Perfluorononanoic Acid Exposure Research Articles

Environmentally relevant concentration PFNA promotes degradation of SMAD7 to drive progression of ovarian cancer via TGF-β/SMADs signaling pathway

Perfluorononanoic acid (PFNA), an acknowledged environmental endocrine disruptor, is increasingly utilized as a substitute for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Despite its growing use, limited research has been conducted to investigate its potential impact on tumorigenesis and progression, and the potential molecular mechanisms. Earlier studies linked perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure to breast and gynecological cancer progression in humans, lacking a clear understanding of the underlying mechanisms, notably in ovarian cancer. Our investigation into PFNA's effects at environmental concentrations (0.25–2 mM) showed no significant impact on cell proliferation but a notable increase in invasion and migration of ovarian cancer cells. This led to alterations in epithelial-mesenchymal transition (EMT) markers, including Claudin1, Vimentin, and Snail. Notably, PFNA exposure activated the TGF-β/SMADs signaling pathway. Crucially, SMAD7 degradation through the ubiquitin-proteasome system emerged as PFNA's pivotal molecular target for inducing EMT, corroborated in mouse models. In summary, this study presented evidence that environmentally relevant concentrations of PFNA could induce SMAD7 degradation via the proteasome pathway, subsequently activating the TGF-β/SMADs signaling pathway, and promoting EMT in ovarian cancer. These results illuminated the association between PFNA exposure and metastasis of ovarian cancer.

Threshold for increased liver weight is protective of other effects in Peromyscus exposed to PFNA.

Perfluorononanoic acid (PFNA) is a commercially relevant, long-chain (8 fully fluorinated carbon) perfluorinated carboxylic acid. PFNA has limited terrestrial ecotoxicity data and is detected in humans, animals, and the environment. This study is the fourth in a series with the objective of investigating the toxicity of a suite of per- and polyfluoroalkyl substances (PFAS) detected on military installations in a mammal indigenous to North America. Peromyscus leucopus (white-footed mice, ∼25/sex/dose) were exposed via oral gavage to either 0, 0.03, 0.14, 1, or 3 mg PFNA/kg-d for 112 consecutive days (4 wk premating exposure followed by an additional 12 wk of exposure after onset of mating). Parental generation animals were assessed for potential reproductive and developmental effects, organ weight changes, thyroid modulation, and immunotoxicity. Pup weight and survival were assessed at postnatal days 0, 1, 4, 7, and 10. Change in liver weight was determined to yield the most sensitive dose response according to benchmark dose analysis, and serves as the most protective point of departure (BMDL = 0.37 mg/kg-d PFNA). Other effects of PFNA exposure included reduced formation of plaque-forming cells, which are indicative of functional immune deficits (BMDL = 2.31 mg/kg-d); decreased serum thyroxine (BMDL = 0.93 mg/kg-d) without changes in some other hormones; and increased stillbirths (BMDL = 0.61 mg/kg-d PFNA). Pup weight and survival were not affected by PFNA exposure. Combined with data from previous studies, data from Peromyscus provide a One Health perspective on health effects of PFAS.

Association between per- and polyfluoroalkyl substances exposure and prevalence of chronic obstructive pulmonary disease: The mediating role of serum albumin

BackgroundNo study has examined the association between per- and polyfluoroalkyl substances (PFAS) exposure and chronic obstructive pulmonary disease (COPD) risk. This study aims to explore this relationship. MethodsThis study enrolled 4541 individuals who had available data on PFAS, COPD, and covariates from NHANES 2007–2018. Serum PFAS including perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) were analyzed, because of high detective rates. Considering the skew distribution of PFAS levels, the natural logarithm-transformed PFAS (Ln-PFAS) was used. Logistic regression analysis, restricted cubic spline (RCS), and weighted quantile sum (WQS) regression were performed to explore the single, nonlinear, and mixed effects. A mediating analysis was used to evaluate the mediated effects of albumin. ResultsIndividuals with COPD had higher levels of PFHxS, PFNA, PFOA, and PFOS compared to those without COPD. Ln-PFNA (OR males: 1.92, 95 % CI:1.31 to 2.80, P: <0.001; OR females: 1.07, 95 % CI: 0.81 to 1.40, P: 0.636) and ln-PFOA (OR males: 2.17, 95 % CI:1.38 to 3.41, P: <0.001; OR females: 1.49, 95 % CI: 1.08 to 2.05, P: 0.016) were associated with COPD risk especially in males. The interaction between PFNA exposure and sex on COPD risk was significant (P interaction: <0.001). The RCS curve demonstrated the nonlinear relationship between the ln-PFOA (P nonlinear:0.001), ln-PFNA (P nonlinear:0.045), and COPD risk in males. WQS analysis showed mixed PFAS exposure was correlated with COPD risk in males (OR: 1.44, 95 % CI:1.18 to 1.75, P: <0.001). Albumin mediated the relationship between PFOA and COPD (mediated proportion: −17.94 %). ConclusionThis study concludes PFOA and PFNA are linked to a higher COPD risk in males, and serum albumin plays a mediating role in the relationship between PFOA and COPD. Thess findings are beneficial for the prevention of COPD. Further studies are required to explore potential mechanisms.

Determination of seven perfluoroalkyl and polyfluoroalkyl substances in serum of pregnant women and evaluation of neonatal neurobehavior based on high performance liquid chromatography-tandem mass spectrometry

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been extensively used as synthetic fluorine-containing compounds in various consumer products, including surfactants, cookware, lubricants, clothing, and food packaging, since the 1950s. Evidence has shown that PFASs cross the placental barrier and interfere with fetal thyroid hormone homeostasis, which is crucial for fetal growth and neurobehavioral development in children aged 2-9 years. However, no epidemiological data on the association between prenatal PFAS exposure and neonatal neurobehavioral development are available. In this study, we explored the association between prenatal PFAS exposure and neonatal neurobehavioral development based on the Ezhou cohort study. Blood samples (10 mL) were collected during the third trimester of pregnancy (28-36 weeks) at the Ezhou maternal and child health hospital. The blood specimens were centrifuged at 4000 r/min for 15 min immediately after collection, separated, stored at -80 ℃. The samples were analyzed for seven PFASs, namely, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonamide (PFOSA). The PFASs were separated using a C18 column (100 mm×2.1 mm, 1.7 μm) at an oven temperature of 40 ℃, injection volume of 10 μL, and flow rate of 0.4 mL/min via gradient elution with methanol and ammonium acetate aqueous solution. The instrument was operated in negative electrospray ionization mode with multiple reaction monitoring. The correlation coefficients (r2), limits of detection (LODs) and quantification (LOQs), and spiked recoveries of the seven PFASs were 0.993-0.999, 0.006-0.020 ng/mL, 0.020-0.066 ng/mL, and 84.6%-116.8%, respectively. Neonatal behavioral neurological assessment (NBNA) was used to evaluate newborn cognitive development 72 h after birth; this tool consisted of five clusters, including behavior (six items), passive muscle tone (four items), active muscle tone (four items), primitive reflexes (three items), and general assessment (three items). Each item was rated on a three-point scale (0, 1, or 2), with the 20 items having a maximum score of 40. A total of 379 mother-newborn pairs were included in the analysis. The PFASs with the highest exposure levels was PFOA, with median levels of 19.4 ng/mL. Linear regression models were used to test the effects of ln-converted PFAS levels in newborns. After adjusting for confounding factors, the linear regression model showed that PFOS exposure during pregnancy was associated with decreased active muscle tone(β(95% CI): 0.36(-0.64, 0.08)) and general assessment(β(95% CI): 0.34(-0.61, 0.07)) in all newborns. Furthermore, PFNA exposure was associated with decreased passive muscle tone(β(95% CI): 0.38(-0.74, 0.01)) and total NBNA(β(95% CI): 0.37(-0.68, 0.06)). PFDA exposure was associated with decreased behavior(β(95% CI): 0.28(-0.54, 0.01)), while PFHxS exposure was associated with elevated total NBNA(β(95% CI): 0.27(0.05-0.48)). Gender stratification analysis showed that PFOS exposure during pregnancy was associated with decreased active muscle tone(β(95% CI): 0.54(-0.73, 0.35)) and general assessment(β(95% CI): 0.50(-0.88, 0.13)), PFNA exposure during pregnancy was associated with decreased passive muscle tone(β(95% CI): 0.67(-1.2, 0.14)) and total NBNA(β(95% CI): 0.45(-0.91, 0.01)), PFDA exposure during pregnancy was associated with decreased behavior(β(95% CI): 0.44(-0.71, 0.17)), PFHxS exposure was associated with elevated total NBNA(β(95% CI): 0.41(0.02-0.80)) in male newborns, and PFOA exposure was associated with decreased general assessment(β(95% CI): -0.27(-0.51, 0.02)), and PFDA exposure was associated with elevated behavior(β(95% CI): 0.46(0.40-0.52)) in female newborns. The proposed method separates and detects various PFASs without the need for cumbersome pretreatment processes, and has the advantages of low LODs, satisfactory recoveries, and accurate precision. Thus, it allows for the simultaneous analysis of trace PFASs in microserum samples from pregnant women. Our results also showed that prenatal PFAS exposure can lead to neurobehavioral disorders in offspring, with male newborns showing greater sensitivity than female newborns.

Prenatal Exposure to Perfluoroalkyl Substances and Child Behavior at Age 12: A PELAGIE Mother-Child Cohort Study.

Per- and polyfluoroalkyl substances (PFAS) are chemical substances spread throughout the environment worldwide. Exposure during pregnancy represents a specific window of vulnerability for child health. Our objective was to assess the impact of prenatal exposure to multiple PFAS on emotional and behavioral functions in 12-y-old children. In the PELAGIE mother-child cohort (France), prenatal exposure to nine PFAS was measured from concentrations in cord serum samples. Behavior was assessed at age 12 y using the parent-reported Strengths and Difficulties Questionnaire (SDQ) and the self-reported Dominic Interactive for Adolescents (DIA) for 444 children. Associations were estimated using negative binomial models for each PFAS. Bayesian kernel machine regression (BKMR) models were performed to assess the exposure mixture effect on children's behavior. In our study population, 73% of mothers had spent more than 12 y in education. Higher scores on SDQ externalizing subscale were observed with increasing cord-serum concentration of perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) [adjusted mean ratio , 95% confidence interval (CI): 1.03, 1.34, and (95% CI: 1.00, 1.29) for every doubling of concentration, respectively]. Results for the hyperactivity score were similar [ (95% CI: 1.04, 1.40) and (95% CI: 1.02, 1.36), respectively]. With regard to major depressive disorder and internalizing subscales, perfluorodecanoic acid (PFDA) was associated with higher self-reported DIA scores [ (95% CI: 1.01, 1.27) and (95% CI: 1.02, 1.21), respectively]. In terms of the anxiety subscale, PFDA and PFNA were associated with higher scores [ (95% CI: 1.02, 1.21) and (95% CI: 1.01, 1.19), respectively]. Concurrent increases in the PFAS concentrations included in the BKMR models showed no change in the SDQ externalizing and DIA internalizing subscales scores. Prenatal exposure to PFNA and PFOA were associated with increasing scores for measures of externalizing behaviors, specifically hyperactivity. We also identified associations between PFNA and PFDA prenatal exposure levels and increasing scores related to internalizing behaviors (general anxiety and major depressive disorder), which adds to the as yet sparse literature examining the links between prenatal exposure to PFAS and internalizing disorders. https://doi.org/10.1289/EHP12540.

Associations between exposure to a mixture of perfluoroalkyl and polyfluoroalkyl substances and age at menarche in adolescent girls utilizing three statistical models

Exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS) is suggested to interfere with endocrine function and may affect female pubertal development. However, the epidemiological evidence on age at menarche associated with PFAS exposure is still inconsistent. Our objective was to investigate association of serum PFAS concentrations with age at menarche among 12–19 years old girls. We used data on 432 girls from National Health and Nutrition Examination Survey (NHANES) 2007–2012 cycles. NHANES reported serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) as quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Age at menarche was self-reported by girls or their guardians. Multivariable linear regression models were applied to estimate the association of individual PFAS exposure with age at menarche. The combined effects of PFAS mixture exposures on age at menarche were assessed using three statistical methods, including Bayesian kernel machine regression (BKMR), weighted quantile sum regression (WQS), and elastic net regression (ENR). In the single-chemical model, girls in the middle tertile of serum PFOA concentration had a lower age at menarche [regression coefficient (β) = -0.73 years, 95% confidence interval (CI): -1.44, -0.01; P = 0.047], compared with those in the lower tertile. Girls in the higher tertile of PFNA exposure were associated with older age at menarche (β = 0.36 years, 95% CI: 0.03, 0.80; P = 0.027), compared with those in the lower tertile. In the multiple-chemical models using BKMR and ENR approaches, higher PFNA exposure was significantly associated with older age at menarche among girls, after adjusting for other PFAS. We found suggestive evidence that higher PFAS mixture exposures may be related to an increase in age at menarche using the BKMR model. In conclusion, exposure to PFNA was associated with the later timing of menarche among girls.

Perfluorononanoic Acid Induces Neurotoxicity via Synaptogenesis Signaling in Zebrafish.

Perfluorononanoic acid (PFNA), commonly used as an alternative polyfluorinated compound (PFC) of perfluorooctanoic acid (PFOA), has been widely detected in the aquatic environment. Previous ecotoxicological and epidemiological results suggested that some neurobehavioral effects were associated with PFC exposure; however, the ecological impacts and underlying neurotoxicity mechanisms remain unclear, particularly in aquatic organisms during sensitive, early developmental stages. In this study, zebrafish embryos were exposed to environmentally relevant concentrations of PFNA for 120 h, and the neurological effects of PFNA were comprehensively assessed using transcriptional, biochemical, morphological, and behavioral assays. RNA sequencing and advanced bioinformatics analyses predicted and characterized the key biological processes and pathways affected by PFNA exposure, which included the synaptogenesis signaling pathway, neurotransmitter synapse, and CREB signaling in neurons. Neurotransmitter levels (acetylcholine, glutamate, 5-hydroxytryptamine, γ-aminobutyric acid, dopamine, and noradrenaline) were significantly decreased in zebrafish larvae, and the Tg(gad67:GFP) transgenic line revealed a decreased number of GABAergic neurons in PFNA-treated larvae. Moreover, the swimming distance, rotation frequency, and activity degree were also significantly affected by PFNA, linking molecular-level changes to behavioral consequences.

Association between per- and polyfluoroalkyl substances and semen quality.

Some studies have suggested that perfluoroalkyl and polyfluoroalkyl substance (PFAS) exposure may be associated with semen quality in the general population, but with inconsistent results. To identify a more precise relationship between them, a meta-analysis was performed. We searched Embase, the PubMed, The Cochrane Library, Ovid databases, and Web of Science databases (before March 2022) for appropriate studies on the correlations of PFAS exposure with semen parameters. We extracted β value and 95% confidence intervals (CIs) to conduct meta-analysis. Subgroup analyses was performed by sample size, geographic location, and sample type. A total of seven articles involving 2190 participants were included in this study. The concentrations of perfluorooctanoic acid (PFOA) (β value = - 1.38; 95% CI: - 2.44, - 0.32) and perfluorononanoic acid (PFNA) (β value = - 1.31, 95% CI: - 2.35, - 0.26) were negatively associated with sperm progressive motility. Subgroup analysis revealed that PFNA exposure was related to sperm morphology in studies with the sample size exceeding 200 people (β value = - 0.14; 95% CI: - 0.26, - 0.01). Our study supports that exposure to some PFASs (e.g., PFNA, PFOA) may be associated with semen quality, such as lower sperm progressive motility. Therefore, it is of great significance for the prevention of male infertility by control the use of PFASs.

Associations of exposure to perfluoroalkyl substances with serum uric acid change and hyperuricemia among Chinese women: Results from a longitudinal study

BackgroundCross-sectional studies have reported associations of perfluorooctanoic acid (PFOA) with concurrent serum uric acid (UA) levels. However, the prospective associations of other commonly detected perfluoroalkyl substances (PFASs) with serum UA and hyperuricemia remain unclear. MethodsA total of 654 females from the Dongfeng-Tongji cohort, who were followed up from 2008 to 2018, were included in this study. We measured their baseline plasma concentrations of six PFASs [including perfluorooctane sulfonic acid (PFOS), PFOA, perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), perfluorodecanoic acid (PFDA), and perfluoroheptanoic acid (PFHpA)], as well as their serum UA levels at both baseline and follow-up visits. General linear and logistic regression models were constructed to explore the associations of each PFAS with annual change of serum UA and incident hyperuricemia. Mixture effects of PFASs were further assessed by using the quantile g-computation approach. ResultsCompared to participants with low PFNA exposure (≤50th), those with high PFNA exposure (>75th) had significantly increased annual increment of serum UA [β(95%CI) = 2.58 (0.60, 4.55)]. No significant associations of PFOS, PFOA, PFDA, PFHxS, or PFHpA with serum UA change were observed. Besides, females with high PFOA or PFHpA (>75th) exposure had higher incident risk of hyperuricemia than those with low exposure (<50th) [OR (95%CI) = 1.94 (1.00, 3.76) and 1.86 (1.03, 3.36), respectively]. No significant associations of PFOS, PFNA, PFDA, and PFHxS with hyperuricemia risk were observed. Quantile g-computation approach didn't find significant effects of PFAS co-exposure on serum UA change or hyperuricemia incidence. ConclusionsOur findings suggested exposure to PFASs as a risk factor for hyperuricemia and shed light on hyperuricemia prevention for elderly females.

Associations of prenatal exposure to perfluoroalkyl substances with preterm birth: A family-based birth cohort study

Studies have investigated associations between maternal exposure to PFAS and preterm birth, but the impact of paternal and overall family exposure to PFAS mixtures on preterm birth remains unknown. To address this knowledge gap, a total of 355 preterm births and 481 controls were selected for a family-based birth cohort study in a coastal area of China, between 2016 and 2018. Seven PFAS, including perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), were quantified in maternal, paternal and neonatal sera. Preterm birth was defined as live delivery at <37 completed gestational weeks. Bayesian kernel machine regression (BKMR) model was used to inspect the combined effect of family PFAS mixtures. Latent class analysis was used to identify family-level PFAS exposure profiles. Multiple linear regression analysis showed higher odds of preterm birth in association with higher maternal PFBA (OR = 1.16, 95%CI:1.09, 1.25), PFOA (OR = 1.51, 95%CI:1.27, 1.80), PFOS (OR = 2.07, 95%CI:1.70, 2.52) and PFNA (OR = 1.36, 95%CI: 1.01, 1.83), and neonatal PFBA (OR = 1.16, 95%CI:1.05,1.29), PFHxA (OR = 1.46, 95%CI:1.32, 1.62), PFHxS (OR = 1.15, 95%CI:1.05, 1.26) and PFNA (OR = 1.30, 95%CI:1.09,1.56). The associations were reversed between individual paternal PFAS exposures and preterm birth. At the family level, higher PFAS mixture concentration was associated with higher odds of preterm birth. In particular, higher PFNA and PFDA exposure was associated with greater preterm birth risk (OR = 2.55, 95%CI:1.45, 4.50). The PFAS-preterm association was modified by family-level seafood consumption. Our results suggest that higher family-level PFNA and PFDA exposure was associated with greater preterm birth risk, although the results for individual paternal, maternal and neonatal PFAS exposures were contradictory. If replicated in other coastal areas, these findings highlight a need to focus on the family triad and to consider seafood consumption when assessing the reproductive toxicity of PFAS exposure.

Effects of Prenatal Exposure to Perfluorononanoic Acid on Neurobehavioral Development in Rat Offspring

BACKGROUND AND AIM: Perfluorononanoic Acid (PFNA), a kind of fluorinated aliphatic molecules, had been extensively used in industrial applications as a surface protectant and known to accumulate in humans and wildlife. Although PFNA had been adversely associated with the growth and development of wild-type mice, much less is known about the impact of short-term exposure to PFNA during gestation on neurobehavioral development in rat offspring. The purpose of this study was to investigate the effects of PFNA on the physical and neurobehavioral development in sprague-dawley rat offspring. METHODS: Dams were dosed daily via oral gavage during gestation days 1-19 with control, 0.02, 0.2, 1.0, and 5.0 mg/kg of PFNA. During postnatal day (PND) 1-21, a series of developmental test battery were conducted, including body weight, maturational milestones (pinnae unfolding, incisor eruption, hair growth and eye opening) and neurobehavioral reflex (surface righting reflex, negative geotaxis, and cliff avoidance tests). Morris water maze tests were performed to study the learning and memory ability of the rat offspring on PND 28. RESULTS:PFNA exposure during gestation resulted in lower weight (≥1.0 mg/kg), later eye opening and worse performance in negative geotaxis (5.0 mg/kg), but no associations were observed between PFNA exposure and other maturational milestones or neurobehavioral reflex. Further, morris water maze tests indicated damaged spatial learning and memory ability of offspring (≥0.2 mg/kg). CONCLUSIONS:Our study reveals that PFNA exposure during gestation produce multiple adverse effects on neuro-development in rat, research is needed to examine the potential mechanisms linked to the adverse effects of PFNA. KEYWORDS: perfluorononanoic acid, neurobehavioral development, rat offspring, prenatal exposure

Perfluorononanoic acid impedes mouse oocyte maturation by inducing mitochondrial dysfunction and oxidative stress

Perfluorononanoic acid (PFNA), a member of PFAS, is frequently detected in human blood and tissues, even in follicular fluid of women. The exposure of PFNA, but not PFOA and PFOS, is positively correlated with miscarriage and increased time to pregnancy. Toxicological studies indicated that PFNA exposure is associated with immunotoxicity, hepatotoxicity, developmental toxicity, and reproductive toxicity in animals. However, there is little information regarding the toxic effects of PFNA on oocyte maturation. In this study, we investigated the toxic effects of PFNA exposure on mouse oocyte maturation in vitro. Our results showed that 600 μM PFNA significantly inhibited germinal vesicle breakdown (GVBD) and polar body extrusion (PBE) in mouse oocytes. Our further study revealed that PFNA induced abnormal metaphase I (MI) spindle assembly, evidenced by malformed spindles and mislocalization of p-ERK1/2 in PFNA-treated oocytes. We also found that PFNA induced abnormal mitochondrial distribution and increased mitochondrial membrane potential. Consequently, PFNA increased reactive oxygen species (ROS) levels, leading to oxidative stress, DNA damage, and eventually early-stage apoptosis in oocytes. In addition, after 14 h culture, PFNA disrupted the formation of metaphase II (MII) spindle in most PFNA-treated oocytes with polar bodies. Collectively, our results indicate that PFNA interferes with oocyte maturation in vitro via disrupting spindle assembly, damaging mitochondrial functions, and inducing oxidative stress, DNA damage, and early-stage apoptosis.

Maternal exposure to perfluoroalkyl chemicals and anogenital distance in the offspring: A Faroese cohort study

Exposure to perfluoroalkyl substances (PFASs) has in some studies been associated with reduced anogenital distance (AGD) in newborns as a sensitive indicator of prenatal anti-androgenic exposure. The aim of this study was to investigate the association between maternal PFAS exposure and offspring AGD in a population with wide ranges of PFAS exposures.Participants were recruited in the Faroe Islands in 2007–2009, and information on AGD and PFAS exposure was obtained from 463 mother-infant pairs. Perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) were measured in maternal serum. Data were analyzed using multiple linear regression analysis adjusted for birth weight, child age at examination, parity, and maternal education level.Among boys, higher maternal serum concentrations of PFOA, PFOS, PFNA and PFDA were significantly associated with a longer AGD, both with the exposure entered as a continuous variable and as quartiles. Boys in the highest quartile of PFOA, PFOS, PFNA and PFDA exposure had an increase in AGD of 1.2 mm (95 % CI 0.1;2.2), 1.3 mm (95 % CI 0.3;2.3), 1.0 mm (95 % CI 0.0:2.0) and 1.3 mm (95 % CI 0.3;2.4), respectively, when compared to boys in the lowest quartile of exposure (p < 0.05). No significant association was found between male AGD and PFHxS. No association was found for girls.In conclusion, elevated maternal exposure to major PFASs was significantly associated with a longer AGD in boys. No significant associations were found among girls, thus suggesting a sex-dimorphic effect of PFAS exposure.

Biomarkers of poly- and perfluoroalkyl substances (PFAS) in Sub-Arctic and Arctic communities in Canada.

Polyfluoroalkyl substances and perfluoroalkyl substances (PFAS) are a family of anthropogenic chemicals that are used in food packaging, waterproof clothing, and firefighting foams for their water and oil resistant properties. Though levels of some PFAS appear to be decreasing in Canada's south, environmental levels have been increasing in the Arctic due to long-range transport. However, the implications of this on human exposures in sub-Arctic and Arctic populations in Canada have yet to be established. To address this data gap, human biomonitoring research was completed in Old Crow, Yukon, and the Dehcho region, Northwest Territories. Blood samples were collected from adults residing in seven northern First Nations and were analyzed by liquid chromatography mass spectrometry. A total of nine PFAS were quantified: perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOS), perfluorohexane sulphonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUdA), perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), and perfluorobutane sulphonic acid (PFBS). In the Dehcho (n=124), five PFAS had a detection rate greater than 50% including PFOS, PFOA, PFHxS, PFNA, and PFDA. In addition to these PFAS, PFUdA was also detected in at least half of the samples collected in Old Crow (n=54). Generally, male participants had higher concentrations of PFAS compared to female participants, and PFAS concentrations tended to increase with age. For most PFAS, Old Crow and Dehcho levels were similar or lower to those measured in the general Canadian population (as measured through the Canadian Health Measures Survey or CHMS) and other First Nations populations in Canada (as measured through the First Nations Biomonitoring Initiative or FNBI). The key exception to this was for PFNA which, relative to the CHMS (0.51μg/L), was approximately 1.8 times higher in Old Crow (0.94μg/L) and 2.8 times higher in Dehcho (1.42μg/L) than observed in the general Canadian population. This project provides baseline PFAS levels for participating communities, improving understanding of human exposures to PFAS in Canada. Future research should investigate site-specific PFNA exposure sources and monitor temporal trends in these regions.

Biomonitoring: A tool to assess PFNA body burdens and evaluate the effectiveness of drinking water intervention for communities in New Jersey.

Elevated perfluorononanoic acid (PFNA) levels, one of many manmade per- and polyfluoroalkyl substances (PFAS), were detected in public water systems/private wells in New Jersey communities. Interventions to end exposure through drinking water were carried out from 2014 to 2016. To evaluate the effectiveness of interventions, a community biomonitoring study was conducted for the communities between 2017 and 2020. A convenience sampling design was used with 120 participants in Year 1 between ages of 20-74 who consumed PFNA-contaminated water. Three blood samples, one year apart, were drawn from each participant and completed for 99 participants. Separated serum samples were measured for 12 PFAS including PFNA. Questionnaires were administered to collect information on demographics and potential sources. Drinking water and house dust collected at the first visit were analyzed for 14 PFAS including PFNA. The PFNA sera levels (Year 1) found 84 out of 120 (70%) participants were higher than the 95th percentile of a nationally representative sample of US adults (NHANES2015-16). Current drinking water and house dust were not significant contributing sources for the study participants. On average, PFNA sera levels were 12±16% (Year 2) and 27±16% (Year 3) lower than the level measured in Year 1 (p<0.01). The PFNA half-life was estimated around 3.52 years, using a mixed model from 68 high-exposed participants (>95th percentile of NHANES2015-16) with controlling for physiological covariates. The decline in adult serum PFNA levels seen in the years following a community drinking water intervention suggests the intervention effectively reduced PFNA exposure via drinking water.

Prenatal exposure to perfluoroalkyl substances and behavioral difficulties in childhood at 7 and 11 years

BackgroundPerfluoroalkyl substances (PFAS) are suggested to interfere with thyroid hormone during pregnancy and influence fetal neurodevelopment. Epidemiological evidence regarding behavioral difficulties in childhood associated with prenatal PFAS exposure has been inconclusive. ObjectiveWe evaluated the association between prenatal PFAS exposure and behavioral difficulties at 7 and 11 years, and investigated the potential mediating role of maternal thyroid hormones. MethodsUsing pooled samples in the Danish National Birth Cohort established between 1996 and 2002, we estimated the associations between concentrations of six types of PFAS in maternal plasma (median, 8 gestational weeks) and child behavioral assessments from the Strength and Difficulties Questionnaire (SDQ), reported by parents at 7 years (n = 2421), and by parents (n = 2070) and children at 11 years (n = 2071). Behavioral difficulties were defined as having a composite SDQ score above the 90th percentile for total difficulties and externalizing or internalizing behaviors. We used logistic regression to estimate the adjusted Odds Ratio (OR) by doubling increase of prenatal PFAS (ng/ml). The possible mediating effect of maternal thyroid function classified based on thyroid stimulating hormone (TSH) and free thyroxine (fT4) levels were evaluated. ResultsPrenatal perfluorononanoic acid (PFNA) was consistently associated with total and externalizing behavioral difficulties in all three SDQ measures reported by parents (OR = 1.40, 95% CI: 1.14–1.73 for age 7; OR = 1.27, 95% CI: 1.05–1.53 for age 11) or children (OR = 1.32, 95% CI: 1.11–1.58) while no consistent associations were observed for other types of PFAS. A small magnitude of natural indirect effects via maternal thyroid dysfunction (ORs ranged from 1.01 to 1.03) of several PFAS were observed for parent-reported total and externalizing behaviors at 7 years only. DiscussionPrenatal PFNA exposure was associated with externalizing behavioral difficulties in childhood in repeated SDQ measures at 7 and 11 years. The slight mediating effects of maternal thyroid hormones in early gestation warrant further evaluation.

Effect of gestational exposure to perfluorononanoic acid on neonatal mice testes.

Perfluoroalkyl acids (PFAAs) are widely used in commercial products and are found in many goods of daily use. Perfluorononanoic acid (PFNA) is one of the PFAAs that possesses endocrine disrupting properties and we have recently shown that PFNA affects testicular functions in Parkes mice. Exposure to environmental endocrine disruptors during fetal life is believed to affect gonadal development and they might produce reproductive abnormalities in males. Therefore, the present study examined the effect of gestational exposure to PFNA on the testes of neonatal mice offspring. Pregnant Parkes mice were orally administered PFNA (2 and 5mg/kg body weight) or distilled water from gestational day 12 until parturition. Male pups were killed on postnatal day 3. PFNA treatment decreased testosterone biosynthesis by inhibiting expression of steroidogenic acute regulatory protein, cytochrome P450scc, and 3β- and 17β-hydroxysteroid dehydrogenase; proliferation of testicular cells was also affected in treated mice. Furthermore, a marked decrease in expression of Wilms tumor 1, steroidogenic factor 1 and insulin-like factor 3 was noted in neonatal mice testes, indicating that the PFNA treatment may affect the development of the testis. Moreover, observation of the dose-related expression of anti-müllerian hormone and c-Kit in neonatal mice testes is also suggestive of an interference with gonadal development by PFNA exposure. In conclusion, the results suggest that the gestational exposure to PFNA decreased testosterone biosynthesis and altered the expression of critical factors involved in the development of the testis, thereby advocating a potential risk of PFNA to male reproductive health.

Exposure to Perfluoroalkyl Substances during Fetal Life and Pubertal Development in Boys and Girls from the Danish National Birth Cohort.

Background:It remains unsettled whether prenatal exposure to perfluoroalkyl substances (PFASs) affects human reproductive health through potential endocrine disruption.Objectives:We aimed to explore the associations between prenatal exposure to several PFASs and various aspects of pubertal development in boys and girls.Methods:We studied two samples ( and 445) from the Puberty Cohort, nested within the Danish National Birth Cohort (DNBC), measuring PFAS in maternal plasma from early gestation. Data on pubertal development were collected biannually from the age of 11 y until full maturation, using web-based questionnaires. Outcomes were age at menarche, voice break, first ejaculation, and Tanner stages 2 to 5 for pubic hair, breast, genital development, and a combined puberty indicator. A regression model for censored data was used to estimate mean difference (months) in age at achieving the pubertal outcomes across tertiles of PFAS concentrations and with a doubling of PFAS concentrations (continuous). For perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), a meta-analysis was used to provide a weighted average of the point estimates from samples 1 and 2.Results:Overall, prenatal exposure to PFOS, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PDFA) (girls) and PFHxS and PFHpS (boys) was associated with lower mean age at puberty marker onset. PFDA and PFNA exposure was associated with higher mean age at onset of puberty in boys. Nonmonotonic associations in girls (PFOS, PFHpS, PFDA) and boys (PFDA, PFNA) were observed, showing larger mean age differences for the combined puberty indicator in the middle tertile [girls: PFOS: mo, 95% confidence interval (CI): , ; PFHpS: mo, 95% CI: , 1.85; PFDA: mo, 95% CI: , 1.83; and boys: PFNA: 4.45 mo, 95% CI: , 10.21; PFDA: 4.59 mo, 95% CI: , 10.11] than in the highest tertile with the lowest as reference.Conclusions:Our population-based cohort study suggests sex-specific associations of altered pubertal development with prenatal exposure to PFASs. These findings are novel, and replication is needed. https://doi.org/10.1289/EHP3567

Prepubertal exposure to perfluorononanoic acid interferes with spermatogenesis and steroidogenesis in male mice

Perfluoroalkyl acids (PFAAs) are widely used in industrial and commercial products and possess endocrine disrupting properties. Perfluorononanoic acid (PFNA), one of PFAAs, has been mainly reported to produce testicular toxicity in adult animals. The objective of the present study was to examine the effect of acute exposure of PFNA to prepubertal male Parkes (P) mice on spermatogenesis and testicular steroidogenesis, and to study the possible mechanism(s) of its action. PFNA (2 and 5 mg/kg) was orally administered to male P mice for 14 days from postnatal day 25–38. Histologically, testis in PFNA-treated mice showed non-uniform diverse degenerative changes in the seminiferous tubules; both normal and affected tubules were seen in the same testicular sections. The treatment caused a reduction in intra-testicular and serum testosterone levels accompanied by a decrease in testicular expression of SF1, StAR, CYP11A1, and 3β- and17β-HSD. Further, the activity of antioxidant enzymes and expression of Nrf2 and HO-1 in the testis were markedly decreased, while the level of lipid peroxidation and expression of IKKβ, NF-κB and caspase-3 were significantly increased in testis of PFNA-treated mice. There was also a decrease in PCNA expression and in PCNA-index and an increase in TUNEL-positive germ cells in testes of PFNA-treated mice. In conclusion, the results suggest that PFNA exposure to prepubertal male mice altered antioxidant enzymes activity and Nrf2-HO-1 signaling, leading to oxidative stress and a decrease in testosterone biosynthesis in the testis; these changes, in turn, caused increased apoptosis and decreased proliferation of germ cells, thereby suppression of spermatogenesis.

Perfluorononanoic acid (PFNA) alters lipid accumulation in bovine blastocysts after oocyte exposure during in vitro maturation

Perfluorononanoic acid (PFNA) is one of the perfluoroalkyl acids present in human tissues. In this study, effects on early embryo development after PFNA exposure were investigated using the bovine in vitro production system. Oocytes were exposed to PFNA during maturation in vitro (10 μg mL−1 and 0.1 μg mL−1), and then fertilized and cultured in parallel with control groups. Developmental parameters (cleavage, blastocyst formation) were followed and embryo quality evaluated (stage, grade). Embryos developed after exposure to 0.1 μg mL−1 were stained to distinguish nuclei, active mitochondria and neutral lipids. 10 μg mL−1 of PFNA had a severe negative effect on blastocyst formation (OR: 0.27 p < 0.05), an effect not observed at 0.1 μg mL−1. However, lipid droplet distribution was significantly altered in embryos exposed to 0.1 μg mL−1, suggesting a disturbance of lipid metabolism after exposure to sublethal levels of PFNA during oocyte maturation in vitro.