations) were identified and suggested to be linked to seasonal grazing behaviours and physiological water requirements. The data showed for the first time that livestock exposure to PFAS is dynamic and with relatively short elimination half-lives, there is opportunity for exposure management. Meat from cattle, grazed on PFAS impacted sites, may exceed health-based guideline values for PFAS, especially for markets with low limits (like the European Commission Maximum Limits or EC MLs). This study found that sites with mean livestock drinking water concentrations as low as 0.003 µg PFOS/L may exceed the EC ML for PFOS in cattle meat. Risk assessment can be used to prioritise site cleanup and development of management plans to reduce PFAS body burden by considering timing of stock rotation and/or supplementation of primary exposure sources.

Physiologically based pharmacokinetic (PBPK) modeling of perfluorohexane sulfonate (PFHxS) in humans.

Per- and polyfluoroalkyl substances (PFAS) are persistent, man-made compounds prevalent in the environment and consistently identified in human biomonitoring samples. In particular, perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid (PFHxS) have been identified at U.S. Air Force installations. The study of human toxicokinetics and physiologically based pharmacokinetic (PBPK) modeling of PFHxS has been less robust and has been limited in scope and application as compared to PFOS and PFOA. The primary goal of the current effort was to develop a PBPK model describing PFHxS disposition in humans that can be applied to retrospective, current, and future human health risk assessment of PFHxS. An existing model developed for PFOS and PFOA was modified and key parameter values for exposure and toxicokinetics were calibrated for PFHxS prediction based on human biomonitoring data, particularly general population serum levels from the U.S. Centers for Disease Prevention and Control (CDC) National Health and Nutrition Examination Survey (NHANES). Agreement between the model and the calibration and evaluation data was excellent and recapitulated observed trends across sex, age, and calendar years. Confidence in the model is greatest for application to adults in the 2000-2018 time frame and for shorter-term future projections.

Per- and poly-fluoroalkyl substances (PFASs) in follicular fluid from women experiencing infertility in Australia.

Per- and poly-fluoroalkyl substances (PFASs) have been widely used and detected in human matrices. Evidence that PFAS exposure may be associated with adverse human reproductive health effects exists, however, data is limited. The use of a human matrix such as follicular fluid to determine chemical exposure, along with reproductive data will be used to investigate if there is a relationship between PFAS exposure and human fertility. OBJECTIVE: This study aims to: (1) assess if associations exist between PFAS concentrations and/or age and fertilisation rate (as determined in follicular fluid of women in Australia who received assisted reproductive treatment (ART)); and (2) assess if associations exist between PFAS concentrations and infertility aetiology. METHODS: Follicular fluids were originally collected from participants who underwent fully stimulated ART treatment cycles at an in vitro fertilisation (IVF) clinic in the period 2006-2009 and 2010-11 in Queensland, Australia. The samples were available for analysis of 32 PFASs including perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA) using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). 97 samples were matched with limited demographic data (age and fertilisation rate) and five infertility factors (three known female factors): 1) endometriosis, 2) polycystic ovarian syndrome (PCOS), and 3) genital tract infections - tubal/pelvic inflammation disease; as well as 4) male factor, and 5) idiopathic or unknown from either males or females. SPSS was used for linear regression analysis. RESULTS: PFASs were detected in all follicular fluid samples with the mean concentrations of PFOS and PFOA, 4.9, and 2.4 ng/ml, respectively. A lower fertilisation rate was observed at higher age when age was added as a covariate, but there was no relationship between PFAS concentrations and fertilisation rate. There were few statistically significant associations between PFAS concentrations in follicular fluid and infertility factors. Log-transformed PFHxS concentrations were lower in females with endometriosis (factor 1) than in women who had reported 'male factors' as a reason of infertility, while PFHpA was higher in women who had infertile due to female factors (factor 1-3) compared to those who had infertile due to male factor. CONCLUSION: PFASs were detected in follicular fluid of Australian women who had been treated at an IVF clinic. PFAS exposure found in follicular fluids is linked to increased risk of some infertility factors, and increased age was associated with decreased fertilisation rate in our data. But there was no relationship between PFAS and ferlitisation rate. Further large-scale investigations of PFAS and health effects including infertility are warranted.

Derivation of a chronic reference dose for perfluorohexane sulfonate (PFHxS) for reproductive toxicity in mice.

Perfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid that was used as an industrial surfactant, but is now found as an environmental contaminant worldwide. In addition to its use as an industrial surfactant, it is a legacy contaminant from the use of aqueous film-forming foams. Despite its widespread occurrence in the environment and evidence of biological activity associated with PFHxS and similar perfluoroalkyl sulfonic acids in rodents, there is no oral toxicity value currently available from the IRIS Database. To derive an oral reference dose (RfD) for PFHxS, available toxicity studies were reviewed using a weight-of-evidence approach. A 42-day mouse reproductive study was chosen as the critical study for the derivation of the oral RfD. Benchmark dose modeling was utilized to derive a point of departure (POD) for a reduction in litter size. A 95% lower confidence limit on the benchmark dose (BMDL) of 13,900 ng/mL (serum PFHxS) was modeled for a reduction in litter size. An oral RfD for PFHxS of 4.0 ng/kg/d was calculated by conversion of the BMDL to a human equivalent oral dose using a human half-life adjusted dosimetric conversion factor and the application of a total uncertainty factor of 300. Additional research is needed to better characterize the toxicity associated with oral exposure to PFHxS and refine the development of toxicity values.

Preventive effects of imperatorin on perfluorohexanesulfonate-induced neuronal apoptosis via inhibition of intracellular calcium-mediated ERK pathway.

Early life neuronal exposure to environmental toxicants has been suggested to be an important etiology of neurodegenerative disease development. Perfluorohexanesulfonate (PFHxS), one of the major perfluoroalkyl compounds, is widely distributed environmental contaminants. We have reported that PFHxS induces neuronal apoptosis via ERK-mediated pathway. Imperatorin is a furanocoumarin found in various edible plants and has a wide range of pharmacological effects including neuroprotection. In this study, the effects of imperatorin on PFHxS-induced neuronal apoptosis and the underlying mechanisms are examined using cerebellar granule cells (CGC). CGC were isolated from seven-day old rats and were grown in culture for seven days. Caspase-3 activity and TUNEL staining were used to determine neuronal apoptosis. PFHxS-induced apoptosis of CGC was significantly reduced by imperatorin and PD98059, an ERK pathway inhibitor. PFHxS induced a persistent increase in intracellular calcium, which was significantly blocked by imperatorin, NMDA receptor antagonist, MK801 and the L-type voltage-dependent calcium channel blockers, diltiazem and nifedipine. The activation of caspase-3 by PFHxS was also inhibited by MK801, diltiazem and nifedipine. PFHxS-increased ERK activation was inhibited by imperatorin, MK801, diltiazem and nifedipine. Taken together, imperatorin protects CGC against PFHxS-induced apoptosis via inhibition of NMDA receptor/intracellular calcium-mediated ERK pathway.

Maternal exposure to perfluorinated chemicals and reduced fecundity: the MIREC study.

STUDY QUESTION: What is the effect of maternal exposure to perfluorooctane sulfonate (PFOS), perflurooctanoic acid (PFOA) and perfluorohexane sulfonate (PFHxS) on female fecundity? SUMMARY ANSWER: Increasing concentrations of PFOA or PFHxS in maternal plasma were associated with reduced fecundability and infertility. WHAT IS KNOWN ALREADY: Perfluorinated chemicals (PFCs) are a group of synthetic compounds used in industrial production. There is a concern about the effect of PFCs on fecundity, as measured by time-to-pregnancy (TTP). Although some recent studies suggest that increasing concentrations of PFCs may decrease fecundity, divergence in the methodological approaches used to evaluate this association have prevented firm conclusions being reached. STUDY DESIGN, SIZE, DURATION: The Maternal-Infant Research on Environmental Chemicals (MIREC) Study is a cohort study of 2,001 women recruited before 14 weeks of gestation in 10 cities across Canada between 2008 and 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: A questionnaire was administered and medical chart data and biospecimens were collected from participants. After excluding women who withdrew, those for whom data were incomplete, those whose pregnancies followed birth control failure, and accounting for male fertility, 1743 participants remained. TTP was defined as the number of months of unprotected intercourse needed to become pregnant in the current pregnancy, as self-reported in the first trimester of pregnancy. Plasma concentrations of PFOA, PFOS and PFHxS measured in the first trimester were considered as a surrogate of preconception exposure. Fecundability odds ratios (FORs) were estimated using Cox proportional hazard models for discrete time. FOR < 1 denote a longer TTP and FORs >1 denote a shorter TTP. The odds of infertility (TTP > 12 months or infertility treatment in the index pregnancy) were estimated using logistic regression. Each chemical concentration (ng/ml) was log-transformed and divided by its SD. MAIN RESULTS AND THE ROLE OF CHANCE: The cumulative probabilities of pregnancy at 1, 6 and 12 months were 0.42 (95% confidence interval (CI) 0.40-0.45), 0.81 (95% CI 0.79-0.83) and 0.90 (95% CI 0.89-0.92), respectively. The mean maternal age was 32.8 (SD 5.0) years. The geometric means (ng/ml) of PFOA, PFOS and PFHxS were 1.66 (95% CI 1.61-1.71), 4.59 (95% CI 4.46-4.72) and 1.01 (95% CI 0.97-1.05), respectively. After adjustment for potential confounders, PFOA and PFHxS were associated with a 11 and 9% reduction in fecundability per one SD increase (FOR = 0.89; 95% CI 0.83-0.94; P < 0.001 for PFOA and FOR = 0.91; 95% CI 0.86-0.97; P = 0.002 for PFHxS), while no significant association was observed for PFOS (FOR = 0.96; 95% CI 0.91-1.02; P = 0.17). In addition, the odds of infertility increased by 31% per one SD increase of PFOA (odds ratio (OR) = 1.31; 95% CI 1.11-1.53; P = 0.001) and by 27% per one SD increase of PFHxS (OR = 1.27; 95% CI 1.09-1.48; P = 0.003), while no significant association was observed for PFOS (OR = 1.14; 95% CI 0.98-1.34; P = 0.09). LIMITATIONS, REASONS FOR CAUTION: Women with the highest concentrations of PFCs might have been excluded from the study if there is a causal association with infertility. The MIREC study did not assess concentrations of PFCs in males, semen quality, menstrual cycle characteristics or intercourse frequency. WIDER IMPLICATIONS OF THE FINDINGS: Our results add to the evidence that exposure to PFOA and PFHxS, even at lower levels than previously reported, may reduce fecundability. STUDY FUNDING/COMPETING INTERESTS: The MIREC study is supported by the Chemicals Management Plan of Health Canada, the Canadian Institutes for Health Research (CIHR, grant no. MOP - 81285) and the Ontario Ministry of the Environment. M.P.V. was supported by a CIHR Fellowship Award, and a CIHR-Quebec Training Network in Perinatal Research (QTNPR) Ph.D. scholarship. W.D.F. is supported by a CIHR Canada Research Chair. There are no conflicts of interest to declare.

Comparative sorption and desorption behaviors of PFHxS and PFOS on sequentially extracted humic substances.

The sorption and desorption behaviors of two perfluoroalkane sulfonates (PFSAs), including perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) on two humic acids (HAs) and humin (HM), which were extracted from a peat soil, were investigated. The sorption kinetics and isotherms showed that the sorption of PFOS on the humic substances (HSs) was much higher than PFHxS. For the same PFSA compound, the sorption on HSs followed the order of HM>HA2>HA1. These suggest that hydrophobic interaction plays a key role in the sorption of PFSAs on HSs. The sorption capacities of PFSAs on HSs were significantly related to their aliphaticity, but negatively correlated to aromatic carbons, indicating the importance of aliphatic groups in the sorption of PFSAs. Compared to PFOS, PFHxS displayed distinct desorption hysteresis, probably due to irreversible pore deformation after sorption of PFHxS. The sorption of the two PFSAs on HSs decreased with an increase in pH in the solution. This is ascribed to the electrostatic interaction and hydrogen bonding at lower pH. Hydrophobic interaction might also be stronger at lower pH due to the aggregation of HSs.

Per- and Polyfluoroalkyl Substances in the Duluth, Minnesota Area: Exposure to and Biomarker Responses in Tree Swallows Relative to Known Fire-Fighting Foam Sources.

Tree swallow nest boxes were deployed at sites proximal to two putative aqueous film forming foam (AFFF) sources in the Duluth, MN area, as well as along the St. Louis River and a reference lake for comparative purposes in 2019, 2020 and 2021. The two AFFF sites were the current Duluth Air National Guard Base (ANG) and the Lake Superior College Emergency Response Training Center. Between 13 and 40 per- and polyfluoroalkyl substances (PFAS), depending on year, were detected and quantified in tree swallow egg, nestling carcasses, and stomach contents. Assessments were made of oxidative stress and ethoxyresorufin-O-dealkylase activity in liver tissue, thyroid hormone levels in plasma and thyroid glands, DNA damage in red blood cells, and two measures of immune response (haptoglobin-like activity and immunoglobulin) in plasma of the nestlings. Additionally, other contaminants, such as polychlorinated biphenyls, legacy organochlorine pesticides, and trace elements, were assessed at sites with no previous data. Total egg PFAS concentrations at the ANG site and north of that site were 30-40 times higher than at the reference lake, while nestling PFAS concentrations were 10-15 times higher. In contrast, the St. Louis River sites had slightly, but non-statistically significant, elevated egg and nestling PFAS concentrations relative to the reference lake (2-5 times higher). One PFAS, perfluorohexane sulfonate (PFHxS), was higher, as a proportion of total PFAS, at sites with a known AFFF source compared to the reference lake, as well as compared to sites along the St. Louis River with mainly urban and industrial sources of PFAS. The ratio of total carboxylates to total sulfonates also distinguished between PFAS sources. There were few to no differences in biomarker responses among sites, and no association with PFAS exposure.

Serum concentrations of per- and polyfluorinated substances and risk of B-cell non-Hodgkin lymphoma.

Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that are detectable in the serum of most U.S. adults. Some studies of highly-exposed individuals have suggested positive associations between PFAS and B-cell non-Hodgkin lymphoma (B-NHL). To investigate whether associations exist at lower exposure levels, we conducted a nested case-control study investigating serum PFAS concentrations and B-NHL within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We measured pre-diagnostic serum concentrations of five PFAS among 706 cases (age at diagnosis = 55-93 years, median 73 years) and 706 controls individually matched on age at blood draw, sex, self-reported race and ethnicity, study center, and year of blood collection (the median follow-up years = 10). We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) for PFAS concentrations in relation to B-NHL, both overall and for selected histologic subtypes [diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL)] using conditional logistic regression. We found no evidence of a positive association with B-NHL for any of the five PFAS. In analyses of histologic subtypes, perfluorohexane sulfonate (PFHxS) was significantly associated with DLBCL in a model adjusting for all other PFAS (OR for highest vs. lowest quintile = 2.19, 95 % CI = 1.21, 3.95; Ptrend = 0.02), but not in a model without mutual adjustment (OR = 1.37, 95 % CI = 0.82, 2.29; Ptrend = 0.26). We also observed an inverse association between perfluorononanoate and DLBCL (mutually-adjusted OR = 0.83, 95 % CI = 0.69, 0.99 per doubling in concentration), although the association was null among participants with blood drawn prior to 1997 (OR<1997 = 1.00, 95 % CI = 0.82, 1.21; OR≥1997 = 0.65, 95 % CI = 0.53, 0.79; Pinteraction = 0.0003). In conclusion, our findings from a prospective cohort study with PFAS serum concentrations comparable to that of the general population do not support an association with increased risk of B-NHL overall. The suggestive evidence of a positive association between PFHxS and DLBCL warrants further investigation.

The pollutant perfluorohexane sulfonate (PFHxS) reduces serum thyroxine but does not alter thyroid action in the postnatal rat brain.

Known as "forever chemicals", per- and polyfluoroalkyl substances (PFAS) are synthetic compounds used in consumer goods but pose significant public health concerns, including disruption of the thyroid system. As thyroid hormones (THs) are required for normal brain development, PFAS may also be developmental neurotoxicants. However, this is not well understood. Here we examine the endocrine and neurodevelopmental consequences of perfluorohexane sulfonate (PFHxS) exposure in pregnant, lactating, and developing rats, and compare its effects to an anti-thyroid pharmaceutical (propylthiouracil, PTU) that induces thyroid-mediated developmental neurotoxicity. We show that PFHxS dramatically reduces maternal serum thyroxine (T4), nearly equivalently to PTU (-55 and -51%, respectively). However, only PTU increases thyroid stimulating hormone. The lactational transfer of PFHxS is significant and reduces pup serum T4 across the postnatal period. Surprisingly, brain THs are only minimally decreased by PFHxS, whereas PTU drastically diminishes them. Evaluation of brain TH action by phenotyping, RNA-Sequencing, and quantification of radial glia cell morphology supports that PTU interrupts TH signaling while PFHxS has limited to no effect. These data show that PFHxS induces abnormal serum TH profiles; however, there were no indications of hypothyroidism in the postnatal brain. We suggest the stark differences between the neurodevelopmental effects of PFHxS and a typical antithyroid agent may be due to its interaction with TH distributing proteins like transthyretin.

Evaluation of the Effect of Perfluorohexane Sulfonate on the Proliferation of Human Liver Cells.

Perfluorohexane sulfonate (PFHxS) is a widely detected replacement for legacy long-chain perfluoroalkyl substances (PFAS) in the environment and human blood samples. Its potential toxicity led to its recent classification as a globally regulated persistent organic pollutant. Although animal studies have shown a positive association between PFHxS levels and hepatic steatosis and hepatocellular hypertrophy, the link with liver toxicity, including end-stage liver cancer, remains inconclusive. In this study, we examined the effects of PFHxS on the proliferation of Hep3B (human hepatocellular carcinoma) and SK-Hep1 (human liver sinusoidal endothelial cells). Cells were exposed to different PFHxS concentrations for 24-48 h to assess viability and 12-14 days to measure colony formation. The viability of both cell lines increased at PFHxS concentrations <200 µM, decreased at >400 µM, and was highest at 50 µM. Colony formation increased at <300 µM and decreased at 500 µM PFHxS. Consistent with the effect on cell proliferation, PFHxS increased the expression of proliferating cell nuclear antigen (PCNA) and cell-cycle molecules (CDK2, CDK4, cyclin E, and cyclin D1). In summary, PFHxS exhibited a biphasic effect on liver cell proliferation, promoting survival and proliferation at lower concentrations and being cytotoxic at higher concentrations. This suggests that PFHxS, especially at lower concentrations, might be associated with HCC development and progression.

Perfluoroalkyl acid depuration from the edible tissues of a migratory recreationally fished species.

Environmental emissions of perfluoroalkyl acids (PFAAs) impact estuarine species and the fisheries that rely on them. Migratory estuarine fishes may be captured for consumption in areas distant to known contaminant sources, but exposure risk depends on how quickly contaminants are depurated. This baseline presents the outcomes from a novel experiment simulating the migration of a popular recreational fish species (Dusky Flathead, Platycephalus fuscus) following environmental exposure to PFAAs, and assessing depuration from edible muscle tissues. Over the 33-day experiment, perfluorooctane sulfonate (PFOS) concentrations declined slowly, with modelling suggesting that concentrations fell below the relevant screening value (5.2 µg kg-1) within ∼558 h (285-1372 h; 90 % CI). Low concentrations (<1.2 µg kg-1) of perfluorohexane sulfonate also depurated rapidly. This study provides useful information for assessing potential exposure risk posed by recreationally targeted fish migrating away from contaminated areas. The experimental design employed has a real-world context that is relevant for future studies.

Spatial and temporal variability of per- and polyfluoroalkyl substances (PFAS) in environmental media of a small pond: Toward an improved understanding of PFAS bioaccumulation in fish.

Per- and polyfluoroalkyl substances (PFAS) are highly fluorinated compounds with many industrial applications, for instance as ingredients in fire-suppressing aqueous film-forming foams (AFFF). Several PFAS have been demonstrated to be persistent, bioaccumulative and toxic. This study better characterizes the bioaccumulation of PFAS in freshwater fish through a spatial and temporal analysis of surface water and sediment from a stormwater pond in a former Naval air station (NAS) with historic AFFF use. We sampled environmental media from four locations twice per week for five weeks and sampled fish at the end of the sampling effort. The primary PFAS identified in surface water, sediment, and biota were perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) followed by perfluorooctanoic acid (PFOA) in environmental media and perfluoroheptane sulfonate (PFHpS) in biota. We observed significant temporal variability in surface water concentrations at the pond headwaters following stochastic events such as heavy rainfall for many compounds, particularly PFHxS. Sediment concentrations varied most across sampling locations. In fish, liver tissue presented the highest concentrations for all compounds except PFHxS, which was highest in muscle tissue, suggesting the influence of fine-scale aqueous PFAS fluctuations on tissue distribution. Calculated log bioaccumulation factors (BAFs) ranged from 0.13 to 2.30 for perfluoroalkyl carboxylates (PFCA) and 0.29-4.05 for perfluoroalkane sulfonates (PFSA) and fluctuated greatly with aqueous concentrations. The variability of PFAS concentrations in environmental media necessitates more frequent sampling efforts in field-based studies to better characterize PFAS contamination in aquatic ecosystems as well as exercising caution when considering single time-point BAFs due to uncertainty of system dynamics.

Perfluorohexane sulfonate induces memory impairment and downregulation of neuroproteins via NMDA receptor-mediated PKC-ERK/AMPK signaling pathway.

Perfluorohexane sulfonate (PFHxS) is a widely used industrial chemical detected in human umbilical cord blood and breast milk, and has been suggested to exhibit developmental neurotoxicity. Previous studies on mice reported that neonatal exposure to PFHxS altered neuroprotein levels in the developing brain, and caused behavioral toxicity and cognitive dysfunction in the mature brain. However, the underlying mechanisms responsible for PFHxS-induced neuroprotein dysregulation are poorly understood. In this study, we examined the effect of neonatal exposure to PFHxS on memory function using an in vivo mice model. Furthermore, we examined the levels of growth associated protein-43 (GAP-43) and calcium/calmodulin dependent protein kinase II (CaMKII) (biomarkers of neuronal development) and the involved signaling pathways using differentiated neuronal PC12 cells. PFHxS decreased cell viability, GAP-43 and CaMKII levels, and neurite formation. These effects were mediated by the NMDA receptor, PKC-α, PKC-δ, AMPK and ERK pathways. MK801, an NMDA receptor antagonist, reduced the activation of PKC-α, PKC-δ, ERK and AMPK. The activation of ERK was suppressed by pharmacological and knockdown inhibition of PKC-α and -δ. Interestingly, the AMPK pathway was selectively inhibited by inhibiting PKC-δ but not PKC-ɑ. Consistent with PFHxS-induced neuronal death, and GAP-43 and CaMKII downregulation, neonatal exposure to PFHxS caused significant memory impairment in adult mice. Collectively, these results demonstrate that PFHxS induces persistent developmental neurotoxicity, as well as GAP-43 and CaMKII downregulation via the NMDA receptor-mediated PKCs (α and δ)-ERK/AMPK pathways.

Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort.

Background & Aims: Exposure to poly- and perfluoroalkyl substances (PFAS), a class of persistent organic pollutants, is ubiquitous. Animal studies suggest that PFAS may increase risk of fatty liver and hepatocellular carcinoma (HCC) via impacts on hepatic lipid, amino acid, and glucose metabolism, but human data is lacking. We examined associations between PFAS exposure, altered metabolic pathways, and risk of non-viral HCC. Methods: In this nested case-control study, pre-diagnostic plasma PFAS and metabolomics were measured in 50 incident HCC cases and 50 individually matched controls from the Multiethnic Cohort (MEC) study. Cases/controls were matched by age, sex, race, and study area. PFAS exposure and risk of HCC were examined using conditional logistic regression. A metabolome-wide association study and pathway enrichment analysis was performed for PFAS exposure and HCC risk, and key metabolites/metabolic pathways were identified using a meet in the middle approach. Results: High perfluorooctane sulfonic acid (PFOS) levels (90th percentile from NHANES; >55 µg/L) were associated with 4.5-fold increased risk of HCC (odds ratio 4.5, 95% CI 1.2-16.0). Pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were also associated with HCC risk. We identified 4 metabolites linking PFOS exposure with HCC, including glucose, butyric acid (a short-chain fatty acid), α-ketoisovaleric acid (a branched-chain α-keto acid), and 7α-hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC. Conclusion: This proof-of-concept analysis shows that exposure to high PFOS levels was associated with increased risk of non-viral HCC, likely via alterations in glucose, amino acid, and bile acid metabolism. Larger studies are needed to confirm these findings. Lay summary: Per- and polyfluoroalkyl substances (PFAS), often referred to as "forever chemicals" because they are difficult to break down and stay in the human body for years, are extremely common and can cause liver damage. In a first of its kind study, we found that exposure to high levels of perfluorooctanesulfonic acid, one of the most common PFAS chemicals, was linked to increased risk of hepatocellular carcinoma in humans. Hepatocellular carcinoma is difficult to treat and is one of the most common forms of liver cancer, and these findings may provide new avenues for helping to prevent this disease.

Chronic exposure to perfluorohexane sulfonate leads to a reproduction deficit by suppressing hypothalamic kisspeptin expression in mice.

BACKGROUND: Perfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid found as an environmental contaminant. This study aims to investigate the effects of PFHxS exposure on female reproduction and the underlying mechanism in mice. METHODS: Eight-week-old ICR mice were divided randomly into four groups administered corn oil (vehicle) and PFHxS at doses of 0.5, 5, and 50 mg/kg/day for 42 days by intragastric administration. Body weight, ovarian weight, estrous cycle, follicle counts, and serum sex hormone levels were evaluated. The expression of kisspeptin and gonadotropin releasing hormone (GnRH) in the hypothalamus was also detected. RESULTS: Compared to vehicle exposure, 5 mg/kg/day PFHxS treatment prolonged the estrous cycle, especially the duration of diestrus, after 42 days of treatment. The numbers of secondary follicles, antral follicles and corpus lutea were significantly reduced in the PFHxS-treated mice. Moreover, compared with the control mice, the PFHxS-treated mice showed decreases in the serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (E2), and reduced GnRH mRNA levels, along with the lack of an LH surge. Furthermore, the PFHxS-treated mice had lower levels of kisspeptin immunoreactivity and kiss-1 mRNA in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) than the control mice. After intraventricular administration of kisspeptin-10, the numbers of secondary follicles, antral follicles and corpus lutea recovered, along with the levels of GnRH mRNA, FSH, and LH in the mice treated with 5 mg/kg/day PFHxS. CONCLUSION: These results indicate that chronic exposure of mice to 5 mg/kg/day PFHxS affects reproductive functions by inhibiting kisspeptin expression in the ARC and AVPV regions, leading to deficits in follicular development and ovulation.

Removal of perfluoroalkanesulfonic acids (PFSAs) from synthetic and natural groundwater by electrocoagulation.

Severe contaminations of perfluoroalkanesulfonic acids (PFSAs) existed in the natural groundwater beneath a fluorochemical industrial park (FIP) in Fuxin of China. In the present study, systematic researches were performed to determine the best conditions of efficient treatment for 1 mg L-1 of PFSAs in the synthetic groundwater samples with the periodically reverse electrocoagulation (PREC) using the Al-Zn electrodes. Based upon the orthogonal experiments, the removal efficiencies of perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) could reach 87.4%, 95.6%, and 100%, respectively, within the initial 10 min, under the optimal conditions of voltage at 12.0 V, pH at 7.0, and stirring speed at 400 rpm. In addition, the optimized PREC technique was further applied to remove the PFSA contaminations from the natural groundwater samples of the Fuxin FIP, subsequently generating the removal efficiencies of three target PFSA analytes in the range between 59.0% and 100% at 60 min. Moreover, the SEM-EDS analyses showed the hydroxide flocs formed during the process of PREC treatment had clear characteristics of floc aggregates, with the major constituents of O, Al, C, N, Zn, and F elements. As a result, long-chain PFHxS and PFOS tended to be eliminated completely from the natural groundwater by their absorptions on the Al-Zn hydroxide flocs, potentially because of their higher hydrophobicity compared with short-chain PFBS.

Perfluoroalkyl substances in umbilical cord serum and gestational and postnatal growth in a Chinese birth cohort.

Although animal studies have found that perfluoroalkyl substances (PFASs) affect gestational and postnatal growth, the epidemiological findings are limited and not in agreement. We explored the associations of PFAS concentrations in umbilical cord blood with gestational and postnatal growth in China. Three hundred thirty-seven singleton newborns and their mothers were recruited from November 2013 to December 2015 in Zhoukou City, China. Umbilical cord blood was collected to measure eleven PFASs by liquid chromatography-mass spectrometry. The index of gestational and postnatal growth contained fetal weight, length, and head circumference. These were obtained at birth and at the follow-up investigation (mean 19 months). Exposed to higher perfluorooctanoic acid (PFOA) were connected with reduced length at birth (p for trend = 0.01) and decreased postnatal weight (ß = -429.2 g; 95% CI: -858.4, -0.121 for 2nd VS. 1st). Exposed to perfluoroundecanoic acid (PFUdA) were positively associated with indications of gestational growth and postnatal growth (p for trend = 0.02 for birth length; p for trend = 0.04 for postnatal length). Exposed to higher perfluorododecanoic acid (PFDoA) were associated with lower birth weight (ß = -122.9 g, 95% CI: -244.7 to -1.2 for 2nd VS. 1st), but higher postnatal length (p for trend = 0.03). Neonates in the highest exposure group of per-fluorohexanesulfonate (PFHxS) showed decreased birth length (ß = -0.33 cm, 95% CI: -0.68 to -0.01, for 2nd VS. 1st), but increased postnatal head circumference (p for trend = 0.04). Increased PFOA concentrations was associated with shorter birth length only in girls (p for trend = 0.04), suggesting that the effect of PFASs on gestational growth were different between boys and girls. In utero exposure to PFASs may affect gestational and postnatal growth.

Effects of steaming on contaminants of emerging concern levels in seafood.

Seafood consumption is a major route for human exposure to environmental contaminants of emerging concern (CeCs). However, toxicological information about the presence of CeCs in seafood is still insufficient, especially considering the effect of cooking procedures on contaminant levels. This study is one among a few who evaluated the effect of steaming on the levels of different CeCs (toxic elements, PFCs, PAHs, musk fragrances and UV-filters) in commercially relevant seafood in Europe, and estimate the potential risks associated with its consumption for consumers. In most cases, an increase in contaminant levels was observed after steaming, though varying according to contaminant and seafood species (e.g. iAs, perfluorobutanoate, dibenzo(ah)anthracene in Mytilus edulis, HHCB-Lactone in Solea sp., 2-Ethylhexyl salicylate in Lophius piscatorius). Furthermore, the increase in some CeCs, like Pb, MeHg, iAs, Cd and carcinogenic PAHs, in seafood after steaming reveals that adverse health effects can never be excluded, regardless contaminants concentration. However, the risk of adverse effects can vary. The drastic changes induced by steaming suggest that the effect of cooking should be integrated in food risk assessment, as well as accounted in CeCs regulations and recommendations issued by food safety authorities, in order to avoid over/underestimation of risks for consumer health.

Perfluoroalkyl acids-induced liver steatosis: Effects on genes controlling lipid homeostasis.

Persistent presence of perfluoroalkyl acids (PFAAs) in the environment is due to their extensive use in industrial and consumer products, and their slow decay. Biochemical tests in rodent demonstrated that these chemicals are potent modifiers of lipid metabolism and cause hepatocellular steatosis. However, the molecular mechanism of PFAAs interference with lipid metabolism remains to be elucidated. Currently, two major hypotheses are that PFAAs interfere with mitochondrial beta-oxidation of fatty acids and/or they affect the transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) in liver. To determine the ability of structurally-diverse PFAAs to cause steatosis, as well as to understand the underlying molecular mechanisms, wild-type (WT) and PPARα-null mice were treated with perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), or perfluorohexane sulfonate (PFHxS), by oral gavage for 7days, and their effects were compared to that of PPARα agonist WY-14643 (WY), which does not cause steatosis. Increases in liver weight and cell size, and decreases in DNA content per mg of liver, were observed for all compounds in WT mice, and were also seen in PPARα-null mice for PFOA, PFNA, and PFHxS, but not for WY. In Oil Red O stained sections, WT liver showed increased lipid accumulation in all treatment groups, whereas in PPARα-null livers, accumulation was observed after PFNA and PFHxS treatment, adding to the burden of steatosis observed in control (untreated) PPARα-null mice. Liver triglyceride (TG) levels were elevated in WT mice by all PFAAs and in PPARα-null mice only by PFNA. In vitro ß-oxidation of palmitoyl carnitine by isolated rat liver mitochondria was not inhibited by any of the 7 PFAAs tested. Likewise, neither PFOA nor PFOS inhibited palmitate oxidation by HepG2/C3A human liver cell cultures. Microarray analysis of livers from PFAAs-treated mice indicated that the PFAAs induce the expression of the lipid catabolism genes, as well as those involved in fatty acid and triglyceride synthesis, in WT mice and, to a lesser extent, in PPARα-null mice. These results indicate that most of the PFAAs increase liver TG load and promote steatosis in mice We hypothesize that PFAAs increase steatosis because the balance of fatty acid accumulation/synthesis and oxidation is disrupted to favor accumulation.