Effect of PFAS Molecules for the Human Health: Comparison
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Per- and polyfluoroalkyl substances (PFAS) are a group of over 4700 heterogeneous compounds with amphipathic properties and exceptional stability to chemical and thermal degradation. The unique properties of PFAS compounds has been exploited for almost 60 years and has largely contributed to their wide applicability over a vast range of industrial, professional and non-professional uses. However, increasing evidence indicate that these compounds represent also a serious concern for both wildlife and human health as a result of their ubiquitous distribution, their extreme persistence and their bioaccumulative potential. In light of the adverse effects that have been already documented in biota and human populations or that might occur in absence of prompt interventions, the competent authorities in matter of health and environment protection, the industries as well as scientists are cooperating to identify the most appropriate regulatory measures, substitution plans and remediation technologies to mitigate PFAS impacts.

  • PFAS
  • PFOA
  • PFOS
  • human health
  • ecosystem
  • remediation technologies

1. Introduction

Per-and polyfluoroalkyl substances (PFAS) constitute an heterogeneous group of fluorinated synthetic compounds characterized by the presence of at least one perfluorinated methyl group (−CF3) or a perfluorinated methylene group (−CF2−), a variable number of carbon atoms, fluorination degree and presence of other chemical groups. PFAS are almost ubiquitous into the environment, mainly due to their wide dispersive use and applicability in a vast number of industrial sectors and consumer products [1,2][1][2]. Increasing concern for human health and wildlife ecology derives from the thermal and chemical stability of PFAS molecules and the multiple routes through which humans and biota can be exposed during their lifetime [3,4,5,6,7][3][4][5][6][7]. Of note, while the PFAS family has rapidly expanded into an impressive number of more than 4700 different substances including both the “legacy PFAS” (i.e., PFOS, PFOA) and the “emerging PFAS” (e.g., GenX) [8,9][8][9] producers, decision makers as well as researchers try to gain insights on their impact and to find the most appropriate measures to mitigate the potential risks associated with their exposure. Common features of PFAS are represented by their chemical stability which causes environmental persistence [10], their high mobility which confers them a long-range transport potential [11] causing their pervasive spreading even into remote regions (e.g., the Arctic’s or Antarctic’s) [12,13,14][12][13][14] and their tendency to bioaccumulate and biomagnify in biota through the contamination of the food chains [15,16,17,18,19][15][16][17][18][19]. The presence of some PFAS has been reported in the blood [20[20][21],21], milk [22[22][23],23], urine [24] tissues [25,26,27][25][26][27] and organs [28,29,30,31,32][28][29][30][31][32] of different human populations living in developed countries and has been associated to a number of adverse health effects. Similarly, relevant concentrations of PFAS have been detected in the air [33[33][34],34], groundwater [35[35][36],36], freshwater [17[17][37],37], marinewater [38[38][39],39], drinking water [40,41][40][41] and soil [42,43,44][42][43][44] potentially causing ecotoxic effects in the aquatic and terrestrial ecosystems at the trophic levels of primary producers, primary consumers and secondary consumers [45,46][45][46]. An additional layer of complexity is given by the coexistence of different mixtures of PFAS substances and other contaminants in the environmental media, for which quantitative risk assessment analysis and toxicologic/ecotoxicologic information is still scarce if not absent [47,48][47][48].

2. PFAS Human Exposure and the Potential Effects for Human Health

It is well recognized that multiple exposure pathways can link PFAS emission from the primary or secondary sources to human receptors represented by professional workers as well as general population. Some of the most relevant exposure routes include the inhalation of air and dust particulate, the ingestion of contaminated food and drinking water and the dermal adsorption [204][49]. Despite the presence of some gaps in outhe researchers understanding, it is generally accepted that the dietary intake and the consumption of drinking water represent major pathways for the general population [205,206][50][51] while the relative contribute of inhalation and dermal contact is far more relevant in case of occupational exposure [207,208,209][52][53][54]. It is also believed that PFOS, PFOA, PFNA and PFHxS are the PFAS species that currently contribute most to human exposure, a reason for which provisional measures limiting their daily intake have been proposed in 2020 by the European Food Safety Authority (EFSA) [75][55]. Irrespectively to the specific exposure pathway through which they can get in contact with human targets, PFAS substances represent a serious concern for human health potentially inducing alterations in the development, lipid metabolism and endocrine system, cancerogenicity, immunotoxicity, hepatotoxicity and reprotoxicity. In terms of PFAS risk assessment, the EFSA CONTAM Panel was the first international scientific body to include the data from epidemiological studies to derive health-based guidance values for PFOA and PFOS in 2018. The critical effects of PFOS were identified as a rise in blood total cholesterol in adults and a reduction in antibody response to immunization in children. On the other hand, the key consequence of PFOA was a rise in blood total cholesterol. Reduced birth weight (for both chemicals) and an increased incidence of elevated blood levels of the liver enzyme alanine aminotransferase (ALT) (for PFOA) were also taken into account. Tolerable weekly intake (TWI) of 13 ng/kg body weight (b.w.) per week was defined for PFOS and 6 ng/kg b.w. per week for PFOA after benchmark modelling of serum levels of PFOS and PFOA and estimated the associated daily intakes. It was also observed that the exposure to a significant fraction of the population to both chemicals exceeded the proposed TWIs EFSA (2018) Risk to human health related to the presence of PFOS and PFOA in food [210][56]. The ATSDR (Agency for Toxic Substances and Disease Registry 2018) also included a decreased antibody response to vaccines (PFOA, PFOS, PFHxS, and PFDA) and increased risk of asthma diagnosis (PFOA) among the list of adverse health effects in PFAS-exposed humans (ATSDR Toxicological Profile for Perfluoroalkyls). Furthermore, the International Agency for Research on Cancer (IARC) classed PFOA as “possibly carcinogenic to humans” (Group 2B), based on limited evidence in humans that it might cause testicular and kidney cancer, as well as limited data in animal studies [211][57].
Potential of PFAS to cause a wide range of negative health impacts depends of various factors, such as the conditions of exposure (dose/concentration, duration, route of exposure, etc.) and characteristics associated with the exposed target (e.g., age, sex, ethnicity, health status, and genetic predisposition) [212][58]. The list of biological functions impacted by PFAS in females and males is rapidly expanding. Endocrine disruptive effects have been reported to affect fertility, body weight control, thyroid and mammary gland function. Developmental effects have been observed in children such as alterations in the behaviour or accelerated puberty but also in the new-borns such as decreased birth weight. Increased risk of kidney, prostate and testicular cancer has been associated with long-term exposure to PFAS in the general population alongside with disturbances in the cholesterol metabolism or reduced efficiency of the immune system against infections.
To illustrate this, in the following paragraphs we will describe more in detail some of the adverse effects caused by PFAS compounds, covering some of the recent in vitro, in vivo and epidemiological studies that have been published in the last ten years.

2.1. In Vitro Studies on PFAS Effects

Selected in vitro studies (published since 2010) exploring toxic effects of PFAS are summarised in Table 1. Majority of the presented in vitro studies investigated the impact of PFOA and/or PFOS, while the main observed effects were on thyroid [213,214,215,216][59][60][61][62] and hepatic cells [217,218,219,220,221][63][64][65][66][67]. In vitro exposure of thyroid cells to different PFAS was shown to have varied thyroid-disrupting effects. Conti et al. (2020) exposed thyroid follicular cells to 1–100 mM PFOS or PFOA, concluding that both substances acutely and reversibly inhibited iodide accumulation by FRTL-5 thyrocytes. Additionally, PFOS prevented sodium iodide symporter-mediated iodide uptake and reduced intracellular iodide concentration in iodide-containing cells. However, this substance did not affect iodide efflux from thyroid cells [213][59]. Furthermore, Song et al. (2012) documented decreased TPO activity in FTC-238/hrTPO/RSK008 cells after the exposure to different PFOS and PFOA concentrations [214][60]. At concentration of 105 nM PFOA/PFOS, a significant inhibition of cell proliferation was found in rat thyroid cell line-5 (FRTL-5), which mostly occurred due to the increased cell death. The results of this study also suggested that PFOA and PFOS enter thyroid cells by a gradient-based passive diffusion mechanism [215][61]. Croce et al. (2019) investigated the impact of different long-chain and short-chain PFAS, including PFOS, perfluorobutanesulfonic acid (PFBS), perfluorobutanoic acid (PFBA), perfluorophosphonic acid (PFPA) and perfluoropentanoic acid (PFPeA), on the same cell line (FRTL-5), at various concentrations (up to 100 μM). However, aside from PFOS (100 μM), neither long, nor short-chain PFCs impacted cell survival or interfered with cAMP synthesis. As a result, the authors came to the conclusion that short-chain PFCs had no acute cytotoxic effect on thyroid cells in vitro [216][62].
Table 1. Selected in vitro studies (published since 2010) exploring the toxicity of polyfluoroalkyl substances (PFAS).
Cell Type Substance Treatment Concentration Incubation Time Effects Ref.
thyroid follicular cells PFOS

PFOA		 PFOS or PFOA (1–100 mM) Cytotoxicity: 1 h
  • PFOS, but not PFOA, acutely and reversibly inhibited iodide accumulation by FRTL-5 thyrocytes, as well as by HEK-293 cells transiently expressing the Sodium Iodide Symporter (NIS)
  • PFOS prevented NIS-mediated iodide uptake and reduced intracellular iodide concentration in iodide-containing cells, mimicking the effect of the NIS inhibitor perchlorate
  • PFOS did not affect iodide efflux from thyroid cells
 (Conti, Strazzeri, and Rhoden 2020) [213](Conti, Strazzeri, and Rhoden 2020) [59]
FTC-238/hrTPO/RSK008 cells PFOS

PFOA		 10
][67].
Oxidative stress and apoptosis/autophagy were also investigated in the light of PFAS-induced neurotoxicity. Li et al. (2017) exposed rat primary hippocampal neurons and astrocytes to PFOS, which led to redox imbalance, increased apoptosis and abnormal autophagy. In astrocytes, PFOS altered extracellular glutamate and glutamine concentrations, decreased glutamine synthase activity and impaired gene expression of glutamine synthase as well as glutamate and glutamine transporters [224][70]. Other PFAS-linked neurotoxic mechanisms included interferences at the gene expression level and calcium homeostasis. Wan Ibrahim et al. (2013) investigated the effect of PFOS on primary rat embryonic neural stem cells (NSCs) and noted an increase in neuronal differentiation. Upregulation of PPARγ was also observed, with no changes in PPARα or PPARδ genes. Additionally, PFOS upregulated mitochondrial uncoupling protein 2 (UCP2) and induced Ca2+ activity [225][71]. Both PFOS and PFOA were found to accumulate in cultured neurons and elevate calcium concentrations via release of intracellular calcium stores. 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) were found to take part in PFOS or PFOA induced calcium release, which caused a perturbation of calcium homeostasis [222][68]. PFOS and PFOA also inhibited the GABA-evoked current in primary rat cortical cultures and acted as non-competitive human GABA-A receptor antagonists. Network activity of rat primary cortical cultures increased following exposure to PFOS [223][69]. Pierozan and Karlsson (2021) studied the effects of PFOS and PFOA on primary neurons and NSC from rats. There were no impacts on cell viability or proliferation in primary neurons. At the lowest studied concentration (1–100 μM), PFOS exposure boosted NSC proliferation, while PFOS and PFOA altered the morphology of NSC-derived neurons. The neurite network was similarly impacted by 1 and 10 μM PFOA exposure, resulting in an increase in the number of processes and branches per cell. The authors concluded that NSC, which mimics the embryonic brain, are more vulnerable to PFOS and PFOA exposure than neurons [226][72].
PFAS effects on reproductive function were also investigated in in vitro studies. Eggert et al. (2019) assessed the effects of 0–100 μg/mL PFOA on foetal rat testes and adult rat seminiferous tubule segments. The findings revealed lower levels of cAMP, progesterone, testosterone, and StAR expression. The number of diploid, proliferative, meiotic, and G2/M-phase cells in adult rat testis was drastically reduced by PFOA. By contrast, PFOA had no effect on foetal, proliferating, or adult rat Sertoli cells. Foetal Leydig cells, on the other hand, showed an increased susceptibility to apoptosis [227][73]. The exposure of human cell lines such as MCF-7, H295R, LNCaP and MDA-kb2PFOA to PFOS and six substitutes including PFHxS, PFBS, PFHxA, PFBA, PMOH and ADONA has revealed that PFOA, PFOS and PMOH enhanced 17β-estradiol-stimulated estrogen receptor β activity, and PFOS, PMOH, PFHxA and PFBA enhanced dihydrotestosterone-stimulated androgen receptor activity. PFOA and PFOS slightly enhanced estrone secretion, and progesterone secretion was marginally increased by PFOA. All these effects were only observed at concentrations above 10 μM [228][74].

2.2. In Vivo Studies on PFAS Effects

PFAS exposure has mostly been linked to adverse outcomes in mice and rats, while the majority of studies explored the toxicity of PFOS, PFOA and PFHxS. Selected in vivo studies (published since 2010) investigating toxic effects of PFAS are presented in Table 2.
Table 2. Selected in vivo studies (published since 2010) exploring the toxicity of polyfluoroalkyl substances (PFAS).
Species Substance Dose and Route of Exposure Exposure Time Effects Ref.
[239][85]. On the other hand, in a study involving 815 participants ≤18 years of age, Geiger et al. (2014) found that serum PFOA and PFOS were related with high total cholesterol and LDL-C levels, regardless of age, gender, race-ethnicity, body mass index, yearly family income, physical activity, or serum cotinine levels. PFOA and PFOS were not shown to be substantially linked with aberrant HDL-C and triglyceride levels [238][84].
Table 3. Selected human studies (published since 2010) exploring the toxicity of polyfluoroalkyl substances (PFAS).
Substance Population Measured Parameters Results Ref.
Rats PFOS
PFOS

20 or 100 ppm, dietary exposure PFOA middle-aged Danish7 days

population; 753 individuals (663 men and 90

women), 50–65 years of age, nested within a Danish cohort of 57,053 participants		 serum levels of

total cholesterol
  • Statistically significant positive associations between PFOS, PFAS and total cholesterol level
  • Sex and prevalent diabetes modified the association between PFOA and PFOS and cholesterol
  • Changes in liver parameters (increased liver weight; decreased plasma cholesterol, alanine aminotransferase, and triglycerides; decreased liver DNA concentration and increased hepatocellular cytosolic CYP450 concentration; increased liver activity of acyl CoA oxidase, CYP4A, CYP2B, and CYP3A; increased liver proliferative index and decreased liver apoptotic index; decreased hepatocellular glycogen-induced vacuoles; increased centrilobular hepatocellular hypertrophy.
  • Thyroid parameters (histology, apoptosis, and proliferation) unaffected.
 (Eriksen et al., 2013)

[237]		(Eriksen et al., 2013)

[83]		(Elcombe et al., 2012)

[229]		(Elcombe et al., 2012)

[75]
−9, 10−8, 10−7, 10−6, 10−5, 10−4 M /
  • Decreased TPO activity
Mice PFOS 10 mg PFOS/kg b.w./day), oral gavage
 14 days
  • Dysregulated proteins in lipid and xenobiotic metabolism in liver
  • 16 overexpressed glycoproteins associated with neutrophil degranulation, cellular responses to stress, and protein processing in the endoplasmic reticulum (ER)
(Song et al., 2012) [214](Song et al., 2012) [60]
100 μg/kg b.w./day and 1000 μg/kg b.w./day, oral gavage 2 months
PFOS

PFOA		 815 participants ≤18 years of age from the National

Health and Nutrition Examination Survey 1999–2008		 dyslipidemia:

total cholesterol >170 mg/dL, low-density lipoprotein cholesterol (LDL-C) >110 mg/dL, high-density lipoprotein

cholesterol (HDL-C) <40 mg/dL or triglycerides >150 mg/dL.
  • Serum PFOA and PFOS-positively associated with high total cholesterol and LDL-C, independent of age, sex, race-ethnicity, body mass index, annual household income, physical activity and serum cotinine levels
  • PFOA and PFOS-not significantly associated with abnormal HDL-C and triglyceride levels.
(Geiger et al., 2014) [238](Geiger et al., 2014) [84](D. Li et al., 2021) [230](D. Li et al., 2021) [76] rat thyroid line-5 (FRTL-5) PFOS

PFOA		 1, 10, 102, 103, 104, and 105 nM 72 h
  • At concentration of 105 nM PFOA/PFOS, a significant inhibition of cell proliferation, mainly due to increased cell death, was found
  • PFOA and PFOS enter thyroid cells by a gradient-based passive diffusion mechanism
 (Coperchini et al., 2015) [215](Coperchini et al., 2015) [61]
  • PFOS accumulated in liver, lungs, kidneys, spleen, heart and brain
 rat thyroid line-5 (FRTL-5) FOA, PFOS, perfluorobutanesulfonic

acid (PFBS), perfluorobutanoic acid (PFBA), pentafluoropropionic anhydride (PFPA), perfluoropentanoic acid

(PFPeA)		 0.0001; 0.001; 0.01; 0.1; 1; 100 μM 24 h
  • Neither long nor short-chain PFCs affected cell viability (apart from PFOS 100 μM), or interfered with cAMP production
  • Short-chain PFCs have no acute cytotoxic effect on thyroid cells in vitro
 (Croce et al. 2019)

[216]		(Croce et al. 2019)

[62]
Human hepatoma cell line (HepG2) perfluorohexane sulfonate (PFHxS),

perfluorooctane sulfonic acid (PFOS), perfluoroctanoic acid (PFOA), perfluorononanoate (PFNA), perfluorodecanoate

(PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA).
PFOS

PFOA		 290 individuals (144 men + 146 women) exposed to background levels of PFOS and elevated concentrations

of PFOA through drinking water,

aged between 20 and 60 years		 expression of genes involved in cholesterol

metabolism
  • Inverse associations between serum PFOA levels and the whole blood expression level of genes involved in cholesterol transport (NR1H2, NPC1 and ABCG1)
  • A positive association between PFOS and a transcript involved in cholesterol mobilisation (NCEH1), and a negative relationship with a transcript involved in cholesterol transport (NR1H3)
  • Reductions in the levels of mRNAs involved in cholesterol transport were seen with PFOA in men (NPC1, ABCG1, and PPARA) and in women (NR1H2 expression)
  • Increase in the levels of a cholesterol mobilisation transcript (NCEH1) in women.
  • PFOS was positively associated with expression of genes involved in both cholesterol mobilisation and transport in women (NCEH1 and PPARA)
  • Its accumulation caused damage in the liver and in the marginal area of the heart
  • PFOS mainly affected glycerophospholipid metabolism and sphingolipid metabolism in liver
  • Up-regulated ceramide and
  • lysophosphatidylcholine (LPC) might lead to liver cell apoptosis
  • Decrease in liver triglyceride (TG) content might result in insufficient energy and cause liver morphological damage
 (Fletcher et al., 2013)

[239]		(Fletcher et al., 2013)(X. Li et al., 2021)

[231]		(X. Li et al., 2021)

[77]


[85] Rats PFOA 5 mg/kg b.w./day, oral gavage 28 days
  • Increase in hepatic (GGT, ALT, AST and ALP) and renal function (urea and creatinine) biomarkers of toxicities
  • Decrease in the activity of the enzymatic antioxidants (CAT, GPx, SOD) in liver and kidney tissue
  • Increase in lipid peroxidation and proinflammatory cytokine IL-1β
  • Decrease of the antiinflammatory cytokine, IL-10
 (Owumi, Bello, and Oyelere 2021)

[232]		(Owumi, Bello, and Oyelere 2021) 2 × 10−7, 1 × 10−6, 2 × 10−6, 1 × 10−5, 2 × 10−5 M 24 h
  • Except for PFDoA, all the other PFAS increased ROS generation
  • For PFHxS and PFUnA the observed ROS increases were dose-dependent
  • Cells exposed to PFOA were found to have a significant lower total antioxidant capacity (TAC) compared with the solvent control, whereas a non-significant trend in TAC decrease was observed for PFOS and PFDoA and an increase tendency for PFHxS, PFNA and PFUnA
PFOA

PFOS

PFHxS PFNA

PFDA		 2883 participants, (1801 non-obese and 1082 obese), aged more than or equal to

20 years old		 liver function parameters: AST, ALT, GGT, ALP, and total bilirubin (TB)
  • Among obese participants only, alanine aminotransferase (ALT)-positively associated with PFOA, PFHxS, and PFNA
  • PFOA and PFNA were associated with gamma GGT in obese participants
 (Jain and Ducatman 2019)

[240]		(Jain and Ducatman 2019)

[86]

[78]
Mice PFOA 1, 5, 10, or 20 mg/kg/day, oral gavage
14 PFCs10 days Healthy men from the general population, median age of 19 years total testosterone (T), estradiol (E), sex hormone-binding globulin (SHBG),

luteinizing hormone (LH), follicle-stimulating hormone (FSH) and inhibin-B and

Semen samples analysis
  • PFOS levels-negatively associated with testosterone, calculated free testosterone (FT), free androgen index (FAI) and ratios of T/LH, FAI/LH and FT/LH
  • Other PFCs were found at lower levels than PFOS and did not exhibit the same associations.
  • PFC levels were not significantly associated with semen quality
  • Increase in Dnmt1 with decreased Rasal1 expression at higher levels of PFOA exposure.
  • Rasal1 hypermethylation, followed by the increase in Hdac1, 3 and 4.
  • Increased mRNA expression levels of TGF-β and α-SMA
 (Joensen et al., 2013)

[241]		(Joensen et al., 2013)

[87]		(Wielsøe et al., 2015)

[218]		(Wielsøe et al., 2015)

[64]
(Rashid et al., 2020)

[233](Rashid et al., 2020)

[79]		 Human Embryo Liver L-02 Cells PFOS 0, 50, 100, 150, 200, or 250 μmol/L 24 or 48 h
  • Decreased cell activities, enhanced ROS levels in a concentration-dependent manner
 Mice
  • Decreased mitochondrial membrane potential (MMP), and induced autophagy and apoptosis
 PFHxS Up to 3 mg/kg b.w./day, oral gavage Administered before mating, for at least 42 days in F0 males, and for F0 females, through gestation and lactation.
PFOA

PFOS PFHxS PFNA		 1682 males and

females 12 to

80 years of age		 testosterone (T), thyroid stimulating hormone (TSH), and free and

total triiodothyronine (FT3, TT3) and thyroxine (FT4, TT4)

F1 pups-directly for 14 days after weaning
  • Exposure to PFAS may be associated with increases in FT3, TT3, and FT4 among adult females
  • During adolescence, PFAS may be related to increases in TSH among males and decreases in TSH among females
  • No significant relationships were observed between PFAS and T in any of the models
  • Adaptive hepatocellular hypertrophy, concomitant decreased serum cholesterol and increased alkaline phosphatase (S. Chang et al., 2018).
  • Enhanced expression of Bax, cleaved-caspase-3, and LC3-II
  • Induced autophagy; decreased MMP; and lowered Bcl-2, p62, and Bcl-2/Bax ratio
  • ROS-triggered autophagy is involved in PFOS-induced apoptosis in L-02 cells
 (Lewis, Johns, and Meeker 2015)

[242]		(Lewis, Johns, and Meeker 2015)

[88]		(Zeng et al., 2021) [219](Zeng et al., 2021) [65]
(Chang et al., 2018)

[234](Chang et al., 2018)

[80]		 Human HepaRG liver cells PFOA, PFOS, and perfluorononanoic acid (PFNA)
6.25, 12.5, 25, 50, 100, 200, 400 μM 6, 24, or 72 h
  • All PFAS induced an increase in cellular triglyceride levels, but had no effect on cholesterol levels
 Rats
 PFHxS 0.05, 5 or

25 mg/kg b.w./day, oral gavage		 From gestation day 7 through to postnatal day 22
PFOS

PFOA		 3076 boys and 2931

girls aged 8–18 years		 subjects were classified as having reached puberty based on either hormone

levels (total >50 ng/dL and free >5 pg/mL testosterone in boys and estradiol >20 pg/mL in girls) or onset of menarche
  • For boys, there was a relationship of reduced odds of reached puberty (raised testosterone) with increasing PFOS (delay of 190 days between the highest and lowest quartile)
  • For girls, higher concentrations of PFOA or PFOS were associated with reduced odds of postmenarche (130 and 138 days of delay, respectively)
  • PFOA, PFOS, and PFNA increase triglyceride levels and inhibit cholesterogenic gene expression
  • PFAS induce endoplasmic reticulum stress, which may be an important mechanism underlying some of the toxic effects of these chemicals
  • PFHxS lowered thyroid hormone levels in both dams and of spring in a dose-dependent manner
  • PFHxS did not change TSH levels, weight, histology, or expression of marker genes of the thyroid gland
 (Louisse et al., 2020) [220](Louisse et al., 2020) [66]
(Ramhøj et al., 2020)

 HepaRG cell line PFOS

PFOA		 100, 250, 500, 750 μM PFOA

50, 100, 250, 500 μM PFOS		 /
  • Cholesterol levels in HepaRG cells were not affected by PFOA or PFOS
  • Both substances strongly decreased synthesis of a number of bile acids
  • The expression of numerous genes whose products are involved in synthesis, metabolism and transport of cholesterol and bile acids was strongly affected by PFOA and PFOS at concentrations above 10 µM
  • Both substances led to a strong decrease of CYP7A1, the key enzyme catalyzing the rate-limiting step in the synthesis of bile acids from cholesterol, both at the protein level and at the level of gene expression
  • Both substances led to a dilatation of bile canaliculi
 Behr et al., 2021) [221]Behr et al., 2021) [67]
[235](Ramhøj et al., 2020)

[81]
Mice   6.1, and 9.1 mg/kg b.w., oral gavage Neonatal exposure from postnatal day 10
  • PFHxS induces persistent developmental neurotoxicity and GAP-43 and CaMKII downregulation via the NMDA receptor-mediated PKCs (α and δ)-ERK/AMPK pathways
  • Significant memory impairment in adult mice
 (Sim and Lee, 2022)

[236]		(Sim and Lee, 2022)

[82]		 Neurons PFOS

PFOA		 30–300 µM 30 min
  • Both PFOS and PFOA can accumulate in cultured neurons and elevate calcium concentrations via release of intracellular calcium stores
  • 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) were found to take part in PFOS or PFOA inducing calcium release from calcium stores
  • Calcium release from intracellular stores may partially account for the perturbation of calcium homeostasis caused by PFOS or PFOA
 (Liu et al., 2011) [222](Liu et al., 2011) [68]
A link between PFOS exposure and hepatic lipid metabolism was found in vivo. After the exposure of C57BL/6 mice to 10 mg PFOS/kg b.w./day by oral gavage for 14 days, 241 proteins involved in lipid and xenobiotic metabolism in liver were found to be dysregulated. 16 overexpressed glycoproteins were associated with neutrophil degranulation, cellular responses to stress, and protein processing in the endoplasmic reticulum (ER) [230][76]. Li et al. (2021) also documented the ability of PFOS to accumulate in the liver of female BALB/c mice after the exposure to 100 μg/kg b.w./day and 1000 μg/kg b.w./day by oral gavage for 2 months. PFOS accumulated in the lungs, kidneys, spleen, heart and brain as well, causing damage in the liver and in the marginal area of the heart. PFOS mainly affected glycerophospholipid metabolism and sphingolipid metabolism in liver. These authors suggested that the upregulated ceramide and lysophosphatidylcholine (LPC) might lead to liver cell apoptosis, while decrease in liver triglyceride (TG) content might result in insufficient energy and cause liver morphological damage [231][77]. After the dietary exposure of rats to 20 or 100 ppm PFOS for 7 days, Elcombe et al. (2012) have also noted alterations in various liver parameters (e.g., increased liver weight; decreased plasma cholesterol, alanine aminotransferase, and triglycerides; increased hepatocellular cytosolic CYP450 concentration; increased liver activity of acyl CoA oxidase, CYP4A, CYP2B, and CYP3A; increased liver proliferative index and decreased liver apoptotic index). However, in the aforementioned study, thyroid parameters (histology, apoptosis, and proliferation) were not unaffected [236][82].
Owumi et al. (2021) investigated hepatic and kidney function of PFOA. After the exposure of rats to PFOA (5 mg/kg b.w./day) for 28 days, the authors noted an increase in hepatic (GGT, ALT, AST and ALP) and renal function (urea and creatinine) as well as biomarkers of toxicity, paralleled by a decrease in the activity of the enzymatic antioxidants (CAT, GPx, SOD) in liver and kidney tissue. In this study, a significant increase in lipid peroxidation and pro-inflammatory cytokine IL-1β in rats’ liver and kidney occurred, while a decrease of the anti-inflammatory cytokine, IL-10 was also observed [232][78]. Similarly, renal damage was found in mice after the exposure to PFOA. Rashid et al. (2020) noted an increase in Dnmt1 with decreased Rasal1 expression at higher levels of PFOA exposure. Rasal1 hypermethylation (an early indicator of fibroblast activation in kidney) was also observed, followed by the increase in Hdac1, 3 and 4, class I & II HDACs which are known to be critically altered in some renal diseases. Furthermore, mRNA levels of TGF-β and α-SMA were significantly increased [233][79].
Health effects of PFHxS have also been investigated in animal studies. After the oral exposure of F0 and F1 CD-1 mice to 3 mg PFHxS/kg b.w/day, equivocal decrease in live litter size at 1 and 3 mg/kg b.w./day was noted, as well as adaptive hepatocellular hypertrophy, concomitant decreased serum cholesterol and increased alkaline phosphatase [234][80]. After treating rat with 0.05, 5 or 25 mg/kg b.w./day PFHxS from gestation day 7 onward to postnatal day 22, Ramhøj et al. (2020) observed a dose-dependent decrease in thyroid hormone levels in both dams and offspring, while TSH levels, weight, histology, or expression of marker genes of the thyroid gland were unaffected [235][81]. Other neurotoxic effects of PFHxS have been investigated as well. Sim and Lee (2022) have found that PFHxS causes long-term developmental neurotoxicity as well as downregulation of GAP-43 and CaMKII via the NMDA receptor-mediated PKCs (and)-ERK/AMPK pathways in mice after the neonatal exposure, together with significant memory impairment in adult mice [236][82].

2.3. Human Studies on PFAS Effects

Selected human studies (published since 2010) investigating toxic effects of PFAS are presented in Table 3. Majority of the human studies explored the linkage between PFAS concentration and lipid status, mainly cholesterol level [237,238][83][84], while a study was also conducted to assess the connection between PFAS and cholesterol at the gene expression level [239][85]. Eriksen et al. (2013) discovered substantial positive relationships between PFOS, PFAS, and total cholesterol in 753 individuals, while sex and prevalence of diabetes were suggested to influence the connection between these two substances and cholesterol [237][83]. Fletcher et al. (2013) observed an inverse relationship between serum PFOA levels and the expression level of genes involved in cholesterol transport in whole blood (NR1H2, NPC1 and ABCG1). A positive correlation was found between PFOS and a transcript involved in cholesterol mobilization (NCEH1), while a negative relationship was seen between PFOS and a transcript involved in cholesterol transport (NCEH2). Sex-specific effects were also noticed in this study
(Lopez-Espinosa et al., 2011)


[
243
]
(Lopez-Espinosa et al., 2011)


[89]
PFOS

PFOA

PFNA		 2292 children (6–9 years of age) estradiol, total testosterone,

and IGF-1
  • In boys, PFOA concentrations were significantly associated with testosterone levels; PFOS with estradiol, testosterone, and IGF-1; and PFNA with IGF-1
  • In girls, significant associations were found between PFOS and testosterone and IGF-1; and PFNA and IGF-1
 (Lopez-Espinosa et al., 2016)

[244]		(Lopez-Espinosa et al., 2016)

[90]
PFOS

PFOA		 424 mother-infant pairs estrone (E1), b-estradiol (E2), and estriol (E3),

infants: head circumference,

body weight, body length
  • PFOS was positively related to E1 and E3, but negatively related to E2
  • Serum PFOA was positively related to serum E1 and negatively related to head circumference at birth
  • Serum E2 was negatively related to head circumference, body weight, and body length at birth and serum E3 was positively related to body weight
  • Serum E3 mediated the relationship between serum PFOS and body weight
  • PFAS could affect estrogen homeostasis and fetal growth during pregnancy and estrogens might mediate the association between exposure to PFAS and fetal growth
 (Wang et al., 2019)

[245]		(Wang et al., 2019)

[91]
Primary rat cortical cultures and hiPSC-derived neuronal co-cultures
PFOS

PFOA		PFOS

PFOA		 0.01, 0.1, 1, 10, 100 µM 47,092

/		 adults alanine transaminase (ALT), γ-glutamyltransferase (GGT), direct bilirubin
  • Positive association between PFOA and PFOS concentrations and serum ALT level, a marker of hepatocellular damage.
  • The relationship with bilirubin appears to rise at low levels of PFOA and to fall again at higher levels.
  • PFOS and PFOA inhibited the GABA-evoked current and acted as non-competitive human GABAA receptor antagonists
  • Network activity of rat primary cortical cultures increased following exposure to PFOS (LOEC 100 µM)
 (Gallo et al., 2012)

[246]		(Gallo et al., 2012)

[92		(Tukker et al., 2020) [223](Tukker et al., 2020) [69]
] Rat primary hippocampal neurons and

astrocytes
PFHpA

PFOA

PFNA

PFDA

PFUnDA

PFOS PFDoDA

PFHxS

PFOSA		 1002 individuals from Sweden (50% women) at ages 70, 75 and 8025, 50, 75, 100, 125 μM for neurons

15, 25, 50,

75, 100 μM for astrocytes		 24 h bilirubin and hepatic enzymes alanine aminotransferase (ALT), alkaline

phosphatase (ALP), and γ-glutamyltransferase (GGT)
  • Positive associations of PFHpA, PFOA, PFNA, PFDA, and PFUnDA with ALP
  • Concentrations of PFHpA, PFOA, PFNA, and PFOS were positively associated with the activity of ALT
  • The changes in PFAS concentrations were positively associated with GGT and inversely associated with the changes in circulating bilirubin
  • Redox imbalance, increased apoptosis and abnormal autophagy in rat primary hippocampal neurons.
  • In astrocytes: altered extracellular glutamate and glutamine concentrations, decreased glutamine synthase activity, as well as decreased gene expression of glutamine synthase, glutamate transporters and glutamine transporters in the glutamate-glutamine cycle
 (Salihovic et al., 2018)

[30]		(Li et al., 2017) [224](Li et al., 2017) [70]
primary rat embryonic neural stem cells (NSCs)
PFOS

PFOA

PFHxS		PFOS 3297 participants from Ronneby, a municipality with drinking water highly contaminated by PFAS (exposed group)12.5–100 nM 48 h thyroid hormone levels, with adjustments for age, sex and BMI
  • No associations between PFAS and thyroid hormones in adults and seniors except for a positive association between PFAS and fT4 in males over 50
  • Higher thyroid hormone levels in the preteen children from Ronneby compared to the reference group
  • Weak evidence of associations between increased PFAS levels and decreased fT3 in preteen boys, and decreased TSH in teenage males
  • Increase in neuronal differentiation
  • Increased number of CNPase-positive cells, pointing to facilitation of oligodendrocytic differentiation
  • Upregulation of PPARγ with no changes in PPARα or PPARδ genes
  • Upregulated mitochondrial uncoupling protein 2 (UCP2)
  • Induced Ca2+ activity
 (Y. Li et al., 2021)

[247]		(Y. Li et al., 2021)

[93]		(Wan Ibrahim et al., 2013) [225](Wan Ibrahim et al., 2013) [71]
rat primary neurons and neural stem cells (NSC)
PFOA

PFOS		PFOS

PFOA		 101 healthy 1-year-old children Antibodies against haemophilus infuenza type b, tetanus and diphtheria, interferon gamma, cholesterol
  • Significant associations between PFOA, but not PFOS concentrations, and adjusted levels of vaccine antibodies against haemophilus influenza type b, tetanus and diphtheria
  • No effects on cell viability or proliferation in primary neurons
Mice PFOS 1–250 μM 24 h
  • PFOA levels inversely related to the interferon gamma (IFN) production of ex-vivo lymphocytes after stimulation with tetanus and diphtheria toxoid
  • No infuence of PFOA and PFOS on infections and cholesterol level during the frst year of life
  • PFOS exposure increased the NSC proliferation at the lowest concentration tested (1–100 μM)
  • PFOS and PFOA caused morphological alterations of NSC-derived neurons. Exposure to 1 and 10 μM PFOA also affected the neurite network and caused an increase in the number of processes and branches per cell NSC, mimicking the immature brain, is clearly more susceptible to PFOS and PFOA exposure than the primary neurons
 (Abraham et al., 2020)

[248]		(Abraham et al., 2020)

[		(Pierozan and Karlsson 2021)

[226]		(Pierozan and Karlsson 2021)

[72]
94] fetal rat testes or

seminiferous tubule segments (stage VII-VIII) of adult rats		 PFOA 0–100 μg/mL 24 h
  • Levels of cAMP, progesterone, testosterone and expression of StAR decreased significantly in PFOA 50 and 100 μg/mL. PFOA affected cell populations significantly by decreasing the amount of diploid, proliferating, meiotic I and G2/M phase cells in adult rat testis
PFOA

PFOS		 1146 children serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7
  • Approximate BMDL of 1 ng/mL serum for both PFOS and PFOA for the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7
  • Proposed reference concentration of about 0.1 ng/mL as the serum-based target
  • PFOA did not affect fetal, proliferating or adult rat Sertoli cells but an increased tendency of apoptosis in fetal Leydig cells was observed
 (Budtz-Jørgensenet al., 2018)

[249]		(Budtz-Jørgensenet al., 2018)

[95		(Eggert et al., 2019) [227](Eggert et al., 2019) [73]
] human cell lines such as MCF-7, H295R, LNCaP and MDA-kb2 PFOA, PFOS, and of six substitutes including perfluorohexanesulfonic acid (PFHxS),

perfluorobutanesulfonic acid (PFBS), perfluorohexanoic acid (PFHxA), perfluorobutanoic acid (PFBA), ammonium

perfluoro(2-methyl-3-oxahexanoate) (PMOH), and 3H-perfluoro-3-[(3-methoxypropoxy) propanoic acid]

(PMPP)		 various concentrations 24 h when cytotoxicity

was assayed in HEK293T, LNCaP or MDA-kb2 cells, for 6 d in

MCF-7 cells and for 48 h in H295R cells
  • PFOA, PFOS and PMOH enhanced 17β-estradiol-stimulated estrogen receptor β activity, and PFOS, PMOH, PFHxA and PFBA enhanced dihydrotestosterone-stimulated androgen receptor activity
  • PFOA and PFOS slightly enhanced estrone secretion, and progesterone secretion was marginally increased by PFOA.
  • All these effects were only observed at concentrations above 10 μM
 (Behr et al.,2018)

[228]		(Behr et al.,2018)

[74]
Some of the in vitro studies explored liver toxicity of the PFAS by investigating the occurrence of the oxidative stress on different hepatic cell lines [218[64][65],219], as well as apoptosis/autophagy [219][65] and cholesterol/bile acids level [221][67]. The impact of PFOS, PFOA, PFHxS, PFNA, PFDA, PFUnA, and PFDoA on the same cell line (HepG2) has been tested. Here, PFHxS, PFOA, PFOS, and PFNA caused a dose-dependent increase in DNA. With the exception of PFDoA, all other PFAS elevated ROS formation. Cells exposed to PFOA had significantly lower total antioxidant capacity (TAC) compared to the control, but PFOS and PFDoA had a non-significant trend in TAC decrease and an increasing tendency for PFHxS, PFNA, and PFUnA [218][64]. Other studies also explored the link between PFOA/PFOS and oxidative stress/apoptosis in different liver cells. Zeng et al. (2021) tested the influence of PFOS on human embryo liver L-02 cells. Reduced cell activity was observed, as well as increased ROS levels in a concentration-dependent manner. Impaired mitochondrial membrane potential (MMP), as well as elevated autophagy and apoptosis were observed, together with the increased expression of Bax, cleaved-caspase-3, and LC3-II. The authors concluded that ROS-dependent autophagy might be the cause of PFOS-induced apoptosis in L-02 cells [219][65]. Other mechanisms underlying PFAS-induced liver injury were also investigated. Human HepaRG liver cells were treated to PFOA, PFOS, and (PFNA at various doses. All PFAS increased cellular triglyceride levels while having no effect on cholesterol levels. In HepaRG cells, PFOA, PFOS, and PFNA enhanced triglyceride levels while inhibiting cholesterogenic gene expression. The authors noted that PFAS-induced endoplasmic reticulum stress might be an essential mechanism underpinning some of the harmful effects caused by these compounds [220][66]. Similarly, Behr et al. (2021) investigated the effects of PFOS/PFAS exposure and found that cholesterol levels in the same cell line (HepaRG) were not affected by neither PFOA nor PFOS. However, in this study, both substances strongly decreased synthesis of a number of bile acids. Moreover, the expression of numerous genes whose products are involved in synthesis, metabolism and transport of cholesterol and bile acids was strongly affected by PFOA and PFOS at concentrations above 10 µM. Indeed, PFOS and PFOA led to a strong decrease of CYP7A1, the key enzyme catalysing the rate-limiting step in the synthesis of bile acids from cholesterol, both at the protein and the mRNA level. Both substances led to a dilatation of bile canaliculi [221
PFHxS, PFOS, PFOA, PFDA, PFNA
275 males and 349 females participated in clinical examinations and provided blood samples at ages 18 months and 5 years
serum concentrations of antibodies against tetanus and diphtheria vaccines determined at age 5
  • Pre-natal exposure showed inverse associations with the antibody concentrations five years later, with decreases by up to about 20% for each two-fold higher exposure
  • Associations for serum concentrations at 18 months and 5 years were weaker
  • Concentrations estimated for ages 3 and 6 months showed the strongest inverse associations with antibody concentrations at age 5 years, particularly for tetanus
  • Joint analyses showed statistically significant decreases in tetanus antibody concentrations by 19–29% at age 5 for each doubling of the PFAS exposure in early infancy
 (Grandjean et al., 2017)

[250]		(Grandjean et al., 2017)

[96]
PFHxS, PFOA, PFOS, PFNA, PFDA. 516 subjects PFAS serum concentrations and concentration of antibodies against diphtheria and tetanus
  • Diphtheria antibody concentrations decreased at elevated PFAS concentrations at 13 y and 7 y; the associations were statistically significant for perfluorodecanoate (PFDA) at 7 y and for perfluorooctanoate (PFOA) at 13 y, both suggesting a decrease by ∼25% for each doubling of exposure
  • Structural equation models showed that a doubling in PFAS exposure at 7 y was associated with losses in diphtheria antibody concentrations at 13 y of 10–30% for the five PFAS
 (Grandjean et al., 2017)

[251]		(Grandjean et al., 2017)

[97]
Other studies explored the link between PFAS concentration and different hormones, such as thyroid [242,247][88][93] and sex hormones [245[91][93][94],247,248], as well as development [243,245][89][91]. By assessing the connection between the levels of 14 PFAS in healthy men from the general population and different sex hormones and semen sample quality, Joensen et al. (2013) found that only PFOS levels were negatively associated with testosterone, calculated free testosterone (FT), free androgen index (FAI) and ratios of T/LH, FAI/LH and FT/LH. Other PFAS were found at lower levels than PFOS and did not exhibit the same associations [241][87]. Also, after measuring PFAS levels in 1682 males and females 12 to 80 years of age, Lewis et al. (2015) found no significant relationships between any of the PFAS and testosterone. PFAS were suggested to be associated with increases in FT3, TT3, and FT4 among adult females. The authors concluded that, during the adolescence, PFAS may be related to increases in TSH among males and decreases in TSH among females [242][88], suggesting sex-specific effects. In contrast, Li et al. (2021) discovered no associations between PFAS and thyroid hormones in adults and seniors in 3297 participants from Ronneby, a municipality with highly contaminated drinking water by PFAS (exposed group), with the exception of a positive association between PFAS and fT4 in males over 50. Thyroid hormone levels were observed to be higher in Ronneby preteen children compared to the control group. Weak evidence of a link between increasing PFAS levels and lower fT3 in preteen boys and lower TSH in adolescent men was found [247][93].
Lopez-Espinosa et al. (2011) aimed to investigate whether PFOS and PFOA were linked to the markers of sexual development. Their study included 3076 boys and 2931 girls aged 8–18 years. For boys, there was a link between increased PFOS and a lower chance of reaching puberty. Higher PFOA or PFOS concentrations in girls were related to a lower risk of post menarche [243][89]. The same group of researchers examined the link between PFAS levels and estradiol, total testosterone, and IGF-1 in 2292 children. In boys, PFOA concentrations were substantially related to testosterone levels; PFOS concentrations were related to estradiol, testosterone, and IGF-1, while PFNA concentrations were linked to IGF-1. Significant linkage was discovered in girls between PFOS and testosterone and IGF-1, as well as PFNA and IGF-1 [244][90]. Furthermore, Wang et al. (2019) concluded that PFAS may affect estrogen homeostasis and foetal growth during pregnancy, and that estrogens may mediate the relationship between PFAS exposure and foetal growth after examining 424 mother-infant pairs [245][91].
Some of the studies also explored the linkage between the PFAS exposure and liver function [31,251,252][31][97][98]. In 47,092 adult participants, Gallo et al. (2012) found a positive association between PFOA and PFOS concentrations and serum ALT level. On the other hand, the relationship with bilirubin appeared to increase at low levels of PFOA and decrease at higher levels [246][92]. In 1002 individuals from Sweden, Salihovic et al. (2018) have also found a positive association of PFHpA, PFOA, PFNA, and PFOS concentrations and ALT activity, but also positive associations of PFHpA, PFOA, PFNA, PFDA, and PFUnDA with ALP. These authors noted that the changes of investigated PFAS concentrations were positively associated with gamma glutamyl transferase (GGT) levels and inversely associated with the changes in circulating bilirubin [30]. On the other hand, in 2883 participants, (1801 non-obese and 1082 obese), Jain and Ducatman investigated the connection between liver function alterations and various PFAS. They concluded that connections might only be observed in the obese participants: alanine aminotransferase (ALT) was positively associated with PFOA, PFHxS, and PFNA. On the other hand, PFOA and PFNA were associated with GGT [240][86]. Epidemiological studies revealed a connection between PFAS and decrease in vaccination antibody production in early infants and children, especially having in mind that, if breastfed, they have a relatively high exposure and may be more susceptible as their immune system develops. Abraham et al. (2020) found significant associations between the concentration of PFOA, but not PFOS, and adjusted levels of vaccine antibodies against Haemophilus influenza type b, tetanus and diphtheria for which no observed adverse effect concentrations (NOAECs) were 12.2, 16.9 and 16.2 µg/L, respectively. Furthermore, PFOA levels were shown to be inversely related to the interferon gamma (IFN-γ) production of ex-vivo lymphocytes after stimulation with tetanus and diphtheria toxoid [248][94]. Furthermore, Budtz-Jorgensen E and Grandjean P (2018) found an approximate BMDL of 1 ng/mL serum for both PFOS and PFOA for the serum concentrations of specific IgG antibodies against tetanus and diphtheria at ages 5 and 7 as outcome parameters. These authors proposed the reference concentration of about 0.1 ng/mL as the serum-based target, a level which is below the most reported human serum-PFAS concentrations [249][95]. Grandjean et al. (2017) discovered that prenatal exposure to PFAS had an inverse relationship with antibody concentrations five years later, while concentrations measured at 3 and 6 months of age had the highest inverse relationships with antibody concentrations at 5 years of age, especially for tetanus [250][96]. The same authors have found that diphtheria antibody concentrations dropped at higher PFAS concentrations at 13 and 7 years after booster vaccinations at 5 years of age; the correlations were statistically significant for PFDA at 7 years and PFOA at 13 years, implying a 25% decrease for each doubling of exposure [251][97].

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