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

ABSTRACT: 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.

SUBMITTER: Jiang W

PROVIDER: S-EPMC7025578 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Jiang Wenyu W Deng Yu Y Song Zifan Z Xie Yajuan Y Gong Lixin L Chen Yilu Y Kuang Haibin H

Frontiers in physiology 20200207

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 i ...[more]

PMID: 32116763

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Project description: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.

Project description:BackgroundPerfluorooctanoic acid (PFOA) is a poly- and perfluoroalkyl substance (PFAS) associated with adverse pregnancy outcomes in mice and humans, but little is known regarding one of its replacements, hexafluoropropylene oxide dimer acid (HFPO-DA, referred to here as GenX), both of which have been reported as contaminants in drinking water.ObjectivesWe compared the toxicity of PFOA and GenX in pregnant mice and their developing embryo-placenta units, with a specific focus on the placenta as a hypothesized target.MethodsPregnant CD-1 mice were exposed daily to PFOA (0, 1, or 5mg/kg) or GenX (0, 2, or 10mg/kg) via oral gavage from embryonic day (E) 1.5 to 11.5 or 17.5 to evaluate exposure effects on the dam and embryo-placenta unit. Gestational weight gain (GWG), maternal clinical chemistry, maternal liver histopathology, placental histopathology, embryo weight, placental weight, internal chemical dosimetry, and placental thyroid hormone levels were determined.ResultsExposure to GenX or PFOA resulted in increased GWG, with increase in weight most prominent and of shortest latency with 10mg/kg/d GenX exposure. Embryo weight was significantly lower after exposure to 5mg/kg/d PFOA (9.4% decrease relative to controls). Effect sizes were similar for higher doses (5mg/kg/d PFOA and 10mg/kg/d GenX) and lower doses (1mg/kg/d PFOA and 2mg/kg/d GenX), including higher maternal liver weights, changes in liver histopathology, higher placental weights and embryo-placenta weight ratios, and greater incidence of placental abnormalities relative to controls. Histopathological features in placentas suggested that PFOA and GenX may exhibit divergent mechanisms of toxicity in the embryo-placenta unit, whereas PFOA- and GenX-exposed livers shared a similar constellation of adverse pathological features.ConclusionsGestational exposure to GenX recapitulated many documented effects of PFOA in CD-1 mice, regardless of its much shorter reported half-life; however, adverse effects toward the placenta appear to have compound-specific signatures. https://doi.org/10.1289/EHP6233.

Project description:BackgroundTitanium dioxide nanoparticles (TiO2 NPs) have recently found applications in a wide variety of consumer goods. TiO2 NPs exposure significantly increases fetal deformities and mortality. However, the potential toxicity of TiO2 NPs on the growth and development of placenta has been rarely studied during mice pregnancy.PurposeThe objective of this study was to investigate the effects of maternal exposure of TiO2 NPs on the placentation.MethodsMice were administered TiO2 NPs by gavage at 0, 1 and 10 mg/kg/day from gestational day (GD) 1 to GD 13. Uteri and placentas from these mice were collected and counted the numbers of implanted and resorbed embryo and measured the placental weight on GD 13. Placental morphometry was observed by hematoxylin and eosin staining. The levels of Hand1, Esx1, Eomes, Hand2, Ascl2 and Fra1 mRNA were assessed by qRT-PCR. Uterine NK (uNK) cells were detected by using DBA lectin. Laminin immunohistochemical staining was to identify fetal vessels. Western blotting and transmission electron micrograph (TEM) were used to assess the apoptosis of placenta.ResultsNo treatment-related difference was observed in the numbers of implanted and resorbed embryos and weight of placenta between the groups. However, 1 mg/kg/day TiO2 NPs treatment significantly reduced the ratio of placenta/body weight on GD 13. The proportion of spongiotrophoblast in the 10 mg/kg/day dose group became higher than that in the control group, yet that of labyrinth was significantly lower in 10 mg/kg/day mice. The expression levels of Hand1, Esx1, Eomes, Hand2, Ascl2 and Fra1 mRNA markedly decreased in TiO2 NP treated placentas. Furthermore, TiO2 NPs treatment impaired the formation of intricate networks of fetal vessels and reduced the number of uNK cells, and inhibited proliferation and induced apoptosis of placenta by nuclear pyknosis, the activation of caspase-3 and upregulation of Bax protein and downregulation of Bcl-2 protein on GD 13.ConclusionGestational exposure to TiO2 NPs significantly impairs the growth and development of placenta in mice, with a mechanism that seems to be involved in the dysregulation of vascularization, proliferation and apoptosis. Therefore, our results suggested the need for great caution while handling of the nanomaterials by workers and specially pregnant consumers.

Project description: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.

Dataset Information

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

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

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