Gestational Perfluorooctanoic Acid Exposure Research Articles

Effects of gestational low dose perfluorooctanoic acid on maternal and "anxiety-like" behavior in dams.

Pregnancy is a unique critical window with nearly ubiquitous exposure to low concentrations of endocrine disrupting chemicals, such as per- and poly-fluoroalkyl substances (PFAS). Human and animal research suggests that PFAS compounds disrupt hypothalamic-pituitary-adrenal axis function, with some evidence of altered “anxiety-like” behavior, but little is known about the potential effects on maternal mental health following exposures during pregnancy. Evaluating the consequences of gestational PFAS exposures on maternal health is essential, because approximately 1 in 10 women experience postpartum depression, often with increased anxiety. To address this gap, dams were exposed to a low dose, 0.1 mg/kg, of perfluorooctanoic acid (PFOA) from gestational day 0 to birth. Maternal behavior was then observed from postnatal days 5–9, and “anxiety-like” behavior was measured using open field spontaneous locomotor behavior and elevated plus maze following weaning. No difference was observed in the litter size or sex of offspring. Gestational PFOA exposure altered maternal behavior. Despite similar nursing durations, PFOA dams spent more time nursing in a flat posture and on their side, and less time in kyphosis. Despite significantly quicker first contact, PFOA dams did not return pups to the nest quicker, indicating reduced retrieval latency. At weaning, dams displayed increased “anxiety-like” behaviors in the elevated plus maze with a significantly higher mean duration in the closed arms and reduced choice frequency with significantly lower number of entries in the closed and open arms. PFOA dams showed reductions in ambulatory movement across the session. Pregnancy exposure to PFOA altered both maternal and “anxiety-like” behavior in dams. Additional assays focused on depression-associated behaviors, such as forced swim, anhedonia, and social preference, will further delineate behavioral mechanisms. Further research on the effects of environmental contaminant exposures during pregnancy should investigate how co-exposures to other risk factors, such as stress, may enhance behavioral toxicity. Understanding how environmental contaminant exposure during pregnancy effects maternal depression-associated, and/or “anxiety-like” behavior is necessary for the public health protection of women.

Physical activity modifies the relation between gestational perfluorooctanoic acid exposure and adolescent cardiometabolic risk

ObjectiveExposure to per- and polyfluoroalkyl substances (PFAS) – endocrine disrupting chemicals – may increase cardiometabolic risk. We evaluated whether adolescent lifestyle factors modified associations between gestational PFAS exposure and cardiometabolic risk using a prospective cohort study. MethodsIn 166 mother-child pairs (HOME Study), we measured concentrations of four PFAS in maternal serum collected during pregnancy. When children were age 12 years, we calculated cardiometabolic risk scores from visceral adiposity area, blood pressure, and fasting serum biomarkers. We assessed adolescent physical activity and Healthy Eating Index scores using the Physical Activity Questionnaire for Older Children (PAQ-C), actigraphy, and 24-h diet recalls. Using multivariable linear regression and weighted quantile sum regression, we examined whether physical activity or diet modified covariate-adjusted associations of PFAS and their mixture with cardiometabolic risk scores. ResultsPhysical activity modified associations between perfluorooctanoic acid (PFOA) and cardiometabolic risk scores. Each doubling of PFOA was associated with worse cardiometabolic risk scores among children with PAQ-C scores < median (β:1.4; 95% CI:0.5, 2.2, n = 82), but not among those with PAQ-C scores ≥ median (β: 0.2; 95% CI: 1.2, 0.7, n = 84) (interaction p-value = 0.01). Associations were most prominent for insulin resistance, leptin-adiponectin ratio, and visceral fat area. We observed results suggesting that physical activity modified the association of PFAS mixture with cardiometabolic risk scores, insulin resistance, and visceral fat area (interaction p-values = 0.17, 0.07, and 0.10, respectively); however, the 95% CIs of the interaction terms included the null value. We observed similar, but attenuated patterns for PFOA and actigraphy-based measures of physical activity. Diet did not modify any associations. Physical activity or diet did not modify associations for other PFAS. ConclusionsChildhood physical activity modified associations of prenatal serum PFOA concentrations with children's cardiometabolic risk in this cohort, indicating that lifestyle interventions may ameliorate the adverse effects of PFOA exposure.

Gestational perfluoroalkyl substance exposure and body mass index trajectories over the first 12 years of life.

Background/Objectives:Gestational exposure to perfluoroalkyl substances (PFAS), a ubiquitous class of persistent endocrine disrupting chemicals, is associated with increased risk of obesity and cardiometabolic disease. However, it is unclear if gestational PFAS exposure is associated with adiposity trajectories related to adult obesity and cardiometabolic health.Subjects/Methods:We measured perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononaoic acid, and perfluorohexanesulfonic acid (PFHxS) concentrations in maternal serum collected between 16-weeks gestation and delivery in a cohort of 345 mother-child pairs in Cincinnati, OH (enrolled 2003–06). From age 4-weeks to 12 years, we measured weight and length or height up to eight times and calculated child BMI (1,865 repeated measures). Using covariate-adjusted linear mixed models and splines to account for repeated BMI measures and non-linear BMI patterns, respectively, we estimated the age/magnitude of infancy BMI zenith (~1 year) and childhood BMI nadir (~5 years), BMI accrual from 8–12 years, and BMI at age 12 years by PFAS terciles.Results:BMI trajectories varied by PFOA concentrations (age × PFOA interaction p-value=0.03). Children born to women with higher PFOA concentrations had lower infancy and early childhood BMI, earlier BMI nadir, accelerating BMI gains in mid-childhood and adolescence, and higher BMI at age 12 years. Some of these associations were non-monotonic. PFOS and PFHxS were not associated with alterations in BMI trajectories, but were monotonically associated with lower BMI across infancy, childhood, and adolescence. Compared to children in the 1st PFOS tercile, those in the 2nd (β:-0.83; 95%CI:-2.11, 0.51 kg/m2) and 3rd (β:-1.41; 95%CI:-2.65, -0.14 kg/m2) had lower BMI at age 12 years.Conclusions:These results suggest that gestational PFOA exposure may be associated with BMI trajectories related to adult obesity and cardiometabolic disease, while PFOS and PFHxS exposure is associated with lower BMI in the first 12 years of life.

Prenatal Perfluorooctanoic Acid Exposure is Associated with Childhood Adiposity Trajectories

Background/Aim: Gestational exposure to perfluoroalkyl substances (PFAS), a class of ubiquitous and persistent endocrine disrupting chemicals, is associated with increased risk of obesity and cardiometabolic disorders in children. However, it is unclear if PFAS exposure is associated with childhood adiposity trajectories. We examined if prenatal PFAS exposure was associated with children’s body mass index (BMI) trajectories from 4 weeks to 12 years of age.Methods: In 295 mother-child pairs from Cincinnati, OH (enrolled 2003-2006), we measured perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid, perfluorononaoic acid, and perfluorohexanesulfonic acid concentrations in maternal serum collected at 16-weeks gestation. At ages 4 weeks and 1, 2, 3, 4, 5, 8, and 12 years, we measured weight and length/height and calculated child BMI (1,827 repeated measures). Using linear mixed models and splines to account for repeated BMI measures and non-linear BMI patterns, respectively, we estimated BMI trajectories as a function of child age for PFAS terciles, adjusting for covariates.Results: BMI trajectories varied by prenatal PFOA in a non-monotonic fashion. Compared with children in the 1st PFOA tercile, children in the 2nd tercile had lower BMI at age 4 weeks, an earlier adiposity nadir (-0.5 years, 95% CI:-1.1, 0.1), and higher BMI at age 12 years (2.2 kg/m2, 95% CI:1.0, 3.4). In contrast, children in the 3rd tercile had on average 0.3 to 0.5 kg/m2 lower BMI values in the first five years of life, accelerated BMI gains between 8 and 12 years, and an earlier adiposity nadir (-0.3 years, 95% CI:-0.3, 0.0). We observed similar patterns for perfluorononaoic acid, but not other PFAS.Conclusion: These results suggest that higher gestational PFOA exposure is associated with BMI patterns in children that have been linked to later life obesity and cardiometabolic disease.

Gestational Perfluorooctanoic Acid Exposure Inhibits Placental Development by Dysregulation of Labyrinth Vessels and uNK Cells and Apoptosis in Mice.

Perfluorooctanoic acid (PFOA) is a widely used perfluorinated compound and known to cause developmental toxicity which includes the increase of resorbed embryo, decrease of fetal survival, and fetal growth retardation. Nevertheless, whether it is associated with alteration of placental development remains unknown. Pregnant mice were gavaged with 0, 2.5, 5, 10 mg PFOA /kg/day from pregnancy day (PD) 1 to PD 13. Results showed that PFOA exposure markedly decreased the placental weight and caused interstitial edema of placenta. Laminin staining indicated that blood sinusoids area was shrunken in placenta of PFOA-exposed mice. Furthermore, PFOA treatment significantly reduced numbers of uNK cells. Western blot analysis revealed that levels of Bax and cleaved-caspase 3 proteins were markedly up-regulated in PFOA-treated groups. In addition, TEM examination showed that PFOA treatment caused rupture of nuclear membrane and nuclear pyknosis and fragmentation. Thus, our results suggested that gestational PFOA exposure significantly inhibited development of early placenta through shrinkage of labyrinth vessels and downregulation of uNK cells and apoptosis induction, which may result in adverse gestational outcomes.

Gestational exposure to perfluorooctanoic acid (PFOA): Alterations in motor related behaviors

Perfluoroalkyl and polyfluoroalkyl substances are used in commercial applications and developmental exposure has been implicated in alterations in neurobehavioral functioning. While associations between developmental perfluorooctanoic acid (PFOA) exposure and human outcomes have been inconsistent, studies in experimental animals suggest alterations in motor related behaviors. To examine a dose-response pattern of neurobehavioral effects following gestational exposure to PFOA, pregnant CD-1 mice received PFOA (0, 0.1, 0.3, 1.0mg/kg/day) via oral gavage from gestational day 1–17 and the male offspring examined. Motor activity assessments on postnatal day (PND)18, 19, and 20 indicated a shift in the developmental pattern with an elevated activity level observed in the 1.0mg/kg/day dose group on PND18. In the adult, no alterations were observed in body weights, activity levels, diurnal pattern of running wheel activity, startle response, or pre-pulse startle inhibition. In response to a subcutaneous injection of saline or nicotine (80μg/kg), all animals displayed a transient increase in activity likely associated with handling with no differences observed across dose groups. Inhibition of motor activity over 18days of 400μg/kg nicotine injection was not significantly different across dose groups. Hyperactivity induced by 2mg/kg (+)-methamphetamine hydrochloride intraperitoneal injection was significantly lower in the 1.0mg/kg/day PFOA dose group as compared to controls. Taken together, these data suggest that the effects on motor-related behaviors with gestational PFOA exposure do not mimic those reported for acute postnatal exposure. Changes were not observed at dose levels under 1.0mg/kg/day PFOA. Further examination of pathways associated with methamphetamine-induced activity is warranted.

Perfluorooctanoic Acid (PFOA)-induced Liver Lesions in Two Strains of Mice Following Developmental Exposures: PPARα Is Not Required.

Perfluorooctanoic acid (PFOA) is a ubiquitous pollutant that causes liver toxicity in rodents, a process believed to be dependent on peroxisome proliferator-activated receptor-alpha (PPARα) activation. Differences between humans and rodents have made the human relevance of some health effects caused by PFOA controversial. We analyzed liver toxicity at 18 months following gestational PFOA exposure in CD-1 and 129/Sv strains of mice and compared PFOA-induced effects between strains and in wild type (WT) and PPARα-knockout (KO) 129/Sv mice. Pregnant mice were exposed daily to doses (0.01-5 mg/kg/BW) of PFOA from gestation days 1 to 17. The female offspring were necropsied at 18 months, and liver sections underwent a full pathology review. Hepatocellular adenomas formed in PFOA-exposed PPARα-KO 129/Sv and CD-1 mice and were absent in untreated controls from those groups and WT 129/Sv. Hepatocellular hypertrophy was significantly increased by PFOA exposure in CD-1, and an increased severity was found in WT 129/Sv mice. PFOA significantly increased nonneoplastic liver lesions in PPARα-KO mice (hepatocyte hypertrophy, bile duct hyperplasia, and hematopoietic cell proliferation). Low-dose gestational exposures to PFOA induced latent PPARα-independent liver toxicity that was observed in aged mice. Evidence of liver toxicity in PPARα-KO mice warrants further investigation into PPARα-independent pathways.

Gestational and Chronic Low-Dose PFOA Exposures and Mammary Gland Growth and Differentiation in Three Generations of CD-1 Mice

Background: Prenatal exposure to perfluorooctanoic acid (PFOA), a ubiquitous industrial surfactant, has been reported to delay mammary gland development in female mouse offspring (F1) and the treated lactating dam (P0) after gestational treatments at 3 and 5 mg PFOA/kg/day.Objective: We investigated the consequences of gestational and chronic PFOA exposure on F1 lactational function and subsequent development of F2 offspring.Methods: We treated P0 dams with 0, 1, or 5 mg PFOA/kg/day on gestation days 1–17. In addition, a second group of P0 dams treated with 0 or 1 mg/kg/day during gestation and their F1 and F2 offspring received continuous PFOA exposure (5 ppb) in drinking water. Resulting adult F1 females were bred to generate F2 offspring, whose development was monitored over postnatal days (PNDs) 1–63. F1 gland function was assessed on PND10 by timed-lactation experiments. Mammary tissue was isolated from P0, F1, and F2 females throughout the study and histologically assessed for age-appropriate development.Results: PFOA-exposed F1 dams exhibited diminished lactational morphology, although F1 maternal behavior and F2 offspring body weights were not significantly affected by P0 treatment. In addition to reduced gland development in F1 females under all exposures, F2 females with chronic low-dose drinking-water exposures exhibited visibly slowed mammary gland differentiation from weaning onward. F2 females derived from 5 mg/kg PFOA-treated P0 dams displayed gland morphology similar to F2 chronic water exposure groups on PNDs 22–63.Conclusions: Gestational PFOA exposure induced delays in mammary gland development and/or lactational differentiation across three generations. Chronic, low-dose PFOA exposure in drinking water was also sufficient to alter mammary morphological development in mice, at concentrations approximating those found in contaminated human water supplies.

Gestational PFOA Exposure of Mice is Associated with Altered Mammary Gland Development in Dams and Female Offspring

Perfluorooctanoic acid (PFOA), with diverse and widespread commercial and industrial applications, has been detected in human and wildlife sera. Previous mouse studies linked prenatal PFOA exposure to decreased neonatal body weights (BWs) and survival in a dose-dependent manner. To determine whether effects were linked to gestational time of exposure or to subsequent lactational changes, timed-pregnant CD-1 mice were orally dosed with 5 mg PFOA/kg on gestation days (GD) 1-17, 8-17, 12-17, or vehicle on GD 1-17. PFOA exposure had no effect on maternal weight gain or number of live pups born. Mean pup BWs on postnatal day (PND) 1 in all PFOA-exposed groups were significantly reduced and decrements persisted until weaning. Mammary glands from lactating dams and female pups on PND 10 and 20 were scored based on differentiation or developmental stages. A significant reduction in mammary differentiation among dams exposed GD 1-17 or 8-17 was evident on PND 10. On PND 20, delays in normal epithelial involution and alterations in milk protein gene expression were observed. All exposed female pups displayed stunted mammary epithelial branching and growth at PND 10 and 20. While control litters at PND 10 and 20 had average scores of 3.1 and 3.3, respectively, all treated litters had scores of 1.7 or less, with no progression of duct epithelial growth evident over time. BW was an insignificant covariate for these effects. These findings suggest that in addition to gestational exposure, abnormal lactational development of dams may play a role in early growth retardation of developmentally exposed offspring.