Article

Brain region-specific perfluoroalkylated sulfonate (PFSA) and carboxylic acid (PFCA) accumulation and neurochemical biomarker Responses in east Greenland polar Bears (Ursus maritimus)

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... U. maritimus in East Greenland had liver levels of PFAS averaging 3546 ng/g wet weight while male U. maritimus had an average of 22.92 ng/g wet weight PFOS, 28.82 ng/g total perfluorosulfonates, 1.09 ng/g PFOA, and 99.40 ng/g total perfluorocarboxylates in the brain (Table 1) [42,52]. Another study on U. maritimus mothers found plasma levels of total PFAS to be 539.0 ± 20.8 ng/g wet weight, with PFOS and PFOA levels equaling 431.9 ± 17.0 ng/g wet weight and 6.4 ± 0.6 ng/g wet weight [68]. ...
... Another study on U. maritimus from East Greenland studied the effects on various parts of the brain [52]. Glutathione synthase activity was positively correlated with levels of PFOS, total perfluorosulfonates, and perfluoroundecanoate (PFUnDA) and borderline correlated to levels of perfluorododecanoate (PFDoDA), perfluorotetradecanoate (PFTrDA), and total perfluorocarboxylates in the occipital lobe, and positively correlated with PFOS and total perfluorosulfonates in the frontal cortex while being negatively correlated with total perfluorosulfonates in the hypothalamus (Table 3) [52]. ...
... Another study on U. maritimus from East Greenland studied the effects on various parts of the brain [52]. Glutathione synthase activity was positively correlated with levels of PFOS, total perfluorosulfonates, and perfluoroundecanoate (PFUnDA) and borderline correlated to levels of perfluorododecanoate (PFDoDA), perfluorotetradecanoate (PFTrDA), and total perfluorocarboxylates in the occipital lobe, and positively correlated with PFOS and total perfluorosulfonates in the frontal cortex while being negatively correlated with total perfluorosulfonates in the hypothalamus (Table 3) [52]. This indicates that there is generally an upregulation of oxidative stress mechanisms with increased levels of PFAS in the brain. ...
Article
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Per- and polyfluoroalkyl substances (PFAS) are a class of chemicals that were widely used in manufacturing and are now present in the environment throughout the world. It is known that various PFAS are quantifiable in human in blood, but potential adverse health outcomes remain unclear. Sentinel and non-traditional model species are useful to study potential toxicity of PFAS in order to understand the relationship between environmental and human health. Here, we present a critical review of studies on the neurotoxicity of PFAS in sentinel and non-traditional laboratory model systems, including Caenorhabditis elegans (nematode), Dugesia japonica (planarian), Rana pipiens (frogs), Danio rerio and Oryzias melastigma (fish), and Ursus maritimus (polar bears). PFAS have been implicated in developmental neurotoxicity in non-traditional and traditional model systems as well as sentinel species, including effects on neurotransmitter levels, especially acetylcholine and its metabolism. However, further research on the mechanisms of toxicity needs to be conducted to determine if these chemicals are affecting organisms in a similar manner. Overall, findings tend to be similar among the various species, but bioaccumulation may vary, which needs to be taken into account in future studies by quantifying target organ concentrations of PFAS to better compare different species. Furthermore, data on the majority of PFAS is lacking in neurotoxicity testing, and additional studies are needed to corroborate findings thus far.
... Similarly, for OHCs there is an established and growing literature base showing that, for example, exposure to PCBs and PBDEs is associated with adverse neurological outcomes (Mariussen and Nonnum, 2006). High-trophic level, fish-eating wildlife species can biomagnify contaminants such as PCBs and PBDEs, which have been shown to elicit exposure-associated neurological effects (Basu and Head, 2010;Basu, 2012Basu, , 2015. Although many studies show Arctic marine mammals can bioaccumulate substantial levels of MeHg and OHCs, little is known about their uptake into brain tissue. ...
... Brain Hg levels are consistently lowest in ringed seal and polar bear, and across all brain regions studied in these species. Brain Hg levels in pilot whale, harbor porpoise, and narwhal are much higher and range at upwards of 80 µg/g dw, levels associated with clinical neurotoxicity in mammals (Basu, 2012(Basu, , 2015. ...
... The study demonstrated that both PFCAs and perfluoroalkyl sulfonates (PFSAs) cross the blood-brain barrier in polar bears and that wet-weight concentrations are brain region-specific. In a follow-up study on PFASs in several brain regions of polar bears from East Greenland collected in 2011-2012 (Pedersen et al., 2015(Pedersen et al., , 2016, the most abundant PFAS was again PFOS and accounted for approximately 90% of ΣPFSAs. The highest concentrations of PFASs were measured in brainstem, cerebellum and hippocampus. ...
... PFAS have been found in the brain, indicating that they cross the blood brain barrier and are potentially neurotoxic (Eggers Pedersen et al., 2015;Greaves and Letcher, 2013). Previous research in mice and rats have conflicting evidence as to whether PFOS causes decreased motor function after developmental exposure (Onishchenko et al., 2011;Johansson et al., 2009;Johansson et al., 2008). ...
... PFOS has also been shown to cause dopaminergic neurotoxicity and decreased motor function in Ceanorhabditis elegans (Sammi et al., 2019). In polar bears, various PFAS have been correlated with increased monoamine oxidase activity, muscarinic acetylcholine receptor density, and decreased acetylcholinesterase (AChE) activity (Eggers Pedersen et al., 2015). Female marine medaka exposed to PFBS also had increased acetylcholine (ACh) and choline levels, while males did not (Chen et al., 2018b). ...
... Taken together with previous findings from our group and others, the literature strongly suggest that the nervous system is an important target organ affected by PFAS exposure. PFOS and other compounds tested here have been shown to bioaccumulate in numerous mammalian taxa, but to our knowledge, this is the first study to demonstrate PFOS accumulation in amphibian brains (Eggers Pedersen et al., 2015;Austin et al., 2003;Dassuncao et al., 2019;Maestri et al., 2006). We measured brain burdens of amphibians exposed to ecologically relevant concentrations of PFAS in water and demonstrate dose-dependent bioaccumulation of PFOS in brain. ...
Article
Per- and polyfluoroalkyl substances (PFAS) are present in water and >99% of human serum. They are found in brains of wildlife; however, little is known about effects on the developing brain. To determine the effects of PFAS on brain and cardiac innervation, we conducted an outdoor mesocosm experiment with Northern leopard frog larvae (Rana pipiens) exposed to control, 10 ppb perfluorooctane sulfonate (PFOS), or a PFAS mixture totaling 10 ppb that mimicked aqueous film forming foam-impacted surface water (4 ppb PFOS, 3 ppb perfluorohexane sulfonate, 1.25 ppb perfluorooctanoate, 1.25 ppb perfluorohexanoate, and 0.5 ppb perfluoro-n-pentanoate). Water was spiked with PFAS and 25 larvae (Gosner stage (GS) 25) added to each mesocosm (n = 4 mesocosms per treatment). After 30 days, we harvested eight brains per mesocosm and remaining larvae developed to GS 46 (i.e. metamorphosis) before brains and hearts were collected. Weight, length, GS, and time to metamorphosis were recorded. Brain concentrations of all five PFAS were quantified using LC/MS/MS. Dopamine and metabolites, serotonin and its metabolite, norepinephrine, γ-aminobutyric acid, and glutamate were quantified using High Performance Liquid Chromatography with electrochemical detection while acetylcholine and acetylcholinesterase activity were quantified with the Invitrogen Amplex Red Acetylcholine Assay. PFOS accumulated in the brain time- and dose-dependently. After 30 days, the mixture decreased serotonin while both PFAS treatments decreased glutamate. Interestingly, acetylcholine increased in PFAS treatments at GS 46. This research shows that developmental environmentally relevant exposure to PFAS changes neurotransmitters, especially acetylcholine.
... Polar bears, the apex predator in Arctic regions, have been found to be among the most contaminated wildlife (Houde et al., 2011). The specific distribution of PFSAs has been studied in brains from East Greenland polar bears Pedersen et al., 2015), showing that these chemicals cross the blood-brain barrier of bears and that inner regions of the brain contained higher concentrations of PFSAs . Long-chain PFCAs (C 11-15 ) and PFOS were also found to be predominant in brain of polar bears. ...
... However, in recent years, toxico-pathologic studies conducted with marine mammals have reported correlations between blood and tissue PFASs concentrations and markers of biological effects. Table 5.2 summarizes several studies that examined the relationship of concentrations of PFASs related to health in Baikal seals (Ishibashi et al., 2008b), sea otters , bottlenose dolphins (Fair et al., 2013), and polar bears (Pedersen et al., 2015(Pedersen et al., , 2016Sonne et al., 2009;Bourgeon et al., 2017). ...
... Significant relationships have also been found between PFSA and multiple neurochemical markers in specific regions of the brain in polar bears from East Greenland (Pedersen et al., 2015). Specifically, monamine oxidase enzyme activity and receptor density of gamma-butyric acid type A were positively associated with PFAS levels (Pedersen et al., 2015). ...
Chapter
Poly- and perfluoroalkyl substances (PFASs) represent one of the more contemporary chemicals of environmental concern for marine mammals. The most recent information on the spatial distribution, temporal trends, and effects of PFAS contamination in cetaceans, pinnipeds, polar bears, and otters is discussed in this chapter. Levels of PFASs in marine mammals are influenced by geographic distribution as well as species-specific differences in metabolism, diet, and habitat. Concentrations of PFASs, particularly perfluoroalkyl carboxylates, are still increasing in several populations worldwide. Few studies examine health outcomes and cause-effect relationships for PFAS exposure, which are difficult to establish in marine mammals, although many studies suggest adverse effects and increased risks for populations with elevated PFAS levels. A specific case study in bottlenose dolphins (Tursiops truncatus) from the East Coast of the United States is presented as an example of integrated research on PFASs in marine ecosystems. Known information on emerging PFASs of concern and future perspectives on the study of PFASs in marine organisms are also discussed.
... Due to the blood-brain barrier (BBB), the brain is rarely considered a target for POPs (Gebbink et al., 2008;Staddon and Rubin, 1996). However a group of newer emerging POPs has been found to accumulate and reach high concentrations in the brain (Pedersen et al., 2015) The per-and polyfluoroalkyl substances (PFASs) used as oil and waterrepellants in e.g. Teflon and Gore-Tex, comprise fully fluorinated carbon-chains (Lehmler, 2005). ...
... The analysis of PFASs in brain tissues from the 10 polar bears are described in details in Pedersen et al. (2015). Concentrations of four PFSAs i.e. perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), PFOS, perfluorodecane sulfonate (PFDS), and ten PFCAs i.e. perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorododecanoic acid (PFDoDA), perfluorotridecanoic acid (PFTrDA), perfluorotetradecanoic acid (PFTeDA), perfluoropentadecanoic acid (PFPeDA) were measured by the National Wildlife Research Centre, Carleton University, Ontario, Canada. ...
... Data from chemical analyses of PFSA (PFBS, PFHxS, PFOS and PFDS) and PFCA (PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnDA, PFDoDA, PFTrDA, PFTeDA and PFPeDA) are presented in Pedersen et al. (2015) along with elaborate description of analysis and quality control. An overview of PFSA and PFCA concentrations is further shown in SI Tables 2 and 3, respectively. ...
Article
Per- and polyfluoroalkyl substances (PFASs) are emerging in the Arctic and accumulate in brain tissues of East Greenland (EG) polar bears. In vitro studies have shown that PFASs might possess endocrine disrupting abilities and therefore the present study was conducted to investigate potential PFAS induced alterations in brain steroid concentrations. The concentrations of eleven steroid hormones were determined in eight brain regions from ten EG polar bears. Pregnenolone (PRE), the dominant progestagen, was found in mean concentrations of 5–47 ng/g (ww) depending on brain region. PRE showed significantly (p
... Eight brain regions were used for steroid determination: thalamus (n = 7), hippocampus (n = 4), occipital lobe (n = 10), temporal cortex (n = 10), striatum (n = 5), cerebellum (n = 10), brain stem (n = 5) and frontal cortex (n = 10). Steroid concentrations reported in the present study are given as brain average based on the mean concentrations in the analysed compartmentalized tissues (Pedersen et al. 2015). There was a marginally significant trend (p = 0.080) towards TS being higher in male (0.25 ng/g ww) compared to female bears (0.17 ng/g ww). ...
... Recent studies have shown how contaminants such as hydroxylated poly chlorinated biphenyls affect steroidogenesis. Other contaminants such as poly fluorinated compounds and mercury are capable of crossing the blood-brain barrier of polar bears to enter the various brain compartments, with the potential to affect neurological transmitter substances (Basu et al. 2009;Pedersen et al. 2015). Considering the challenges that polar bears are facing regarding Arctic pollution and climate changes, these matters should be studied further. ...
Article
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The polar bear (Ursus maritimus) is threatened by climate changes and also from persistent organic pollutants affecting polar bear endocrinology governing growth and reproduction. To provide further insight into basic polar bear endocrinology, we determined the levels of steroids in multiple tissues and plasma from East Greenland polar bears. Tissue samples from 10 polar bears, 5 males (2 adults, 3 juveniles) and 5 females (all juveniles) were obtained from the Inuit hunt in Scoresby Sound during springtime. Eleven steroids: pregnenolone, 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone, dihydrotestosterone, estrone, 17α-estradiol and 17β-estradiol were determined in brain, adrenal cortex, testis, testicular vein, plasma, and ovary using GC–MS/MS. In brain tissue, the neuroactive progestagen pregnenolone (11.9 ± 4.4 ng/g ww) and dehydroepiandrosterone (2.26 ± 0.43 ng/g ww) were found in high concentrations. Very high levels of testosterone and androstenedione were observed in testes (>100 ng/g ww) and plasma from testicular vein (testosterone: 108 ± 41 ng/ml; androstenedione: 35.2 ± 11.1 ng/ml). Additionally, a strong correlation was found between the levels of steroids in testes and testicular vein plasma. Progestagens were found in very high levels in ovaries from juvenile females (>100 ng/g ww). Finally, our study indicates that polar bears synthesize androstenedione via the ∆-4 pathway. The present study adds new insight to our knowledge on polar bear endocrinology, which may be used in future studies on polar bear ecology and studies on some of the threats from pollution and climate changes that these animals are facing.
... 10,15 Results from other taxa also suggest blood, liver, and kidney contain the highest concentrations of multiple perfluoroalkyl acids (PFAAs), with some indication of preferential uptake of long-chain perfluoroalkyl carboxylic acids (PFCAs, C n F 2n+1 COOH, n ≥ 7) in the brains of marine mammals. 8,14,16 This is in stark contrast to the behavior of hydrophobic organic chemicals like polychlorinated biphenyls (PCBs), which prefer fatty tissue storage. ...
... 9,13,14 Our results indicate that ether-based PFAS chemistries readily migrate across the highly selective blood−brain barrier in vertebrate wild animals subject to environmentally relevant PFEA exposures. Data from polar bears, 16 frogs, 36 and mice 37 suggest some legacy PFAS (PFOS, PFCAs) are associated with alterations of neurochemical signaling and proteins critical for brain development, with uncertain long-term implications. Modeling suggests ether-based PFAS have similar or higher toxic potency compared to PFAAs. ...
Article
Of the thousands of per- and polyfluoroalkyl substances (PFAS) in the environment, few have been investigated in detail. In this study, we analyzed 36 legacy and emerging PFAS in multiple seabird tissues collected from individuals from Massachusetts Bay, Narragansett Bay, and the Cape Fear River Estuary. PFOS was the dominant compound across multiple tissues, while long-chain perfluorinated carboxylic acids (PFCAs) dominated in brain (mean = 44% of total concentrations). Emerging perfluoroalkyl ether acids (PFEAs) - Nafion byproduct-2 and PFO5DoDA - were detected in greater than 90% of tissues in birds obtained from a nesting region downstream from a major fluorochemical production site. Compound ratios, relative body burden calculations, and electrostatic surface potential calculations were used to describe partitioning behavior of PFEAs in different tissues. Novel PFEAs preferentially partition into blood compared to liver and were documented in brain for the first time. PFO5DoDA showed a reduced preference for brain compared to PFCAs and Nafion BP2. These results suggest future monitoring efforts and toxicological studies should focus on novel PFAS and long-chain PFCAs in multiple tissues beyond liver and blood, while exploring the unique binding mechanisms driving uptake of multi-ether PFEAs.
... Steenland et al., 2010). With respect to neurological effects, PFAS (especially PFOS) have been shown to accumulate in the brains of large mammals and have been associated with alterations in neurotransmission Eggers Pedersen et al., 2015). In laboratory animals, PFOS toxicity studies suggest potential neurotoxicity. ...
... Similarly, we observed up to a 13-fold bioconcentration in C. elegans. PFAS accumulate in mammalian brain, suggesting that it will be critical to study total brain and subregional half-lives (blood is usually reported) and adjust dosing regimens accordingly Eggers Pedersen et al., 2015). ...
Article
Perfluorooctane sulfonate (PFOS) has been widely utilized in numerous industries. Due to long environmental and biological half-lives, PFOS is a major public health concern. While the literature suggests PFOS may induce neurotoxicity, neurotoxic mechanisms and neuropathology are poorly understood. Thus, the primary goal of this study was to determine if PFOS is selectively neurotoxic and potentially relevant to specific neurological diseases. Nematodes (Caenorhabditis elegans) were exposed to PFOS or related per- and polyfluoroalkyl substances (PFAS) for 72 hr and tested for evidence of neuropathology through examination of cholinergic, dopaminergic, GABAergic, and serotoninergic neuronal morphologies. Dopaminergic and cholinergic functional analyses were assessed through 1-nonanol and Aldicarb assay. Mechanistic studies assessed total reactive oxygen species, superoxide ions, and mitochondrial content. Finally, therapeutic approaches were utilized to further examine pathogenic mechanisms. Dopaminergic neuropathology occurred at lower exposure levels (25 ppm, ∼50 µM) than required to produce neuropathology in GABAergic, serotonergic, and cholinergic neurons (100 ppm, ∼200 µM). Further, PFOS exposure led to dopamine-dependent functional deficits, without altering acetylcholine-dependent paralysis. Mitochondrial content was affected by PFOS at far lower exposure level than required to induce pathology (≥1 ppm, ∼2 µM). PFOS exposure also enhanced oxidative stress. Further, mutation in mitochondrial superoxide dismutase rendered animals more vulnerable. Neuroprotective approaches such as antioxidants, PFAS-protein dissociation and targeted (mitochondrial) radical and electron scavenging were neuroprotective, suggesting specific mechanisms of action. In general, other tested PFAS were less neurotoxic. The primary impact is to prompt research into potential adverse outcomes related to PFAS-induced dopaminergic neurotoxicity in humans.
... synaptogenesis and synaptic plasticity by altering neuroprotein and neurotransmitter levels, disrupting neural cell differentiation, increasing neuronal cell apoptosis and oxidative stress, and thyroid hormone disruption (Berntsen et al., 2017;Eggers Pedersen et al., 2015;Johansson et al., 2009;Lee and Viberg, 2013;Lee et al., , 2016Liu et al., 2013Liu et al., , 2015Long et al., 2013;Reistad et al., 2013;Slotkin et al., 2008;Yu et al., 2016). Despite the observed biological mechanisms for PFAS neurotoxicity, epidemiological studies have been inconclusive about PFAS' potential to affect cognitive development. ...
... Berntsen et al. (2017) reported that PFOA and PFNA have a more dispersed distribution compared to the aggregate accumulation of PFOS and PFHxS. PFNA also accumulates more in human brain tissue compared to PFOS and PFOA (Eggers Pedersen et al., 2015). Effect measure modification by child sex in our study revealed higher scores in FSIQ among females, but not in males, born to mothers with higher PFOA. ...
Article
Background: Toxicological studies indicate that poly- and perfluoroalkyl substances (PFAS) may be neurotoxic, but human studies have yet to provide compelling evidence for PFAS' impact on cognitive abilities. Objective: To test whether prenatal and childhood PFAS are associated with cognitive abilities at 8 years and whether sex modifies these associations. Methods: We included 221 mother-child pairs from the Health Outcomes and Measures of the Environment (HOME) Study, a birth cohort in Cincinnati, OH (USA). We quantified PFAS in maternal serum at 16 ± 3 weeks gestation and in child serum at 3 and 8 years. We used the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) at age 8 years, assessing Full Scale IQ (FSIQ), verbal comprehension, perceptual reasoning, working memory, and processing speed. We used multiple informant models to estimate covariate-adjusted differences in WISC-IV scores by repeated ln-transformed PFAS. Results: Prenatal and childhood perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were not associated with WISC-IV measures. We observed an increase of 4.1-points (95% CI 0.3, 8.0) and 5.7-points (95% CI 1.2, 10.2) in working memory with 1-ln unit increase in prenatal perfluorooctanoate (PFOA) and perfluorononanoate (PFNA), respectively. In addition, PFNA at 3 years was associated with better FSIQ and perceptual reasoning. Child sex modified the relationship between prenatal PFOA and FSIQ; the association was positive in females only. Sex also modified the association between concurrent PFOS and FSIQ, with males having higher scores. Conclusion: We did not observe adverse associations between prenatal and childhood PFAS and cognitive function at age 8 years.
... Studies of large mammals suggest that PFAS can potentially be neurotoxic to exposed individuals. In polar bears (Ursus maritimus), brain PFAS levels were found to correlate with neurotransmitter alterations (Pedersen et al., 2015). Further, PFAS in North Atlantic pilot whales (Globicephala melas) were found to accumulate in brain, with higher levels only detected in the liver (Dassuncao et al., 2019). ...
... There are not many studies that have reported effects of PFAS on Mao activity. However, a study on Polar bears from Greenland reported a positive relationship between Mao activity and PFAS across brain regions (Pedersen et al., 2015). While this finding may contradict our data, it should be noted, that the ƩPFAS concentrations in the Polar bears were almost 100-fold higher than the measured concentration in the Bank voles from the skiing area. ...
Article
Perfluoroalkyl substances (PFAS) are contaminants that are applied in a wide range of consumer products, including ski products. The present study investigated the neuro-dopamine (DA) and cellular steroid hormone homeostasis of wild Bank voles (Myodes glareolus) from a skiing area in Norway (Trondheim), in relation to tissue concentrations of PFAS. We found a positive association between brain DA concentrations and the concentration of several PFAS, while there was a negative association between PFAS and dopamine receptor 1 (dr1) mRNA. The ratio between DA and its metabolites (3,4-dihydroxyphenylacetic acid: DOPAC and homovanillic acid: HVA) showed a negative association between DOPAC/DA and several PFAS, suggesting that PFAS altered the metabolism of DA via monoamine oxidase (Mao). This assumption is supported by an observed negative association between mao mRNA and PFAS. Previous studies have shown that DA homeostasis can indirectly regulate cellular estrogen (E2) and testosterone (T) biosynthesis. We found no association between DA and steroid hormone levels, while there was a negative association between some PFAS and T concentrations, suggesting that PFAS might affect T through other mechanisms. The results from the current study indicate that PFAS may alter neuro-DA and steroid hormone homeostasis in Bank voles, with potential consequences on reproduction and general health.
... In humans (Homo sapiens), one of the earliest indicators of neurotoxic disease is the disruption of brain neurochemistry resulting in effects on the control of movements, motivation, and cognition (Arias-Carrion and Poppel, 2007;Grandjean and Landrigan, 2006;Manzo et al., 2001;Stamler et al., 2005). Three studies investigated the effects of Hg on polar bear brain neurotransmitters or epigenetics (Basu et al., 2009;Krey et al., 2014;Pilsner et al., 2010) and two studies investigated the effects of PFASs on neurotransmitters (Pedersen et al., 2015(Pedersen et al., , 2016. A study on 82 East Greenland polar bears reported that N-methyl-Daspartate glutamate receptor levels were negatively related to THg and MeHg concentrations in brain stem tissue (oblongated medulla), whereas several other neurotransmitters were not related to Hg concentrations (Basu et al., 2009). ...
... Related in vitro experiments, however, demonstrated that Hg can also inhibit cholinesterase activity and muscarinic acetylcholine receptor binding (Krey et al., 2014). Correlations between PFASs and three neurochemical enzymes and the densities of three central neuroreceptors were further studied across several brain compartments of East Greenland polar bears (n = 6-9), and both positive and negative relationships were reported (Pedersen et al., 2015). The authors concluded that it is unknown whether these alterations are related to negative effects on neurochemistry in the studied bears. ...
Article
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The polar bear (Ursus maritimus) is among the Arctic species exposed to the highest concentrations of long-range transported bioaccumulative contaminants, such as halogenated organic compounds and mercury. Contaminant exposure is considered to be one of the largest threats to polar bears after the loss of their Arctic sea ice habitat due to climate change. The aim of this review is to provide a comprehensive summary of current exposure, fate, and potential health effects of contaminants in polar bears from the circumpolar Arctic required by the Circumpolar Action Plan for polar bear conservation. Overall results suggest that legacy persistent organic pollutants (POPs) including polychlorinated biphenyls, chlordanes and perfluorooctane sulfonic acid (PFOS), followed by other perfluoroalkyl compounds (e.g. carboxylic acids, PFCAs) and brominated flame retardants, are still the main compounds in polar bears. Concentrations of several legacy POPs that have been banned for decades in most parts of the world have generally declined in polar bears. Current spatial trends of contaminants vary widely between compounds and recent studies suggest increased concentrations of both POPs and PFCAs in certain subpopulations. Correlative field studies, supported by in vitro studies, suggest that contaminant exposure disrupts circulating levels of thyroid hormones and lipid metabolism, and alters neurochemistry in polar bears. Additionally, field and in vitro studies and risk assessments indicate the potential for adverse impacts to polar bear immune functions from exposure to certain contaminants.
... Furthermore, the same authors indicated that longer chained PFCAs (C 10 eC 15 ) may be transported across the BBB via mechanisms resembling the transport of saturated fatty acids (Greaves et al., 2013) which may perhaps explain the increased accumulation of the longer chained PFCAs in the brain. Literature on PFUnDA in the brain is sparse, but it was found to be one of the most abundant PFAS measured in the brains of polar bears from Greenland (Eggers Pedersen et al., 2015). Here, PFUnDA was detected at same average concentrations as PFOS across different brain regions, but at lower levels than PFTrDA (Eggers Pedersen et al., 2015). ...
... Literature on PFUnDA in the brain is sparse, but it was found to be one of the most abundant PFAS measured in the brains of polar bears from Greenland (Eggers Pedersen et al., 2015). Here, PFUnDA was detected at same average concentrations as PFOS across different brain regions, but at lower levels than PFTrDA (Eggers Pedersen et al., 2015). Also, in brain samples from harbour seals and red-throated divers the longer chained PFAAs such as PFUnDA have been found to accumulate to a higher extent in brain relative to blood, than shorter chained compounds (Ahrens et al., 2009;Rubarth et al., 2011). ...
Article
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Male and female mice pups were exposed to a low and high dose of a human relevant mixture of persistent organic pollutants (POPs) during pregnancy and lactation. Most compounds detected in the dams were found in offspring brains. The mice offspring exhibited changed expression of hippocampal genes involved in cognitive function (Adora2a, Auts2, Crlf1, Chrnb2, Gdnf, Gnal, Kcnh3), neuroinflammation (Cd47, Il1a), circadian rhythm (Per1, Clock), redox signalling (Hmox2) and aryl hydrocarbon receptor activation (Cyp1b1). A few genes were differentially expressed in males versus females. Mostly, similar patterns of gene expression changes were observed between the low and high dose groups. Effects on learning and memory function measured in the Barnes maze (not moving, escape latency) were found in the high dose group when combined with moderate stress exposure (air flow from a fan). Mediation analysis indicated adaptation to the effects of exposure since gene expression compensated for learning disabilities (escape latency, walking distance and time spent not moving in the maze). Additionally, random forest analysis indicated that Kcnh3, Gnal, and Crlf1 were the most important genes for escape latency, while Hip1, Gnal and the low exposure level were the most important explanatory factors for passive behaviour (not moving). Altogether, this study showed transfer of POPs to the offspring brains after maternal exposure, modulating the expression level of genes involved in brain function.
... In vitro experiments using isolates from polar bear brain tissue, however, demonstrated that Hg can inhibit activity/binding of all the three studied molecules (Krey et al., 2014). Pedersen et al. (2015) studied correlations between PFAS exposure and neurochemical transmitter systems in different brain regions of East Greenland polar bears. The results based on measurements from five to nine individuals support the hypothesis that PFAS concentrations in polar bears from East Greenland are above the threshold limits for neurochemical alterations (Pedersen et al., 2015). ...
... Pedersen et al. (2015) studied correlations between PFAS exposure and neurochemical transmitter systems in different brain regions of East Greenland polar bears. The results based on measurements from five to nine individuals support the hypothesis that PFAS concentrations in polar bears from East Greenland are above the threshold limits for neurochemical alterations (Pedersen et al., 2015). ...
Chapter
Anthropogenic contaminants are present in the pristine Arctic mainly due to long-range transport through air and ocean currents. Regional differences in contamination, variation in food web structure, biotransformation processes, age, sex, breeding status, seasonal changes in food availability, and energy needs may all explain variation in contaminant concentrations within and between Arctic marine mammal species. Contaminant effects have mainly been investigated using correlative approaches based on field samples, whereas an increasing number of modeling and in vitro studies have been published during recent years. In polar bears (Ursus maritimus), contaminant exposures have been associated with adverse health effects at the organismal level, from the molecular level, via the physiologic and pathological levels, and indicatively up to the population level, whereas studies on contaminant effects in Arctic seals and whales are scarcer. Decline of the Arctic sea ice is likely to make polar bears more susceptible to contaminant-related effects.
... Tissue-specific [11,12] bioaccumulation of PFASs in the brain of polar bears has been reported previously , where PFASs were observed to accumu- [13] late preferentially in lipid-rich tissues of the brain (e.g. brain stem) and in particular lipid-rich regions which have fresh supply of blood (e.g. ...
... . A study of PFOA accumulation in [13,14] male and female rat tissue has shown that PFOA accumulates in the liver and blood, but not in adipose tissues . Fundamental [15] studies on the interaction of PFASs with simple model systems are required to understand the interactions of PFASs with more complex biological membranes. ...
Article
The interactions between perfluoroalkyl substances (PFASs) and a phospholipid bilayer (1,2-dimyristoyl-sn-glycero-3-phosphocholine) were investigated at the molecular level using neutron reflectometry. Representative PFASs with different chain length and functional groups were selected in this study including: perfluorobutane sulfonate (PFBS), perfluorohexanoate (PFHxA), perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA), perfluorooctane sulfonate (PFOS), and perfluorooctane sulfonamide (FOSA). All PFASs were found to interact with the bilayer by incorporation, indicating PFAS ability to accumulate once ingested or taken up by organisms. The interactions were observed to increase with chain length and vary with the functional group as SO2NH2(FOSA)>SO2O(-)(PFOS)>COO(-)(PFNA). The PFAS hydrophobicity, which is strongly correlated with perfluorocarbon chain length, was found to strongly influence the interactions. Longer chain PFASs showed higher tendency to penetrate into the bilayer compared to the short-chain compounds. The incorporated PFASs could for all substances but one (PFNA) be removed from the lipid membrane by gentle rinsing with water (2mLmin(-1)). Although short-chain PFASs have been suggested to be the potentially less bioaccumulative alternative, we found that in high enough concentrations they can also disturb the bilayer. The roughness and disorder of the bilayer was observed to increase as the concentration of PFASs increased (in particular for the high concentrations of short-chain substances i.e. PFHxA and PFBS), which can be an indication of aggregation of PFASs in the bilayer.
... Two studies analyzing the concentrations of different PFAS in Frontiers in Toxicology | www.frontiersin.org April 2022 | Volume 4 | Article 881584 8 brains of polar bear (Ursus maritimus) collected after annual Inuit subsistence hunting in East Greenland, reported PFAS concentrations of several different carboxylated and sulfonated congeners across different brain regions (Greaves et al., 2013;Eggers Pedersen et al., 2015). The highest concentrations of PFAS were reported in the hypothalamus, brain stem, thalamus, and cerebellum, whereas the lowest concentrations were observed in the cortex (Greaves et al., 2013;Eggers Pedersen et al., 2015). ...
... April 2022 | Volume 4 | Article 881584 8 brains of polar bear (Ursus maritimus) collected after annual Inuit subsistence hunting in East Greenland, reported PFAS concentrations of several different carboxylated and sulfonated congeners across different brain regions (Greaves et al., 2013;Eggers Pedersen et al., 2015). The highest concentrations of PFAS were reported in the hypothalamus, brain stem, thalamus, and cerebellum, whereas the lowest concentrations were observed in the cortex (Greaves et al., 2013;Eggers Pedersen et al., 2015). Greaves et al. (2013) also reported a positive correlation between longer chain perfluorinated carboxylic acids (PFCAs) and extractable lipid content in the brainstem and cerebellum, hypothesizing that PFCAs with carbon chain lengths between 10 and 15 may be binding to serum proteins and crossing the BBB in a similar way to saturated fatty acids. ...
Article
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Per- and polyfluoroalkyl substances (PFAS) are a class of structurally diverse synthetic organic chemicals that are chemically stable, resistant to degradation, and persistent in terrestrial and aquatic environments. Widespread use of PFAS in industrial processing and manufacturing over the last 70 years has led to global contamination of built and natural environments. The brain is a lipid rich and highly vascularized organ composed of long-lived neurons and glial cells that are especially vulnerable to the impacts of persistent and lipophilic toxicants. Generally, PFAS partition to protein-rich tissues of the body, primarily the liver and blood, but are also detected in the brains of humans, wildlife, and laboratory animals. Here we review factors impacting the absorption, distribution, and accumulation of PFAS in the brain, and currently available evidence for neurotoxic impacts defined by disruption of neurochemical, neurophysiological, and behavioral endpoints. Emphasis is placed on the neurotoxic potential of exposures during critical periods of development and in sensitive populations, and factors that may exacerbate neurotoxicity of PFAS. While limitations and inconsistencies across studies exist, the available body of evidence suggests that the neurobehavioral impacts of long-chain PFAS exposures during development are more pronounced than impacts resulting from exposure during adulthood. There is a paucity of experimental studies evaluating neurobehavioral and molecular mechanisms of short-chain PFAS, and even greater data gaps in the analysis of neurotoxicity for PFAS outside of the perfluoroalkyl acids. Whereas most experimental studies were focused on acute and subchronic impacts resulting from high dose exposures to a single PFAS congener, more realistic exposures for humans and wildlife are mixtures exposures that are relatively chronic and low dose in nature. Our evaluation of the available human epidemiological, experimental, and wildlife data also indicates heightened accumulation of perfluoroalkyl acids in the brain after environmental exposure, in comparison to the experimental studies. These findings highlight the need for additional experimental analysis of neurodevelopmental impacts of environmentally relevant concentrations and complex mixtures of PFAS.
... The most widely studied PFAS have been shown to disrupt the hormone system in animals and are therefore classed as endocrine disruptors 21 . PFAS have been detected in marine mammals, seabirds and predators across the world 22,23 , with levels in remote Greenland polar bears high enough to cause potential neurological damage 24 . Animal studies have also shown links to reduced immunity 25 , liver damage 26 , pancreatic damage 27 and disruption to the growth and development of young, even at low levels 28,29 . ...
... Finally, alteration of behavior caused by contaminant exposure has been observed in other mammals (Clotfelter et al. 2004;Patisaul and Adewale 2009;Zimmer et al. 2009). Therefore, combining contaminant concentration information with behavioral observations of wild polar bears may be useful given that the contaminants can affect vitamin and hormone concentrations (Villanger et al. 2011;Bechshoft et al. 2015;Pedersen et al. 2015;Bechshoft et al. 2016b), which in turn may affect behavior. Similarly, a change in feeding behavior could affect contaminant exposure (McKinney et al. 2013;McKinney et al. 2015). ...
Article
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Ecotoxicology evolved as a scientific field as awareness of the unintended effects of anthropogenic pollutants in biota increased. Polar bears (Ursus maritimus) are often the focus of Arctic contaminant exposure studies because they are apex predators with high contaminant loads. While early studies focused on describing and quantifying pollutants, present-day polar bear toxicological papers often incorporate ecological variables. This systematic literature review investigates the ecological and physiological variables that have been integrated in such studies. The systematic literature search resulted in 207 papers, published between 1970 and 2016. Representation of each of the 19 polar bear subpopulations varied from 0 to 72 papers; East Greenland, Barents Sea, Southern Beaufort Sea, and Lancaster Sound had the most published research, with over 30 papers each. Samples were collected between 1881 and 2015, primarily from harvested bears (66%); most from the 1990s and 2000s. Adipose tissue, liver, and blood were the most common tissues examined, and mean number of bears analyzed per paper was 76 (range 1–691). Papers investigating temporal trends did so using a mean sample of 61 bears over a 6-year period.The frequency with which ecological and physiological variables were integrated into toxicological papers varied. Age and (or) sex was the only ecological variable(s) considered in 51% of papers. Further, a total of 37% of the papers included in the review investigated physiological effects in relation to contaminant concentrations. Of the papers, 98% dealt with contaminant exposure at the individual level, leaving population level effects largely unstudied. Solitary subadult and adult polar bears were included in 57% and 79% of the papers, respectively. Younger bears were included in fewer papers: yearlings in 20% and cubs-of-the-year in 13%. Only 12% of the papers examined reproduction relative to contaminants. Finally, body condition was included in 26% of the research papers, whereas variables related to polar bear diet were included in ≤9%. Based on our findings, we suggest future polar bear toxicology studies increase sample sizes, include more ecological variables, increase studies on family groups, and increase the applicability of studies to management and conservation by examining pollution effects on reproduction and survival.
... There is considerable concern regarding PFAS' roles in human neurodevelopment given the accumulating data from animal studies highlighting cognitive and behavioral effects in prenatally and neonatally exposed mice (Fuentes et al. 2007;Johansson et al. 2008;Johansson et al. 2009;Viberg et al. 2013). Potential biological pathways for PFAS neurotoxicity include disrupting thyroid hormone homeostasis, affecting neuronal differentiation, altering the cholinergic system, and promoting neuronal cell apoptosis and reactive oxidative stress formation (Berntsen et al. 2017;Eggers Pedersen et al. 2015;Johansson et al. 2008;Johansson et al. 2009;Lee and Viberg 2013;Lee et al. 2016;Liu et al. 2013;Liu et al. 2015;Long et al. 2013;Reistad et al. 2013;Slotkin et al. 2008;Yu et al. 2016). PFAS have been detected in mouse brain (Yu et al. 2016) and can cross human placenta (Monroy et al. 2008). ...
Article
Background: Despite evidence from toxicological studies describing the potential neurotoxicity of perfluoroalkyl substances (PFAS), their role in neurodevelopment remains uncertain amid inconsistent findings from epidemiological studies. Methods: Using data from 218 mother-child dyads from the Health Outcomes and Measures of the Environment Study, we examined prenatal and childhood (3 and 8 years) serum concentrations of four PFAS and inattention, impulsivity, and visual spatial abilities. At 8 years, we used the Conners' Continuous Performance Test-II to assess attention and impulse control and the Virtual Morris Water Maze (VMWM) to measure visual spatial abilities. Results: In multiple informant models, there was no evidence to indicate that prenatal or childhood PFAS are associated with attention. However, there was an inverse association between prenatal ln-perfluorooctanoate (PFOA) and errors of commission (β = -2.0, 95% Confidence Interval [CI] -3.8, -0.3). Ln-perfluorononanoate (PFNA) at 3 years was associated with longer (poorer) VMWM completion times of 3.6 seconds (CI 1.6, 5.6). However, higher concurrent concentrations of ln-perfluorohexane sulfonate (PFHxS) (β = -2.4 s, 95% CI -4.4, -0.3) were associated with shorter (better) times. Higher prenatal PFHxS was positively associated with percentage of traveling distance in the correct quadrant (β = 4.2%, 95% CI 0.8, 7.7), indicating better performance. Conclusion: Findings were mixed for prenatal and childhood PFAS concentrations and visual spatial abilities. There is not enough evidence to support that PFAS are associated with visual spatial abilities as assessed by the VMWM or CPT-II measures of inattention or impulsivity in children at age 8 years.
... These useful properties lend PFASs an important commercial value, which resulted in their employment for over 60 years in a large number of industrial and consumer applications, including stain-resistant coatings, oil-resistant claddings applied to food packaging materials, firefighting foams, insecticides and detergents (Prevedouros et al., 2006;Lindstrom et al., 2011). The extended production of PFASs during the last 60 years, combined with their high resistance against thermal degradation, hydrolysis, photolysis and biodegradation, have resulted in their global distribution, persistence in the environment, even in areas far from anthropogenic activities, and accumulation in biota (Ahrens and Bundschuh, 2014;Eggers Pedersen et al., 2015). Their potential to accumulate is not fully understood yet, depending on each compound's chemical structure (Conder et al., 2008), however it is known that, unlike other persistent halogenated compounds, they have high affinity to proteins and are then easily found in human plasma, where they have a long half-life: Sundström et al. (2012) estimated a mean elimination half-life of 2665 days for perfluorohexanesulfonate. ...
Article
Full-text available
Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are pollutants of anthropic origin with possible side effects on human health. Diet, and in particular fish and seafood, is considered the major intake pathway for humans. The present study investigated the levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) contamination in twenty-five samples of fresh fillet of five widely consumed fish species purchased from large retailers in Italy, to be used for an estimation of the Italian population exposure to these contaminants. PFOS and PFOA were found in all samples, at concentrations up to 1,896 (mean = 627 ng/kg) and 487 ng/kg (mean = 75 ng/kg), respectively, confirming the role of fish as high contributor to human exposure. However, a remarkable inter-species variability was observed, and multiple factors were suggested as potentially responsible for such differences, suggesting that the preferential consumption of certain species could likely increase the intake, and thus the exposure. The exposure estimates for both average and high fish consumers resulted far below the TDIs for PFOS and PFOA in all age groups, confirming the outcomes of EFSA’s scientific report. In particular, the calculated total dietary exposure for the 95th percentile consumers belonging to the toddler age class, the most exposed group, resulted equal to 9.72 ng/kg b.w./day for PFOS and 8.39 ng/kg b.w./day for PFOA.
... Laboratory studies highlight PFAS' roles as potential neurotoxicants, with reports of pronounced effects on cognition and behavior in mice exposed to PFAS during development (Fuentes et al. 2007;Johansson et al. 2008;Johansson et al. 2009;Viberg et al. 2013). Biological mechanisms for PFAS neurotoxicity include alteration of levels of neuroproteins and neurotransmitters involved in synaptogenesis and synaptic plasticity, alteration of neurochemical signaling and homeostasis, disruption of neural cell differentiation, induction of neuronal cell apoptosis, promotion of reactive oxidative stress, and disruption of thyroid hormone homeostasis (Berntsen et al. 2017;Eggers Pedersen et al. 2015;Johansson et al. 2009;Lee and Viberg 2013;Lee et al. 2016;Liu et al. 2013;Liu et al. 2015;Long et al. 2013;Reistad et al. 2013;Slotkin et al. 2008;Yu et al. 2016). Few epidemiological studies have investigated the potential neurotoxicity of childhood PFAS exposures and reported mixed findings of increased impulsivity (Gump et al. 2011), contradictory conclusions regarding ADHD diagnoses (Hoffman et al. 2010;Stein and Savitz 2011), and higher full-scale IQ with increased PFAS concentrations (Stein et al. 2013). ...
Article
Background: Toxicological studies highlight the potential neurotoxicity of perfluoroalkyl substances (PFAS) during fetal development. However, few epidemiological studies have examined the impact of childhood PFAS on neurodevelopment. Methods: We employed data from 208 children in the Health Outcomes and Measures of the Environment Study, a birth cohort (Cincinnati, OH), to examine associations of six serum PFAS concentrations measured at 3 and 8 years with executive function assessed at 8 years using the validated parent-completed Behavior Rating Inventory of Executive Function survey. We used multiple informant models to identify susceptible windows of neurotoxicity to PFAS and executive function. We investigated trajectories of PFAS concentrations and whether sex modified these associations. Results: Each ln-increase in perfluorononanoate (PFNA) at 8 years was associated with a 3.4-point increase (95% CI 0.4, 6.3) in metacognition score, indicating poorer function. Children with PFNA above the median at 8 years had poorer global executive functioning compared to children with concentrations consistently below median levels (β = 6.5, 95% CI 0.2, 12.9). Higher concurrent PFNA was associated with poorer behavior regulation among males, while associations among females were null (pPFNA×sex = 0.018). Children with higher concurrent perfluorooctanoate (PFOA) had increased odds of being at risk of having clinical impairments in metacognition (OR = 3.18, 95% CI 1.17, 8.60). There were no associations between perfluorooctane sulfonate and perfluorohexane sulfonate and executive function. Conclusions: PFNA and PFOA at 8 years, but not 3 years, may be related to poorer executive function at 8 years. Results need to be confirmed in cohort studies with larger sample sizes.
... Field studies of behavioural effects of POPs in polar bears are difficult to conduct due to logistical and ethical constraints. However, several POPs reported in brain tissue of polar bears [74,[108][109][110][111][112] are confirmed or suspected developmental neurotoxicants in humans and experimental animals [29,107,113,114]. POPs might affect brain function or development through many mechanisms, for instance by interacting with brain neurotransmitter systems [113]. ...
Article
Exposure to long-range transported industrial chemicals, climate change and diseases is posing a risk to the overall health and populations of Arctic wildlife. Since local communities are relying on the same marine food web as marine mammals in the Arctic, it requires a One Health approach to understand the holistic ecosystem health including that of humans. Here we collect and identify gaps in the current knowledge of health in the Arctic and present the veterinary perspective of One Health and ecosystem dynamics. The review shows that exposure to persistent organic pollutants (POPs) is having multiple organ-system effects across taxa, including impacts on neuroendocrine disruption, immune suppression and decreased bone density among others. Furthermore, the warming Arctic climate is suspected to influence abiotic and biotic long-range transport and exposure pathways of contaminants to the Arctic resulting in increases in POP exposure of both wildlife and human populations. Exposure to vector-borne diseases and zoonoses may increase as well through range expansion and introduction of invasive species. It will be important in the future to investigate the effects of these multiple stressors on wildlife and local people to better predict the individual-level health risks. It is within this framework that One Health approaches offer promising opportunities to survey and pinpoint environmental changes that have effects on wildlife and human health.
... 23 An increase in carbonchain length has also been associated with a decrease in neuron viability in rats 35 and altered brain activity in polar bears. 36 3.5. Implications for Bioaccumulation. ...
Article
Exposure to poly- and perfluoroalkyl substances (PFASs) has been linked to many negative health impacts in humans and wildlife. Unlike neutral hydrophobic organic pollutants, many PFASs are ionic and have been hypothesized to accumulate in both phospholipids and protein-rich tissues. Here we investigate the role of phospholipids for PFAS accumulation by analyzing associations among concurrent measurements of phospholipid, total protein, total lipid and 24 PFASs in the heart, muscle, brain, kidney, liver, blubber, placenta and spleen of North Atlantic pilot whales (Globicephala melas). The sum of 24 PFASs ( ∑ 24 PFAS ) was highest in the liver (median 260 ng g-1; interquartile range (IQR) 216-295 ng g-1) and brain (86.0; IQR 54.5-91.3 ng g-1), while phospholipid levels were highest in brain. The relative abundance of PFASs in the brain greatly increases with carbon chain lengths of 10 or greater, suggesting shorter-chained compounds may cross the blood-brain barrier less efficiently. Phospholipids were significant predictors of the tissue distribution of the longest-chained PFASs: perfluorodecanesulfonate (PFDS), perfluorododecanoate (PFDoA), perfluorotridecanoate (PFTrA), and perfluorotetradecanoic acid (PFTA) (rs = 0.5-0.6). In all tissues except the brain, each 1 mg g-1 increase in phospholipids led to a 12%-25% increase in the concentration of each PFAS. We conclude that partitioning to phospholipids is an important mechanism of bioaccumulation for long-chained PFASs in marine mammals.
... The negative relationship between SPCBs and BCI shown in Fig. 5 indicates that these POPs may still have a negative impact on male polar bear health depending on their condition, and thus particularly in years with little sea ice, when the bears may have low access to food, and thus a low BCI. Furthermore, a recent study shows that emerging contaminants such as perfluoroalkyl substances may affect polar bear physiology (Pedersen et al., 2015) which may add to the negative consequences of climate changes and legacy POPs. ...
Article
The aim of this study was to determine the effects of persistent organic pollutants (POPs) and biometric variables on circulating levels of steroid hormones (androgens, estrogens and progestagens) in male polar bears (Ursus maritimus) from Svalbard, Norway (n = 23). Levels of pregnenolone (PRE), progesterone (PRO), androstenedione (AN), dehydroepiandrosterone (DHEA), testosterone (TS), dihydrotestosterone (DHT), estrone (E1), 17α-estradiol (αE2) and 17β-estradiol (βE2) were quantified in polar bear serum by gas chromatography tandem mass spectrometry (GC-MS/MS), while POPs were measured in plasma. Subsequently, associations between hormone concentrations (9 steroids), POPs (21 polychlorinated biphenyls (PCBs), 8 OH-PCBs, 8 organochlorine pesticides (OCPs) and OCP metabolites, and 2 polybrominated diphenyl ethers (PBDEs)) and biological variables (age, head length, body mass, girth, body condition index), capture date, location (latitude and longitude), lipid content and cholesterol levels were examined using principal component analysis (PCA) and orthogonal projections to latent structures (OPLS) modelling. Average concentrations of androgens, estrogens and progestagens were in the range of 0.57-83.7 (0.57-12.4 for subadults, 1.02-83.7 for adults), 0.09-2.69 and 0.57-2.44 nmol/L, respectively. The steroid profiles suggest that sex steroids were mainly synthesized through the Δ-4 pathway in male polar bears. The ratio between androgens and estrogens significantly depended on sexual maturity with androgen/estrogen ratios being approximately 60 times higher in adult males than in subadult males. PCA plots and OPLS models indicated that TS was positively related to biometrics, such as body condition index in male polar bears. A negative relationship was also observed between POPs and DHT. Consequently, POPs and body condition may potentially affect the endocrinological function of steroids, including development of reproductive tissues and sex organs and the general condition of male polar bears.
... The potency of some BFRs was higher than the potency for natural ligands or clinical drugs used as positive controls. The perfluoroalkyl substances have been shown to alter neurochemical activity in polar bears (Eggers-Pedersen et al., 2015). Many POPs can be found in brain lipids. ...
Chapter
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Wild mammals have a diversity of reproductive strategies and endocrine adaptations to survive and reproduce under hostile environmental conditions. The endocrine system has highly integrated cause and effect physiology with genetic and epigenetic interactivity during a life history. Embryo fetal development is an once-in-a-lifetime event. The fetus has inherent plasticity under maternal influences, and anthropogenic chemicals can have toxicophysiological effects on fetal plasticity. Endocrine-disrupting chemicals (EDCs) in the fetus can cause congenital misprogramming of life stages of the endocrine system, and expression may not occur until puberty and adult life. Congenital changes to the endocrine system also can cause unexpected sensitivity to environmental stimuli. Exposure to EDCs can alter reproductive outcomes. Female fecundity is generally considered to be more sensitive in terms of environmental levels of EDCs required to lower the total lifetime progeny as compared with the environmental level of EDCs that would decrease the fecundity of males. The environmental chemistry of persistent organic pollutants (POPs) is complex, and some POPs may become more toxic after being released into the environment. Exposure of wild mammals to EDCs can occur in utero, from milk ingested during nursing and from the food web. There is also interactivity of the different pollutants in fauna at various life stages. Physical agents can alter reproductive successes.
... Generally, there is a lack of studies investigating the health impact of any PFAS in Arctic marine mammals. The few existing studies have focused on polar bear subpopulations in Svalbard and East-Greenland (recently reviewed by Routti et al., 2019a); studies report possible endocrine disruption (thyroid and steroid hormones) (Bourgeon et al., 2017;Pedersen et al., 2016), neuroendocrine modulations in the brain (Pedersen et al., 2015;Pedersen et al., 2016), and alterations in lipid and energy metabolism (Routti et al., 2019b;Tartu et al., 2017b), as well as potentially carcinogenic, reproductive and immune system effects (only PFOS; risk assessment based) Sonne, 2010). Although concentrations in the present white whales are considerably lower than in polar bears for most PFASs (except FOSA), a study of hooded seals with similar plasma PFAS concentration as in the present white whales, indicated disruption of thyroid function in the seals (Grønnestad et al., 2018). ...
Article
Full-text available
The objective of the present study was to investigate recent concentrations of perfluoroalkyl substances (PFASs) in white whales (Delphinapterus leucas) from Svalbard and compare them to concentrations found in white whales sampled from that same area 15 years ago. Plasma collected from live-captured white whales from two time periods (2013–2014, n = 9, and 1996–2001, n = 11) were analysed for 19 different PFASs. The 11 PFASs detected included seven C8–C14 perfluoroalkyl carboxylates (PFCAs) and three C6–C8 perfluoroalkyl sulfonates (PFSAs) as well as perfluorooctane sulfonamide (FOSA). Recent plasma concentrations (2013–2014) of the dominant PFAS in white whales, perfluorooctane sulfonate (PFOS; geometric mean = 22.8 ng/mL), was close to an order of magnitude lower than reported in polar bears (Ursus maritimus) from Svalbard. PFOS concentrations in white whales were about half the concentrations in harbour (Phoca vitulina) and ringed (Pusa hispida) seals, similar to hooded seals (Cystophora cristata) and higher than in walruses (Odobenus rosmarus) from that same area. From 1996 to 2001 to 2013–2014, plasma concentrations of PFOS decreased by 44%, whereas four C9-12 PFCAs and total PFCAs increased by 35–141%. These results follow a similar trend to what has been reported in other studies of Arctic marine mammals from Svalbard. The most dramatic change has been the decline of PFOS concentrations since 2000, corresponding to the production phase-out of PFOS and related compounds in many countries around the year 2000 and a global restriction on these substances in 2009. Still, the continued dominance of PFOS in white whales, and increasing concentration trends for several PFCAs, even though exposure is relatively low, calls for continued monitoring of concentrations of both PFCAs and PFSAs and investigation of biological effects.
... Diverging results in DA responses after PFAS exposure at different concentrations in different species have also been reported in previous studies (Long et al., 2013;Pedersen et al., 2015;Salgado et al., 2016;Yu et al., 2016;Foguth et al., 2019). For example, adult male rats exposed to PFOS showed increased DA concentrations in the hippocampus and prefrontal cortex (Salgado et al., 2015;Salgado et al., 2016) and male Balb/c mice exposed to PFOA showed increased brain DA concentrations, compared to control (Yu et al., 2016). ...
Article
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In the present study, we investigated the dopaminergic and steroid hormone systems of A/J mice fed environmentally relevant concentrations of a perfluoroalkyl substance (PFAS) mixture over a period of 10 weeks. The PFAS mixture was chosen based on measured PFAS concentrations in earthworms at a Norwegian skiing area (Trondheim) and consisted of eight different PFAS. Dietary exposure to PFAS led to lower total brain dopamine (DA) concentrations in male mice, as compared to control. On the transcript level, brain tyrosine hydroxylase (th) of PFAS exposed males was reduced, compared to the control group. No significant differences were observed on the transcript levels of enzymes responsible for DA metabolism, namely - monoamine oxidase (maoa and maob) and catechol-O methyltransferase (comt). We detected increased transcript level for DA receptor 2 (dr2) in PFAS exposed females, while expression of DA receptor 1 (dr1), DA transporter (dat) and vesicular monoamine transporter (vmat) were not affected by PFAS exposure. Regarding the steroid hormones, plasma and muscle testosterone (T), 11-ketotestosterone (11-KT) and 17β-estradiol (E2) levels, as well as transcripts for estrogen receptors (esr1 and esr2), gonadotropin releasing hormone (gnrh) and aromatase (cyp19) were unaltered by the PFAS treatment. These results indicate that exposure to PFAS doses, comparable to previous observation in earthworms at a Norwegian skiing area, may alter the dopaminergic system of mice with overt consequences for health, general physiology, cognitive behavior, reproduction and metabolism.
... Thus, PFUnDA would stay at relatively significant levels in the brain for at least until hatching. PFUnDA is one of the most abundant PFASs in the brains of polar bears from Greenland (Eggers Pedersen et al., 2015). Also, in brain samples from harbour seals and red-throated divers the longer chained PFASs such as PFUnDA have been found to accumulate to a higher extent in brain relative to blood, than shorter chained compounds (Ahrens et al., 2009;Rubarth et al., 2011). ...
Article
Persistent organic pollutants (POPs) can reach the fetal brain and contribute to developmental neurotoxicity. To explore the distribution of POPs to the fetal brain, we exposed chicken embryos to a POP mixture, containing 29 different compounds with concentrations based on blood levels measured in the Scandinavian human population. The mixture was injected into the allantois at embryonic day 13 (E13), aiming at a theoretical concentration of 10 times human blood levels. POPs concentrations in the brain were measured at 0.5, 1, 2, 4, 6, 24, 48, and 72 h after administration. Twenty-seven of the individual compounds were detected during at least one of the time-points analyzed. Generally, the concentrations of most of the measured compounds were within the order of magnitude of those reported in human brain samples. Differences in the speed of distribution to the brain were observed between the per- and polyfluoroalkyl substances (PFASs), which have protein binding potential, and the lipophilic polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and brominated flame retardants (BFRs). Based on pharmacokinetic modeling, PFASs were best described by a one compartment model. PFASs displayed relatively slow elimination (Kel) and persisted at high levels in the brain. Lipophilic OCPs and PCBs could be fitted to a 2-compartment model. These showed high levels in the brain relative to the dose administrated as calculated by area under the curve (AUC)/Dose. Altogether, our study showed that chicken is a relevant model to explore the distribution of POPs into the developing brain at concentrations which are relevant for humans.
... For example, PCBs and other organochlorine pesticides, trace elements including Hg and Pb, and several PFAS (in particular PFOS) are commonly detected in brain tissue. [121][122][123][124][125][126] These are relevant to human health, particularly in situations where humans and wildlife live in the same geographical region and share similar pathways of exposure. In the Arctic, similar exposure to neurotoxic chemicals such as MeHg, PCBs, PFAS, and POPs occurs among Arctic marine mammals (e.g. ...
Chapter
The study and protection of environmental and human health is complex given the variety of anthropogenic and natural stressors threatening the well-being of exposed organisms. Researchers have turned to wild animals as sentinel species to study the critical questions relating to environmental chemical contamination and potential adverse health effects of contaminant exposure. Marine mammals are one group of animals that are particularly suited as indicators of environmental health because of their long lifespan, high trophic level, spatial distribution at various scales, and propensity to accumulate and respond to environmental contaminants. This chapter discusses how marine mammals are used to monitor and identify chemical pollutants of concern and determine potential health effects on practically all vertebrate physiological systems and across biological scales, from the molecular to the population level. We highlight the diversity of study designs, pollutant classes, methodological tools, and unique insights gained on source, transport, fate, and health effects of contaminants from studies of marine mammal toxicology to showcase the usefulness of these sentinel species as indicators in ecotoxicology.
... There is little experimental evidence that reported polar bears from central East Greenland are experiencing Hg-induced neurological damage (Basu et al. 2009). Similar conclusions were made for PFAS (mainly PFOS), as concentrations were highest in the lowest part of the brain, like brain stem (Eggers-Pedersen et al. 2015). For the teeth, low dental concentrations of THg were reported for East Greenland polar bears (Aubail et al. 2012). ...
Article
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Historical (or legacy) contaminants, such as metals and persistent organic pollutants (POPs; e.g., polychlorinated biphenyls) have been measured in circumpolar subpopulations of polar bears, especially from Hudson Bay, East Greenland, and Svalbard, but substantially less is currently known about new and/or emerging contaminants such as polychlorinated naphthalenes, current-use pesticides, organotins, and polycyclic aromatic compounds (PACs). The polar bear (Ursus maritimus) is an apex Arctic predator that accumulates high levels of bioaccumulative POPs and mercury (Hg), but there is currently no comprehensive profiling of the present knowledge on contaminants in tissue and body compartments in polar bears. Based on current literature reports and data, and including archived museum samples (as far back as the 1300s) and up to 2018, the aim of this review is to utilize available data to examine the comparative distribution and burden of mainly lipophilic contaminants in kidney, liver, fat, and other body compartments, such as milk, blood, and brain. Highlight outcomes from this review include the following: (1) the kidneys are one of the most important tissue depots of contaminants in polar bears; (2) there is a critical lack of data concerning the presence of metals of concern (other than Hg); and (3) there currently are no data available on the concentrations of many newer and emerging contaminants, such as PACs, which is especially relevant given the increasing oil and gas development in regions, such as the Beaufort Sea (Canada). Additionally, given the vulnerability of polar bear populations worldwide, there is a need to develop non-invasive approaches to monitor contaminant exposure in polar bears.
... Studies have shown that sub-lethal exposure to PFOS and PFOA generates similar responses in organisms indicating the possibility of a PFAS class-based response (Gaballah et al., 2020;Kwiatkowski et al., 2020;Vandenbrouck et al., 2010;Yu et al., 2016). However, studies have also questioned whether the inherent differences in the chemistry of these, sulfonic acid vs. carboxylic acid (PFOS and PFOA respectively) leads to differences in the metabolic perturbations observed (Eggers Pedersen et al., 2015;Gebbink and Letcher, 2012;Goodrum et al., 2021). Consequently, this study will determine whether the chemistry of PFAS pollutants impacts the toxic mode of action and types of biochemical pathways that are disrupted while uncovering if the metabolic perturbations caused by sub-lethal GenX exposure reflects that of a class-based response already exhibited by other PFAS. ...
Article
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Per- and polyfluoroalkyl substances (PFAS) are a class of pollutants of concern due to their ubiquitous presence, persistence, and toxicity in aquatic environments. Legacy PFAS pollutants such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been more widely studied in aquatic environments. However, replacement PFAS, such as ammonium perfluoro (2-methyl-3-oxahexanoate; GenX) are increasingly being detected with little known information surrounding their toxicity. Here, Daphnia magna, a model organism for freshwater ecotoxicology was used to compare the acute sub-lethal toxicity of PFOS, PFOA, GenX, and PFAS mixtures. Using liquid chromatography with tandem mass spectrometry (LC-MS/MS), the targeted polar metabolic profile extracted from single Daphnia was quantified to investigate perturbations in the exposure groups versus the unexposed organisms. Multivariate statistical analyses demonstrated significant non-monotonic separation in PFOA, GenX, and PFAS mixture exposures. Sub-lethal exposure to concentrations of PFOS did not lead to significant separation in multivariate analyses. Univariate statistics and pathway analyses were used to elucidate the mode of action of PFAS exposure. Exposure to all individual PFAS led to significant perturbations in many amino acids including cysteine, histidine, tryptophan, glycine, and serine. These perturbations are consistent with biochemical pathway disruptions in the pantothenate and Coenzyme A (CoA) biosynthesis, thiamine metabolism, histidine metabolism, and aminoacyl-tRNA biosynthesis pathways. Overall, the collected metabolomic data is consistent with disruptions in energy metabolism and protein synthesis as the primary mode of action of sub-lethal PFAS exposure. Secondary modes of action among individual pollutant exposures demonstrated that the structural properties (carboxylic acid vs. sulfonic acid group) may play a role in the metabolic perturbations observed. Sub-lethal exposure to PFAS mixtures highlighted a mixed response when compared to the individual pollutants (PFOS, PFOA, and GenX). Overall, this study highlights the niche capability of environmental metabolomics to differentiate secondary modes of action from metabolic perturbations in both single pollutant and pollutant mixtures within the same chemical class.
... More so than in birds, researchers have noted significant associations between PFAS concentrations and effects in these species. In polar bears, significant correlations were observed between brain concentrations of PFOS and PFCAs with changes in a suite of enzymes integral to the neurochemical transmitter system (Pedersen et al. 2015). Kidney concentrations of summed PFCAs, summed PFSAs, and 4 specific PFSAs from 16 species of cetaceans that had been stranded on beaches in Hawaii were significantly correlated with PPARα and cytochrome P4504a (cyp4a) expression in liver (Kurtz et al. 2019 Kannan et al. 2006). ...
Article
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Per- and poly-fluoroalkyl substances (PFAS) encompass a large, heterogenous group of chemicals of potential concern to human health and the environment. Based on information for a few relatively well understood PFAS such as perfluorooctane sulfonate and perfluorooctanoate, there is ample basis to suspect that at least a subset can be considered persistent, bioaccumulative, and/or toxic. However, data suitable for determining risks in either prospective or retrospective assessments are lacking for the majority of PFAS. In August 2019, the Society of Environmental Toxicology and Chemistry sponsored a workshop that focused on the state-of-the-science supporting risk assessment of PFAS. This paper summarizes discussions concerning ecotoxicology and ecological risks of PFAS. First, we summarize currently available information relevant to problem formulation/prioritization, exposure, and hazard/effects of PFAS in the context of regulatory and ecological risk assessment activities from around the world. We then describe critical gaps and uncertainties relative to ecological risk assessments for PFAS and propose approaches to address these needs. Recommendations include the development of more comprehensive monitoring programs to support exposure assessment, an emphasis on research to support the formulation of predictive models for bioaccumulation, and the development of in silico, in vitro, and in vivo methods to efficiently assess biological effects for potentially sensitive species/endpoints. Addressing needs associated with assessing the ecological risk of PFAS will require cross-disciplinary approaches that employ both conventional and new methods in an integrated, resource-effective manner. This article is protected by copyright. All rights reserved.
... Through various mechanisms, contaminants can influence mating and other reproductive behaviours, motivation, communication, aggression, dominance and other social behaviours, as well as learning and other cognitive abilities Landrigan 2006, 2014). Although several POPs are reported in brain tissue of polar bears (Pedersen et al. 2015(Pedersen et al. , 2016, it is extremely difficult to conduct field studies that would provide information on behavioural effects of POPs in polar bears. However, investigations of correlations between contaminant levels and brain neurotransmitters and receptors have been conducted in polar bears from the indigenous hunt in Greenland. ...
Chapter
Exposure to long-range transported industrial chemicals such as persistent organic pollutants (POPs) and other pollutants such as mercury pose a risk to the overall health and populations of Arctic wildlife and the local Inuits. Since local communities are relying on the same marine food web as marine mammals in the Arctic, it requires a One Health approach to understand the holistic ecosystem health including that of the environment, animals and humans. Given the long marine food chains and the biomagnification of most contaminants, top predators such as Inuits, polar bears and toothed whales end up with extremely high exposures posing risks of effects. Here we give a brief overview of the current knowledge on POPs and mercury in the Arctic environment, animals and humans and a discussion on adverse health effects in relation to other stressors such as climate change and zoonotic infectious diseases. Finally, we discuss possible population-level effects of these anthropogenic pollutants and future perspectives for wildlife-human interactions in the Arctic.
... PFCAs have been extensively used in many consumer products such as Scotchgard and the Teflon brand products due to their chemical and thermal stability. PFCAs such as perfluorooctanoic acid (PFOA, C8), PFNA (perfluorononanoic acid, C9), and perfluorodecanoic acid (PFDA, C10) have raised increasing public health concerns due to their highly persistent and bio-accumulative nature, and have been detected in ecosystems (Falandysz et al., 2006;Sinclair et al., 2006) (Smithwick et al., 2005;Calafat et al., 2006;De Silva and Mabury, 2006;Eggers Pedersen et al., 2015;Pasanisi et al., 2016;Boisvert et al., 2019;Jarvis et al., 2021). ...
Article
Perfluorinated carboxylic acids (PFCAs) are environmental pollutants for which human exposure has been documented. PFCAs at high doses were known regulate xenobiotic transporters partly through PPARα and CAR in rodents. Less is known regarding how various PFCAs at a lower concentration modulate transporters for endogenous substrates such as amino acids in human hepatocytes. Such studies are of particular importance because amino acids are involved in chemical detoxification and their transport system may serve as promising therapeutic targets for structurally similar xenobiotics. The focus of this study was to further elucidate how PFCAs modulate transporters involved in intermediary metabolism and xenobiotic biotransformation. We tested the hepatic transcriptomic response of HepaRG cells exposed to 45 mM PFOA, PFNA, or PFDA in triplicates for 24 h (vehicle: 0.1% DMSO), as well as the prototypical ligands for PPARα (WY-14643, 45 µM) and CAR (CITCO, 2 µM). PFCAs with increasing carbon chain lengths (C8-C10) regulated more liver genes, with amino acid metabolism and transport ranked among the top enriched pathways and PFDA ranked as the most potent PFCA tested. Genes encoding amino acid transporters, which are essential for protein synthesis, were novel inducible targets by all 3 PFCAs, suggesting a potentially protective mechanism to reduce further toxic insults. None of the transporter regulations appeared to be through PPARα or CAR but potential involvement of Nrf2 is noted for all 3 PFCAs. In conclusion, PFCAs with increasing carbon chain lengths up-regulate amino acid transporters and modulate xenobiotic transporters to limit further toxic exposures in HepaRG cells. Significance Statement Little is known regarding how various PFCAs modulate the transporters for endogenous substrates in human liver cells. Using HepaRG cells, this study is among the first to show that PFCAs with increasing carbon chain lengths up-regulate amino acid transporters, which are essential for protein synthesis, and modulate xenobiotic transporters to limit further toxic exposures at concentrations lower than what was used in literature.
... Available data also link PFAAs and some of their precursors with several of the environmental hazard traits identified in California's Green Chemistry Hazard Traits Regulations: phytotoxicity (Latała et al. 2009), wildlife developmental impairment (Hagenaars et al. 2011;Ulhaq et al. 2013;Shi et al. 2017a), wildlife reproductive impairment (Liu et al. 2009), and wildlife survival impairment (O'Connor et al. 2014;Klaunig et al. 2015;Eggers Pedersen et al. 2015;Shi et al. 2017a). ...
Article
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Background: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a group of manmade chemicals containing at least one fully fluorinated carbon atom. The widespread use, large number, and diverse chemical structures of PFAS pose challenges to any sufficiently protective regulation, emissions reduction, and remediation at contaminated sites. Regulating only a subset of PFAS has led to their replacement with other members of the class with similar hazards, that is, regrettable substitutions. Regulations that focus solely on perfluoroalkyl acids (PFAAs) are ineffective, given that nearly all other PFAS can generate PFAAs in the environment. Objectives: In this commentary, we present the rationale adopted by the State of California's Department of Toxic Substances Control (DTSC) for regulating PFAS as a class in certain consumer products. Discussion: We at the California DTSC propose regulating certain consumer products if they contain any member of the class of PFAS because: a) all PFAS, or their degradation, reaction, or metabolism products, display at least one common hazard trait according to the California Code of Regulations, namely environmental persistence; and b) certain key PFAS that are the degradation, reaction or metabolism products, or impurities of nearly all other PFAS display additional hazard traits, including toxicity; are widespread in the environment, humans, and biota; and will continue to cause adverse impacts for as long as any PFAS continue to be used. Regulating PFAS as a class is thus logical, necessary, and forward-thinking. This technical position may be helpful to other regulatory agencies in comprehensively addressing this large class of chemicals with common hazard traits. https://doi.org/10.1289/EHP7431.
... This could be explained through the geographical locations of these interactions; mammalian and aquatic predators tend to live in the same area and always hunt in the same area, whereas avian predators tend to venture further afield. 242 For example, significant concentrations of PFASs have been found in polar bears, 244 as well as in different trophic levels of fish. 245 Clearly, we also belong in the food chain and as such are also susceptible to such bioaccumulation. ...
Article
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Over the last 100-120 years, due to the ever-increasing importance of fluorine-containing compounds in modern technology and daily life, the explosive development of the fluorochemical industry led to an enormous increase of emission of fluoride ions into the biosphere. This made it more and more important to understand the biological activities, metabolism, degradation, and possible environmental hazards of such substances. This comprehensive and critical review focuses on the effects of fluoride ions and organofluorine compounds (mainly pharmaceuticals and agrochemicals) on human health and the environment. To give a better overview, various connected topics are also discussed: reasons and trends of the advance of fluorine-containing pharmaceuticals and agrochemicals, metabolism of fluorinated drugs, withdrawn fluorinated drugs, natural sources of organic and inorganic fluorine compounds in the environment (including the biosphere), sources of fluoride intake, and finally biomarkers of fluoride exposure.
... Maternal PFAS serum concentrations during pregnancy were weakly to moderately correlated with 3-year-old children's serum concentrations (Kingsley et al., 2018), whereas concurrent PFAS serum concentrations between child and mother from the same family were moderately correlated Wu et al., 2015). PFAS have been shown to have potential neurobehavioral toxicity in studies with laboratory animals (Mariussen, 2012;Johansson et al., 2008Johansson et al., , 2009Sobolewski et al., 2014;Onishchenko et al., 2011;Sato et al., 2009;Eggers Pedersen et al., 2015;Pinkas et al., 2010). In humans, the associations between exposures to PFAS and neurodevelopmental or behavioral problems are still inconclusive (Braun et al., 2014;Hoffman et al., 2010;Stein and Savitz, 2011;Fei and Olsen, 2011;Niu et al., 2019). ...
Article
Background/objective Per- and polyfluoroalkyl substances (PFAS) display neurobehavioral toxicity in laboratory animal studies. We examined associations of modeled prenatal maternal exposure to PFAS with child diagnosis of autism spectrum disorder (ASD). Methods Participants were 453 mother-child pairs from CHARGE (CHildhood Autism Risk from Genetics and Environment), a population-based case-control study. Children underwent psychometric testing and were clinically confirmed for ASD (n = 239) or typical development (TD, n = 214). At the end of the clinic visit, maternal blood specimens were collected. We quantified nine PFAS in maternal serum samples collected when their child was 2–5 years old. As surrogate in utero exposure, we used a model built from external prospective data in pregnancy and 24 months post-partum and then reconstructed maternal PFAS serum concentrations during pregnancy in this case-control sample. We used logistic regression to evaluate associations of modeled prenatal maternal PFAS concentrations with child ASD. Results Modeled prenatal maternal perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) were borderline associated with increased odds of child diagnosis of ASD (per nanogram per milliliter increase: odds ratio [OR] = 1.46; 95% confidence interval [CI]: 0.98, 2.18 for PFHxS, OR = 1.03; 95% CI: 0.99, 1.08 for PFOS). When compared to the lowest quartile (reference category), the highest quartile of modeled prenatal maternal PFHxS was associated with increased odds of child diagnosis of ASD (OR = 1.95; 95% CI: 1.02, 3.72). Conclusions In analyses where modeled prenatal maternal PFAS serum concentrations served as in utero exposure, we observed that prenatal PFHxS and PFOS exposure, but not other PFAS, were associated with increased odds of child diagnosis of ASD. Further studies in which PFAS concentrations are prospectively measured in mothers and children at a range of developmental stages are needed to confirm these findings.
... PFAS can disrupt thyroid hormone levels, alter neural cell differentiation, disturb neurochemical signaling and homeostasis, alter the susceptibility of the cholinergic system, stimulate neuronal cell apoptosis, and induce the formation of reactive oxidative stress (Berntsen et al., 2017;Eggers Pedersen et al., 2015;Johansson et al., 2009;Johansson et al., 2008;Lee and Viberg, 2013;Lee et al., 2016;Liu et al., 2013;Liu et al., 2015;Long et al., 2013;Reistad et al., 2013;Slotkin et al., 2008;Yu et al., 2016). Experimental studies in mice have reported disturbances in cognition and behavior from PFAS exposures occurring prenatally and neonatally (Fuentes et al., 2007;Johansson et al., 2009;Johansson et al., 2008;Viberg et al., 2013). ...
Article
Background Toxicological studies have raised concerns regarding the neurotoxic effects of per- and polyfluoroalkyl substances (PFAS). However, observational evidence from human studies investigating the association between childhood PFAS and neurobehavior is limited and remains unclear. Objectives To examine whether childhood PFAS concentrations are associated with neurobehavior in children at age 8 years and whether child sex modifies this relationship. Methods We used data from 208 mother-child dyads in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort (Cincinnati, OH, USA). We quantified PFAS in child serum at 3 and 8 years. We assessed neurobehavioral domains using the Behavior Assessment System for Children-2 at 8 years. We used multiple informant models to estimate score changes per ln-increase in repeated PFAS concentrations. Results Childhood PFAS were not associated with Externalizing or Internalizing Problems at 8 years. However, we noted effect measure modification by sex, with higher scores in Externalizing Problems among males per ln-unit increase in perfluorononanoate (PFNA) at 3 years (β = 4.3 points, 95% CI: 1.0, 7.7) while females had lower scores (β = −2.8 points, 95% CI: −4.7, −1.0). More Internalizing Problems were observed among males per ln-unit increase in concurrent PFNA concentrations (β = 3.7 points, 95% CI: 0.7, 6.8), but not in females (β = −1.7 points, 95% CI: −4.6, 1.2). Childhood PFNA concentrations were associated with lower scores for attention problems and activity of daily living. Conclusion While findings do not consistently support an association between childhood PFAS serum concentrations and neurobehavior, child sex may play a role in this relationship.
... However, as revealed in hooded seals (Cystophora cristata) and killer whales (Orcinus orca), maternal transfer of contaminants is recognised as having an important role in determining the relationship between PFOS concentration and age (Andvik et al., 2021;Gabrielsen et al., 2011;Gebbink et al., 2016). High concentrations of PFAS have been reported to disrupt the endocrine system, which can lead to neurological impacts in some species (Dietz et al., 2019;Gabrielsen et al., 2011;Pedersen et al., 2015). High concentrations of PFAS (923 ng/g lipid weight) have further been linked to changes in the immune system in male walruses (Odobenus rosmarus) (Routti et al., 2019). ...
Article
Profiles of 33 PFAS analytes and 12 essential and non-essential trace elements were measured in livers of stranded common dolphins (Delphinus delphis) from New Zealand. PFAS concentrations reported were largely comparable to those measured in other marine mammal species globally and composed mostly of long-chain compounds including perfluorooctanesulfonic acid (PFOS), perfluorododecanoic acid (PFDoDA), perfluorotridecanoic acid (PFTrDA) and perfluorooctanesulfonamide (FOSA). PFAS profiles did not vary significantly by location, body condition, or life history. Notably, significant positive correlations were observed within respective PFAS and trace elements. However, only negative correlations were evident between these two contaminant types, suggesting different exposure and metabolic pathways. Age-associated concentrations were found for PFTrDA and four trace elements, i.e. silver, mercury, cadmium, selenium, indicating differences in the bioaccumulation biomagnification mechanisms. Overall, our results contribute to global understanding of accumulation of PFAS by offering first insights of PFAS exposure in cetaceans living within South Pacific Australasian waters.
Article
Per- and polyfluoroalkyl substances (PFAS) are a group of persistent environmental pollutants that are ubiquitously found in the environment and virtually in all living organisms, including humans. PFAS cross the blood–brain barrier and accumulate in the brain. Thus, PFAS are a likely risk for neurotoxicity. Studies that measured PFAS levels in the brains of humans, polar bears, and rats have demonstrated that some areas of the brain accumulate greater amounts of PFAS. Moreover, in humans, there is evidence that PFAS exposure is associated with attention-deficit/hyperactivity disorder (ADHD) in children and an increased cause of death from Parkinson’s disease and Alzheimer’s disease in elderly populations. Given possible links to neurological disease, critical analyses of possible mechanisms of neurotoxic action are necessary to advance the field. This paper critically reviews studies that investigated potential mechanistic causes for neurotoxicity including (1) a change in neurotransmitter levels, (2) dysfunction of synaptic calcium homeostasis, and (3) alteration of synaptic and neuronal protein expression and function. We found growing evidence that PFAS exposure causes neurotoxicity through the disruption of neurotransmission, particularly the dopamine and glutamate systems, which are implicated in age-related psychiatric illnesses and neurodegenerative diseases. Evaluated research has shown there are highly reproduced increased glutamate levels in the hippocampus and catecholamine levels in the hypothalamus and decreased dopamine in the whole brain after PFAS exposure. There are significant gaps in the literature relative to the assessment of the nigrostriatal system (striatum and ventral midbrain) among other regions associated with PFAS-associated neurologic dysfunction observed in humans. In conclusion, evidence suggests that PFAS may be neurotoxic and associated with chronic and age-related psychiatric illnesses and neurodegenerative diseases. Thus, it is imperative that future mechanistic studies assess the impact of PFAS and PFAS mixtures on the mechanism of neurotransmission and the consequential functional effects.
Article
The toxicity of long chained perfluoroalkyl acids (PFAAs) has previously been reported to be related to the length of the perfluorinated carbon chain and functional group attached. In the present study, we compared the cytotoxicity of six PFAAs, using primary cultures of rat cerebellar granule neurons (CGNs). Two perfluoroalkyl sulfonic acids (PFSAs, chain length C6 and C8) and four perfluoroalkyl carboxylic acids (PFCAs, chain length C8-C11) were studied. These PFAAs have been detected in human blood and the brain tissue of mammals. The cell viability trypan blue and MTT assays were used to determine toxicity potencies (based on LC50 values) after 24hrs exposure (in descending order): perfluoroundecanoic acid (PFUnDA) ≥ perfluorodecanoic acid (PFDA)> perfluorooctanesulfonic acid potassium salt (PFOS)> perfluorononanoic acid (PFNA)> perfluorooctanoic acid (PFOA)>perfluorohexanesulfonic acid potassium salt (PFHxS). Concentrations of the six PFAAs that produced equipotent effects after 24hrs exposure were used to further explore the dynamics of viability changes during this period. Therefore viability was assessed at 10, 30, 60, 90, 120 and 180min as well as 6, 12, 18 and 24hrs. A difference in the onset of reduction in viability was observed, occurring relatively quickly (30-60min) for PFOS, PFDA and PFUnDA, and much slower (12-24hrs) for PFHxS, PFOA and PFNA. A slight protective effect of vitamin E against PFOA, PFNA and PFOS-induced reduction in viability indicated a possible involvement of oxidative stress. PFOA and PFOS did not induce lipid peroxidation on their own, but significantly accelerated cumene hydroperoxide-induced lipid peroxidation. When distribution of the six PFAAs in the CGN-membrane was investigated using NanoSIMS50 imaging, two distinct patterns appeared. Whereas PFHxS, PFOS and PFUnDA aggregated in large hotspots, PFOA, PFNA and PFDA showed a more dispersed distribution pattern. In conclusion, the toxicity of the investigated PFAAs increased with increasing carbon chain length. For molecules with a similar chain length, a sulfonate functional group led to greater toxicity than a carboxyl group.
Article
Data on the occurrences of legacy and alternative per- and polyfluoroalkyl substances (PFASs) in glioma are scarce. It remains unclear if PFASs exposure is related to the prevalence of glioma. A total of 137 glioma and 40 non-glioma brain tissue samples from patients recruited from the Nanfang Hospital, South China were analyzed for 17 PFAS compounds. Perfluorohexanoic acid, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorooctane sulfonamide (FOSA), and 6:2 chlorinated polyfluorinated ether sulfonate were frequently detected (> 60 %) in glioma. The total concentrations (range; median) of 17 PFASs in glioma (0.20–140; 3.1 ng g⁻¹) were slightly higher than those in non-glioma (0.35–32; 2.2 ng g⁻¹), but without statistical significance. The PFAS concentrations in males were statistically higher (p < 0.05) than those in females. Elevated glioma grades were associated with higher concentrations of PFOA, PFOS, and FOSA. Positive correlations were observed between PFAS concentrations (especially for PFOA) and Ki-67 or P53 expression, pathological molecular markers of glioma. Our findings suggested that exposure to PFASs might increase the probability to develop glioma. This is the first case study demonstrating associations between PFASs exposure and brain cancer. More evidences and potential pathogenic mechanisms warranted further investigations.
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Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals colloquially known as "forever chemicals" because of their high persistence. PFAS have been detected in the blood, liver, kidney, heart, muscle and brain of various species. Although brain is not a dominant tissue for PFAS accumulation compared to blood and liver, adverse effects of PFAS on brain functions have been identified. Here, we review studies related to the absorption, accumulation, distribution and toxicity of PFAS in the brain. We summarize evidence on two potential mechanisms of PFAS entering the brain: initiating blood-brain barrier (BBB) disassembly through disrupting tight junctions and relying on transporters located at the BBB. PFAS with diverse structures and properties enter and accumulate in the brain with varying efficiencies. Compared to long-chain PFAS, short-chain PFAS may not cross cerebral barriers effectively. According to biomonitoring studies and PFAS exposure experiments, PFAS can accumulate in the brain of humans and wildlife species. With respect to the distribution of PFAS in specific brain regions, the brain stem, hippocampus, hypothalamus, pons/medulla and thalamus are dominant for PFAS accumulation. The accumulation and distribution of PFAS in the brain may lead to toxic effects in the central nervous system (CNS), including PFAS-induced behavioral and cognitive disorders. The specific mechanisms underlying such PFAS-induced neurotoxicity remain to be explored, but two major potential mechanisms based on current understanding are PFAS effects on calcium homeostasis and neurotransmitter alterations in neurons. Based on the information available about PFAS uptake, accumulation, distribution and impacts on the brain, PFAS have the potential to enter and accumulate in the brain at varying levels. The balance of existing studies shows there is some indication of risk in animals, while the human evidence is mixed and warrants further scrutiny.
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Legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and emerging perfluoroalkyl substances (PFASs) were measured in vegetation and soil samples collected at remote lakes in the Canadian High Arctic. Field studies were carried out in 2015 and 2016 to assess concentrations of POPs, study the relevant sorbing phases, and determine whether Arctic soils were sinks or sources of legacy POPs to the atmosphere and to neighboring lakes. The patterns of legacy POPs in vegetation and soils were dominated by low molecular weight PCB congeners along with OCPs, confirming the importance of long-range atmospheric transport. Lipid and non-lipid organic matter was a key determinant of legacy POPs in Arctic vegetation. Soil organic matter was the main descriptor of hydrophobic PCBs and OCPs in soils, while soil inorganic carbon content, was an important driver of the sorption of PFASs in soils. While contaminant concentrations were low in soil and vegetation, higher PCBs and PFOS organic and inorganic carbon-normalized concentrations were found at Resolute Lake indicating the presence of local sources of contamination. Comparison of fugacities of PCBs in soil and air from Resolute Lake indicated soils as net sources of PCBs to the atmosphere.
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Perfluoroalkyl acids (PFAAs) are persistent environmental contaminants that are associated with various adverse health outcomes. Perfluorooctanoic acid (PFOA) is one of the most prominently detected PFAAs in the environment, which is now replaced with shorter chain carbon compounds including perfluorohexanoic acid (PFHxA) and perfluorobutyric acid (PFBA). The aim of this study was to compare the toxicity of four PFAAs as a function of chain length and head group (carboxylate versus sulfonate) with in vitro and in vivo zebrafish assessments, which were subsequently compared to other cell and aquatic models. Mortality rate increased with chain length (PFOA > PFHxA ≫ PFBA) in both whole embryo/larvae and embryonic cell models. The sulfonate group enhanced toxicity with perfluorobutane sulfonate (PFBS) showing higher toxicity than PFBA and PFHxA in both larvae and cells. Toxicity trends were similar among different aquatic models, but sensitivities varied. Discrepancies with other zebrafish studies were confirmed to be associated with a lack of neutralization of acidic pH of dosing solutions in these other investigations, demonstrating the need for rigor in reporting pH of exposure solutions in all experiments. The zebrafish embryonic cell line was also found to be similar to most other cell lines regardless of exposure length. Overall, results agree with findings in other cell lines and organisms where longer chain length and sulfonate group increase toxicity, except in investigations not neutralizing the exposure solutions for these acidic compounds.
Article
Being at the food chain apex, polar bears (Ursus maritimus) are highly contaminated with persistent organic pollutants (POPs). Females transfer POPs to their offspring through gestation and lactation, therefore, young cubs present higher POPs concentrations than their mothers. Recent studies suggest that POPs affect lipid metabolism in female polar bears, however, the mechanisms and impact on their offspring remain unknown. Here, we hypothesized that exposure to POPs differentially alters genome-wide gene transcription in adipose tissue from mother polar bears and their cubs, highlighting molecular differences in response between adults and young. Adipose tissue biopsies were collected from 13 adult female polar bears and their twin cubs in Svalbard, Norway, in April 2011, 2012 and 2013. Total RNA extracted from biopsies was subjected to next-generation RNA sequencing. Plasma concentrations of summed PCBs, organochlorine pesticides and polybrominated diphenyl ethers in mothers ranged from 897 to 13,620 ng/g wet weight and were associated with altered adipose tissue gene expression in both mothers and cubs. In mothers, 2,502 and 2,586 genes in total were respectively positively and negatively correlated to POP exposure, whereas in cubs, 2,585 positively and 1,690 negatively genes. Between mothers and cubs, 743 positively and negatively genes overlapped between mothers and cubs suggesting partially shared molecular responses to ΣPOPs. ΣPOPs associated genes were involved in numerous metabolic pathways in mothers and cubs, indicating that POP exposure alters energy metabolism, which, in turn, may be linked to metabolic dysfunction.
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Since the last Arctic Monitoring and Assessment Programme (AMAP) effort to review biological effects of the exposure to organohalogen compounds (OHCs) in Arctic biota, there has been a considerable number of new Arctic effect studies. Here, we provide an update on the state of the knowledge of OHC, and also include mercury, exposure and/or associated effects in key Arctic marine and terrestrial mammal and bird species as well as in fish by reviewing the literature published since the last AMAP assessment in 2010. We aimed at updating the knowledge of how single but also combined health effects are or can be associated to the exposure to single compounds or mixtures of OHCs. We also focussed on assessing both potential individual as well as population health impacts using population-specific exposure data post 2000. We have identified quantifiable effects on vitamin metabolism, immune functioning, thyroid and steroid hormone balances, oxidative stress, tissue pathology, and reproduction. As with the previous assessment, a wealth of documentation is available for biological effects in marine mammals and seabirds, and sentinel species such as the sledge dog and Arctic fox, but information for terrestrial vertebrates and fish remain scarce. While hormones and vitamins are thoroughly studied, oxidative stress, immunotoxic and reproductive effects need further investigation. Depending on the species and population, some OHCs and mercury tissue contaminant burdens post 2000 were observed to be high enough to exceed putative risk threshold levels that have been previously estimated for non-target species or populations outside the Arctic. In this assessment, we made use of risk quotient calculations to summarize the cumulative effects of different OHC classes and mercury for which critical body burdens can be estimated for wildlife across the Arctic. As our ultimate goal is to better predict or estimate the effects of OHCs and mercury in Arctic wildlife at the individual, population and ecosystem level, there remain numerous knowledge gaps on the biological effects of exposure in Arctic biota. These knowledge gaps include the establishment of concentration thresholds for individual compounds as well as for realistic cocktail mixtures that in fact indicate biologically relevant, and not statistically determined, health effects for specific species and subpopulations. Finally, we provide future perspectives on understanding Arctic wildlife health using new in vivo, in vitro, and in silico techniques, and provide case studies on multiple stressors to show that future assessments would benefit from significant efforts to integrate human health, wildlife ecology and retrospective and forecasting aspects into assessing the biological effects of OHC and mercury exposure in Arctic wildlife and fish.
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Information on the occurrence and trophodynamics of per- and polyfluoroalkyl substances (PFASs) in the Antarctic region is limited. We investigated the occurrence of PFASs in an ecosystem in the Fildes Peninsula at King George Island and Ardley Island, Antarctica. The profiles, spatial distribution, and trophic transfer behavior of PFASs were further studied. ∑PFASs ranged from 0.50 ± 38.0 ng/g dw (dry weight) in algae to 4.97 ± 1.17 ng/g dw in Neogastropoda (Ngas), which was lower than those in the low- and mid-latitude regions and even Arctic regions. Perfluorobutyric acid (PFBA) was predominant with detection frequencies above 50% in all types of samples, and the relative contribution of PFBA ranged from 22% to 57% in the biota samples. The biomagnification factors of PFBA, perfluoroheptanoate (PFHpA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) between Archaeogastropoda (Agas) and Ngas were 0.67 ± 0.54, 0.77 ± 0.38, 1.04 ± 1.56, 3.30 ± 4.07, and 1.61 ± 0.89, respectively. The trophic magnification factors of PFHxS and PFOS were 2.09 and 2.92, respectively, which indicated that they could be biomagnified through the food chain. Considering the increasing production and uncertain toxicological risks of emerging PFASs and the sensitive ecosystems in Antarctic regions, more attention should be paid, especially for the short-chain ones in the Antarctic region.
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Perfluoroalkyl acids (PFAAs) are man-made organic pollutants that are found ubiquitously in the environment and may impact human health. Here, we review the published literature concerning PFAA impacts on neurobiological, neuroendocrine, and neurobehavioral outcomes. We find that there are many mechanisms through which PFAAs may enter the brain and interact with biochemical endpoints to impact neurological function. These results are supported by epidemiological evidence in humans and experimental evidence in animals that demonstrate numerous and varied PFAA impacts on the nervous system. However, the methods commonly used in animal models of PFAA exposure result in durations of exposure and serum PFAA concentrations in blood that may not appropriately mimic human absorption, distribution, metabolism, and excretion. If animal models lack validity, confidence in mechanistic inferences regarding PFAA exposure and brain function is reduced, limiting these studies' utility. Finally, we end by suggesting some potential impacts of PFAA exposure in human neurological health and disease states whose associations may not readily present themselves in the epidemiological literature.
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Data remain scarce regarding the occurrence of per- and polyfluoroalkyl substances (PFASs) in the human brain for better understanding the cerebral disorders. In this study, we measured the concentrations and profiles of 26 traditional and emerging PFASs in cerebrospinal fluid (CSF), which is a preferred matrix to monitor pollutants in the human brain. Our results indicated perfluorooctanesulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonate (PFHxS) and n-methylperfluorooctanesulfonamidoacetic acid were the most frequently detected congeners (detection frequency >90%). As the predominant congeners, PFOA and PFOS contributed 27.7% and 14.5% of the total amount of PFASs (ΣPFASs), with respective mean concentration of 221 and 115 pg mL⁻¹. In addition, the concentrations of ΣPFASs in CSF of males were generally higher than those of females, which may be related to the different half-lives of PFASs in different sexes. Interestingly, the concentrations of ΣPFASs and several individual congeners (e.g., perfluorohexanoic acid, perfluorodecanoic acid, perfluorononanoic acid, PFHxS and PFOS) increased with age. The highest concentration of ΣPFASs was found in the elderly compared with other age groups, which may be due to the decreased CSF output as age increased. Our data are valuable for further studies regarding the toxic effects of PFASs on the human brain.
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Perfluorinated fatty acids (PFFAs), such as perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA), are known peroxisome proliferators and hepatocarcinogens. A causal link between an increase in the oxidative stress by peroxisomes and tumor promotion has been proposed to explain the hepatocarcinogenicity of PFOA and PFDA. However, the down‐regulation of gap junctional intercellular communication (GJIC) has also been linked to the tumor‐promoting properties of many carcinogens. Therefore, the effect of PFFAs on GJIC in WB‐rat liver epithelial cells was determined. The chain length of the PFFAs tested for an effect on GJIC ranged from 2 to 10, 16 and 18 carbons. Carbon lengths of 7 to 10 inhibited GJIC in a dose–response fashion, whereas carbon lengths of 2 to 5, 16 and 18 did not appreciably inhibit GJIC. Inhibition occurred within 15 min and was reversible, with total recovery from inhibition occurring within 30 min after the removal of the compound from the growth medium. This short time of inhibition suggests that GJIC was modified at the post‐translational level. Also, this short time period was not long enough for peroxisome proliferation. The post‐translational modification of the gap junction proteins was not a consequence of altered phosphorylation as determined by Western blot analysis. Perfluorooctanesulfonic acid also inhibited GJIC in a dose–response fashion similar to PFDA, indicating that the determining factor of inhibition was probably the fluorinated tail, which required 7–10 carbons. Our results suggest that PFFAs could potentially act as hepatocarcinogens at the level of gap junctions in addition to or instead of through peroxisome proliferation.Int. J. Cancer 78:491–495, 1998. © 1998 Wiley‐Liss, Inc.
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The acute biological activity of a homologous series of perfluorinated carboxylic acids - perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) - was studied. To analyze the potential risk of the perfluorinated acids to humans and the environment, different in vitro toxicity test systems were employed. The cytotoxicity of the chemicals towards two different types of mammalian cell lines and one marine bacteria was investigated. The viability of cells from the promyelocytic leukemia rat cell line (IPC-81) and the rat glioma cell line (C6) was assayed calorimetrically with WST-1 reagent. The evaluation was combined with the Vibrio fischeri acute bioluminescence inhibition assay. The biological activity of the compounds was also determined at the molecular level with acetylcholinesterase and glutathione reductase inhibition assays. This is the first report of the effects of perfluorinated acids on the activity of purified enzymes. The results show these compounds have a very low acute biological activity. The observed effective concentrations lie in the millimole range, which is well above probable intracellular concentrations. A relationship was found between the toxicity of the perfluorinated carboxylic acids and the perfluorocarbon chain length: in every test system applied, the longer the perfluorocarbon chain, the more toxic was the acid. The lowest effective concentrations were thus recorded for perfluorononanoic and perfluorodecanoic acids.
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The goal of this article is to summarize new biological monitoring information on perfluorinated compounds (PFCs) in aquatic ecosystems (post-2005) as a followup to our critical review published in 2006. A wider range of geographical locations (e.g., South America, Russia, Antarctica) and habitats (e.g., high-mountain lakes, deep-ocean, and offshore waters) have been investigated in recent years enabling a better understanding of the global distribution of PFCs in aquatic organisms. High concentrations of PFCs continue to be detected in invertebrates, fish, reptiles, and marine mammals worldwide. Perfluorooctane sulfonate (PFOS) is still the predominant PFC detected (mean concentrations up to 1900 ng/g ww) in addition to important concentrations of long-chain perfluoroalkyl carboxylates (PFCAs; sum PFCAs up to 400 ng/g ww). More studies have evaluated the bioaccumulation and biomagnification of these compounds in both freshwater and marine food webs. Several reports have indicated a decrease in PFOS levels over time in contrast to PFCA concentrations that have tended to increase in tissues of aquatic organisms at many locations. The detection of precursor metabolites and isomers has become more frequently reported in environmental assessments yielding important information on the sources and distribution of these contaminants. The integration of environmental/ecological characteristics (e.g., latitude/longitude, salinity, and/or trophic status at sampling locations) and biological variables (e.g., age, gender, life cycle, migration, diet composition, growth rate, food chain length, metabolism, and elimination) are essential elements in order to adequately study the environmental fate and distribution of PFCs and should be more frequently considered in study design.
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Persistent organic pollutants (POPs) encompass an array of anthropogenic organic and elemental substances and their degradation and metabolic byproducts that have been found in the tissues of exposed animals, especially POPs categorized as organohalogen contaminants (OHCs). OHCs have been of concern in the circumpolar arctic for decades. For example, as a consequence of bioaccumulation and in some cases biomagnification of legacy (e.g., chlorinated PCBs, DDTs and CHLs) and emerging (e.g., brominated flame retardants (BFRs) and in particular polybrominated diphenyl ethers (PBDEs) and perfluorinated compounds (PFCs) including perfluorooctane sulfonate (PFOS) and perfluorooctanic acid (PFOA) found in Arctic biota and humans. Of high concern are the potential biological effects of these contaminants in exposed Arctic wildlife and fish. As concluded in the last review in 2004 for the Arctic Monitoring and Assessment Program (AMAP) on the effects of POPs in Arctic wildlife, prior to 1997, biological effects data were minimal and insufficient at any level of biological organization. The present review summarizes recent studies on biological effects in relation to OHC exposure, and attempts to assess known tissue/body compartment concentration data in the context of possible threshold levels of effects to evaluate the risks. This review concentrates mainly on post-2002, new OHC effects data in Arctic wildlife and fish, and is largely based on recently available effects data for populations of several top trophic level species, including seabirds (e.g., glaucous gull (Larus hyperboreus)), polar bears (Ursus maritimus), polar (Arctic) fox (Vulpes lagopus), and Arctic charr (Salvelinus alpinus), as well as semi-captive studies on sled dogs (Canis familiaris). Regardless, there remains a dearth of data on true contaminant exposure, cause-effect relationships with respect to these contaminant exposures in Arctic wildlife and fish. Indications of exposure effects are largely based on correlations between biomarker endpoints (e.g., biochemical processes related to the immune and endocrine system, pathological changes in tissues and reproduction and development) and tissue residue levels of OHCs (e.g., PCBs, DDTs, CHLs, PBDEs and in a few cases perfluorinated carboxylic acids (PFCAs) and perfluorinated sulfonates (PFSAs)). Some exceptions include semi-field studies on comparative contaminant effects of control and exposed cohorts of captive Greenland sled dogs, and performance studies mimicking environmentally relevant PCB concentrations in Arctic charr. Recent tissue concentrations in several arctic marine mammal species and populations exceed a general threshold level of concern of 1 part-per-million (ppm), but a clear evidence of a POP/OHC-related stress in these populations remains to be confirmed. There remains minimal evidence that OHCs are having widespread effects on the health of Arctic organisms, with the possible exception of East Greenland and Svalbard polar bears and Svalbard glaucous gulls. However, the true (if any real) effects of POPs in Arctic wildlife have to be put into the context of other environmental, ecological and physiological stressors (both anthropogenic and natural) that render an overall complex picture. For instance, seasonal changes in food intake and corresponding cycles of fattening and emaciation seen in Arctic animals can modify contaminant tissue distribution and toxicokinetics (contaminant deposition, metabolism and depuration). Also, other factors, including impact of climate change (seasonal ice and temperature changes, and connection to food web changes, nutrition, etc. in exposed biota), disease, species invasion and the connection to disease resistance will impact toxicant exposure. Overall, further research and better understanding of POP/OHC impact on animal performance in Arctic biota are recommended. Regardless, it could be argued that Arctic wildlife and fish at the highest potential risk of POP/OHC exposure and mediated effects are East Greenland, Svalbard and (West and South) Hudson Bay polar bears, Alaskan and Northern Norway killer whales, several species of gulls and other seabirds from the Svalbard area, Northern Norway, East Greenland, the Kara Sea and/or the Canadian central high Arctic, East Greenland ringed seal and a few populations of Arctic charr and Greenland shark.
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Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) belong to the family of perfluorinated compounds. They are used in industrial and consumer applications, e.g., clothing fabrics, carpets, and food packaging. PFOS and PFOA are present in the environment and are found in dust and human milk, which implies that newborns and toddlers can be directly exposed to these agents during brain development. Recently, we reported that PFOS and PFOA can cause neurobehavioral defects and changes in the cholinergic system, in the adult animal, when given directly to neonatal mice, and thereby showing similarities with other investigated persistent organic pollutants, such as dichloro-diphenyl-trichloroethan, polychlorinated biphenyls, and polybrominated diphenyl ethers (PBDEs). In recent studies, we have also seen that highly brominated PBDEs can affect the levels of proteins that are important for neuronal growth and synaptogenesis in the neonatal mouse brain. The present study shows that a single oral dose of either 21 micromol PFOS or PFOA/kg body weight (11.3 or 8.70 mg), given directly to the neonatal mice on postnatal day 10, significantly increased the levels of CaMKII, GAP-43, and synaptophysin in the hippocampus of the neonatal mouse. Both compounds significantly increased the levels of synaptophysin and tau in cerebral cortex, and PFOA also increased the levels of tau in hippocampus. These proteins are important for normal brain development, and altered levels of these proteins during a critical period of the brain growth spurts could be one of the mechanisms behind earlier reported behavioral defects.
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Gap junctional intercellular communication (GJIC) is the major pathway of intercellular signal transduction, and is thus important for normal cell growth and function. Recent studies have revealed a global distribution of some perfluorinated organic compounds, especially perfluorooctane sulfonic acid (PFOS) in the environment. Because other perfluoroalkanes had been shown to inhibit GJIC, the effects of PFOS and related sulfonated fluorochemicals on GJIC were studied using a rat liver epithelial cell line (WB-F344) and a dolphin kidney epithelial cell line (CDK). In vivo effects on GJIC were studied in Sprague-Dawley rats orally exposed to PFOS for 3 days or 3 weeks. Effects on GJIC were measured using the scrape loading dye technique. PFOS, perfluorooctane sulfonamide (PFOSA), and perfluorohexane sulfonic acid (PFHA) were found to inhibit GJIC in a dose-dependent fashion, and this inhibition occurred rapidly and was reversible. Perfluorobutane sulfonic acid (PFBS) showed no significant effects on GJIC within the concentration range tested. A structure activity relationship was established among all 4 tested compounds, indicating that the inhibitory effect was determined by the length of fluorinated tail and not by the nature of the functional group. The results of the studies of the 2 cell lines and the in vivo exposure were comparable, suggesting that the inhibitory effects of the selected perfluorinated compounds on GJIC were neither species- nor tissue-specific and can occur both in vitro and in vivo.
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Disruption of neurochemical parameters in blood and brain tissues can be used as early biomarkers of neurotoxicity in human and wildlife epidemiological studies. To investigate the feasibility of biomarker measurements in field samples obtained from remote locations, tissue storage limits were determined with human blood and mink cortex tissue using efficient and cost-effective microplate assays. Results show that isolated blood platelets and plasma can be stored at 4 degrees C for 4 wk before measurement of monoamine oxidase (MAO) and cholinesterase (ChE) activities, while human lymphocytes can be stored at 4 degrees C for up to 2 d before muscarinic acetylcholine (mACh) receptor binding analysis. Blood cells stored frozen resulted in decreased MAO activity and mACh receptor function. These data suggest that mink brain tissue obtained from field samples can be stored at various temperatures without affecting dopamine (D2) and mACh receptor densities; however, MAO and ChE activities were most stable in samples stored in a -20 degrees C domestic freezer or at 4 degrees C. Multiple freeze/thaw cycles alter mACh and D2 receptors and MAO activity in mink cortex samples and should therefore be minimized. In conclusion, these neurochemical biomarkers can efficiently be measured in large human and wildlife neurotoxicity studies, provided proper storage conditions are maintained.
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Perfluoroalkyl substances were determined in liver tissues and blood of polar bears (Ursus maritimus) from five locations in the North American Arctic and two locations in the European Arctic. Concentrations of perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate, heptadecafluorooctane sulfonamide, and perfluoroalkyl carboxylates with C(8)-C(15) perfluorinated carbon chains were determined using liquid chromatography tandem mass spectrometry. PFOS concentrations were significantly correlated with age at four of seven sampling locations, while gender was not correlated to concentration for any compound measured. Populations in South Hudson Bay (2000-2730 ng/g wet wt), East Greenland (911-2140 ng/g wet wt), and Svalbard (756-1290 ng/g wet wt) had significantly (P < 0.05) higher PFOS concentrations than western populations such as the Chukchi Sea (435-729 ng/g wet wt). Concentrations of perfluorocarboxylic acids (PFCAs) with adjacent chain lengths (i.e., C9:C10 and C10:C11) were significantly correlated (P < 0.05), suggesting PFCAs have a common source within a location, but there were differences in proportions of PFCAs between eastern and western location sources. Concentrations of PFOS in liver tissue at five locations were correlated with concentrations of four polychlorinated biphenyl congeners (180, 153, 138, and 99) in adipose tissue of bears in the same populations, suggesting similar transport pathways and source regions of PFOS or precursors.
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Mercury (Hg) is a global pollutant that is neurotoxic to many mammalian species. The present study was conducted to determine if the bioaccumulation of Hg by wild river otters (Lontra canadensis) could be related to variations in the activities of key neurochemical enzymes. River otters were collected from Ontario and Nova Scotia (Canada) during the trapping seasons, spanning 2002-2004, and their brains were dissected into the cerebral cortex and cerebellum. The activities of cholinesterase (ChE) and monoamine oxidase (MAO) were measured from each sample and correlated with concentrations of brain Hg from the same animal. Significant negative correlations were found between concentrations of brain Hg and ChE (total Hg: r= -0.42; MeHg: r= -0.33) and MAO (total Hg: r= -0.31; MeHg: r= -0.42) activity in the cerebral cortex. The scatterplots relating concentrations of brain Hg and enzyme activity in the cerebral cortex were wedge-shaped, and could be fitted with quantile regression modeling, suggesting that Hg may act as a limiting factor for ChE and MAO activity. No relationships were found in the cerebellum. These data suggest that environmentally relevant concentrations of Hg may influence the activities of ChE and MAO in the cerebral cortex of river otters, and by extension, other fish-eating mammals.
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Perfluorooctane sulfonate (PFOS; C8F17SO3-) is a fully fluorinated organic compound which has been manufactured for decades and was used widely in industrial and commercial products. The recent toxicological knowledge of PFOS mainly concerns mono-substance exposures of PFOS to biological systems, leaving the potential interactive effects of PFOS with other compounds as an area where understanding is significantly lacking. However, a recent study, reported the potential of PFOS to enhance the toxicity of two compounds by increasing cell membrane permeability. This is of particular concern since PFOS has been reported to be widely distributed in the environment where contaminants are known to occur in complex mixtures. In this study, PFOS was evaluated alone and in combination with cyclophosphamide (CPP) to investigate whether a presence of PFOS leads to an increased genotoxic potential of CPP towards hamster lung V79 cells. Genotoxicity was investigated using the micronucleus (MN) assay according to the recent draft ISO/DIS 21427-2 method. PFOS alone demonstrated no genotoxicity up to a concentration of 12.5 microg/ml. However, PFOS combined with two different concentrations of CPP, with metabolic activation, caused a significant increase in the number of micronucleated cells compared to treatments with CPP alone. These results provide a first indication that PFOS has the potential to enhance the genotoxic action of CPP towards V79 cells, suggesting, together with the alterations in cell membrane properties shown previously, that genotoxicity of complex mixtures may be increased significantly by changes in chemical uptake. Together with an earlier study performed by the own working group, it can be concluded that PFOS alone is not genotoxic in this bioassay using V79 cells up to 12.5 microg/ml, but that further investigations are needed to assess the potential interaction between PFOS and other substances, in particular regarding the impact of membrane alterations on the uptake of toxic substances.
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The widespread detection of perfluoroalkyl acids and their derivatives in wildlife and humans, and their entry into the immature brain, raise increasing concern about whether these agents might be developmental neurotoxicants. We evaluated perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonamide (PFOSA), and perfluorobutane sulfonate (PFBS) in undifferentiated and differentiating PC12 cells, a neuronotypic line used to characterize neurotoxicity. We assessed inhibition of DNA synthesis, deficits in cell numbers and growth, oxidative stress, reduced cell viability, and shifts in differentiation toward or away from the dopamine (DA) and acetylcholine (ACh) neurotransmitter phenotypes. In general, the rank order of adverse effects was PFOSA > PFOS > PFBS approximately PFOA. However, superimposed on this scheme, the various agents differed in their underlying mechanisms and specific outcomes. Notably, PFOS promoted differentiation into the ACh phenotype at the expense of the DA phenotype, PFBS suppressed differentiation of both phenotypes, PFOSA enhanced differentiation of both, and PFOA had little or no effect on phenotypic specification. These findings indicate that all perfluorinated chemicals are not the same in their impact on neurodevelopment and that it is unlikely that there is one simple, shared mechanism by which they all produce their effects. Our results reinforce the potential for in vitro models to aid in the rapid and cost-effective screening for comparative effects among different chemicals in the same class and in relation to known developmental neurotoxicants.
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Gap junctional intercellular communication (GJIC) is the major pathway of intercellular signal transduction, and is thus important for normal cell growth and function. Recent studies have revealed a global distribution of some perfluorinated organic compounds, especially perfluorooctane sulfonic acid (PFOS) in the environment. Because other perfluoroalkanes had been shown to inhibit GJIC, the effects of PFOS and related sulfonated fluorochemicals on GJIC were studied using a rat liver epithelial cell line (WBF344) and a dolphin kidney epithelial cell line (CDK). In vivo effects on GJIC were studied in Sprague-Dawley rats orally exposed to PFOS for 3 days or 3 weeks. Effects on GJIC were measured using the scrape loading dye technique. PFOS, perfluorooctane sulfonamide (PFOSA), and perfluorohexane sulfonic acid (PFHA) were found to inhibit GJIC in a dose-dependent fashion, and this inhibition occurred rapidly and was reversible. Perfluorobutane sulfonic acid (PFBS) showed no significant effects on GJIC within the concentration range tested. A structure activity relationship was established among all 4 tested compounds, indicating that the inhibitory effect was determined by the length of fluorinated tail and not by the nature of the functional group. The results of the studies of the 2 cell lines and the in vivo exposure were comparable, suggesting that the inhibitory effects of the selected perfluorinated compounds on GJIC were neither species
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Thousands of environmental contaminants have neurotoxic properties though their ecological risk is poorly characterized. Contaminant-associated disruptions to animal behavior and reproduction, both of which are regulated by the nervous system, provide compelling evidence of harm to decision makers but such apical endpoints are of limited predictive or harm preventative value. Neurochemical biomarkers, which may be used to indicate subtle changes at the subcellular level, may help overcome these limitations. Neurochemical biomarkers have been used for decades in the human health sciences and are now gaining increased attention in the environmental realm. In this review, the applications and implications of neurochemical biomarkers to the field of ecotoxicology are discussed. The paper provides a brief introduction to neurochemistry, covers neurochemical-based adverse outcome pathways (AOPs), discusses pertinent strengths and limitations of neurochemical biomarkers, and provides selected examples across invertebrate and vertebrate taxa (worms, bivalves, fish, terrestrial and marine mammals, birds) to document contaminant-associated neurochemical disruption. With continued research and development, neurochemical biomarkers may increase understanding of mechanisms that underlie injury to ecological organisms, complement other measures of neurological health, and be integrated into risk assessment practices. Environ Toxicol Chem © 2014 SETAC
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Dietary fats affect the fatty acid composition of brain membranes, but the consequences of the fatty acid changes on brain functional activities are poorly understood and not yet established. In order to investigate the effects of diet-induced changes on myelin deposition and on the cholinergic system, the present experiment was designed. Three groups of 10 male Sprague-Dawley rats (initial weight 100 ± 5 g) were fed for 6 weeks diets containing 15% (wt/wt) fish oil (FO), soybean oil (SO), and coconut oil (CO) rich in n-3 fatty acids (38%), n-6 fatty acids (55%), and saturated fatty acids (84%), respectively. The 2′-3′-cyclic nucleotide 3′-phosphodiesterase activity (CNPase) in the whole brain and in the cerebral cortex and the acetylcholinesterase activity (AChE) were determined along with the density and affinity of muscarinic receptor sites. The CNPase activity was significantly higher in the SO-fed group than in the other two groups (62.5 versus 47.0 and 54.4 μmol/hr/mg of protein), and the activity was correlated positively with Σ n-6 and negatively with Σ n-3. The AChE activity, the density, and the affinity of the receptor muscarinic receptor sites were not statistically different among the three groups. The results indicate the favorable effect of soybean oil and the adverse effect of fish oil on myelin deposition and the absence of effect of dietary oils on the cholinergic system. (J. Nutr. Biochem. 7:113-117, 1996.).
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Since 2000 there has been an on-going industrial transition to replace long-chain perfluoroalkyl carboxylic acids(PFCAs), perfluoroalkane sulfonic acids (PFSAs) and their precursors. To date, information on these replacements including their chemical identities, however, has not been published or made easily accessible to the public, hampering risk assessment and management of these chemicals. Here we review information on fluorinated alternatives in the public domain. We identify over 20 fluorinated substances that are applied in [i] fluoropolymer manufacture, [ii] surface treatment of textile, leather and carpets, [iii] surface treatment of food contact materials,[iv] metal plating, [v] fire-fighting foams, and [vi] other commercial and consumer products.We summarize current knowledge on their environmental releases, persistence, and exposure of biota and humans. Based on the limited information available, it is unclear whether fluorinated alternatives are safe for humans and the environment.We identify three major data gaps that must be filled to perform meaningful risk assessments and recommend generation of the missing data through cooperation among all stakeholders (industry, regulators, academic scientists and the public).