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LncRNA MEG3 alleviates PFOS induced placental cell growth inhibition through its derived miR-770 targeting PTX3
2022
Li, Jing | Quan, Xiaojie | Lei, Saifei | Chen, Gang | Hong, Jiawei | Huang, Zhenyao | Wang, Qi | Song, Weiyi | Yang, Xinxin
Perfluorooctane sulfonic acid (PFOS) is a persistent environmental pollutant. Exposure to PFOS has been associated with abnormal fetal development. The long non-coding RNA (lncRNA) has been showed to play a role in fetal growth restriction (FGR), preeclampsia (PE) and other pregnancy complications. Whether the lncRNA contributes to PFOS-induced toxicity in the placenta remains unknown. In this study, we investigated the function of lncRNA MEG3 and its derived miR-770 in PFOS-induced placental toxicity. Pregnant mice received gavage administration of different concentrations of PFOS (0.5, 2.5, and 12.5 mg/kg/day) from GD0 to GD17, and HTR-8/SVneo cells were treated with PFOS in the concentrations of 0, 10⁻¹, 1, 10 μM. We found that expression levels of miR-770 and its host gene MEG3 were reduced in mice placentas and HTR-8/SVneo cells with exposure of PFOS. A significant hypermethylation was observed at MEG3 promoter in placentas of mice gestational-treated with PFOS. We also confirmed that MEG3 and miR-770 overexpression alleviated the cell growth inhibition induced by PFOS. Furthermore, PTX3 (Pentraxin 3) was identified as the direct target of miR-770 and it was enhanced after PFOS exposure. In summary, our results suggested that MEG3 alleviate PFOS-induced placental cell inhibition through MEG3/miR-770/PTX3 axis.
Показать больше [+] Меньше [-]Effects of incremental endosulfan sulfate exposure and high fat diet on lipid metabolism, glucose homeostasis and gut microbiota in mice
2021
Yan, Jin | Wang, Dezhen | Meng, Zhiyuan | Yan, Sen | Teng, Miaomiao | Jia, Ming | Li, Ruisheng | Tian, Sinuo | Weiss, Carsten | Zhou, Zhiqiang | Zhu, Wentao
The influence of pollutants on metabolic diseases such as type 2 diabetes mellitus is an emerging field in environmental medicine. Here, we explored the effects of a low-dose endosulfan sulfate (ES), a major metabolite of the pesticide endosulfan and a bio-persistent contaminant detected in environmental and human samples, on the progress of obesity and metabolic disorders. Pregnant CD-1 mice were given ES from gestational day 6 to postnatal day 21 (short-term). After weaning, male pups of exposed dams were provided with a low-fat or a high-fat diet (LFD or HFD) and assessed after an additional 12 weeks. At the same time, one group of male pups continuously received ES (long-term). Treatment with low-dose ES, short or long-term, alleviated the development of obesity and accumulation of hepatic triglycerides induced by HFD. Analysis of gene expression, metabolic profile and gut microbiome indicates that ES treatment inhibits adipogenesis induced by HFD due to enhanced lipid catabolism, fatty acid oxidation and disturbance of gut microbiota composition. However, impaired glucose and insulin homeostasis were still conserved in HFD-fed mice exposed to ES. Furthermore, ES treatment impaired glucose tolerance, affected hepatic gene expression, fatty acids composition and serum metabolic profile, as well as disturbed gut microbiota in LFD-fed mice. In conclusion, ES treatment at levels close to the accepted daily intake during fetal development directly impact glucose homeostasis, hepatic lipid metabolism, and gut microbiome dependent on the type of diet consumed. These findings provide a better understanding of the complex interactions of environmental pollutants and diet at early life stages also in the context of metabolic disease.
Показать больше [+] Меньше [-]Persistent organic pollutants exposure in newborn dried blood spots and infant weight status: A case-control study of low-income Hispanic mother-infant pairs
2020
Gross, Rachel S. | Ghassabian, Akhgar | Vandyousefi, Sarvenaz | Messito, Mary Jo | Gao, Chongjing | Kannan, Kurunthachalam | Trasande, Leonardo
Persistent organic pollutants (POPs) are believed to alter metabolic homeostasis during fetal development, leading to childhood obesity. However, limited studies have explored how fetal chemical exposures relate to birth and infant weight outcomes in low-income Hispanic families at the highest risk of obesity. Therefore, we sought to determine associations between neonatal POPs exposure measured in newborn dried blood spots (DBS) and prenatal diet quality, birth weight, and overweight status at 18 months old. We conducted a case-control study nested within the Starting Early Program randomized controlled trial comparing POPs concentrations in infants with healthy weight (n = 46) and overweight status (n = 52) at age 18 months. Three categories of POPs, organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs) and perfluoroalkyl substances (PFASs) were measured in archived newborn DBS. We assessed correlations between prenatal diet quality and neonatal POPs concentrations. Multivariable regression analyses examined associations between POPs (dichotomized at the mean) and birth weight z-score and weight status at 18 months, controlling for confounders. Seven of eight chemicals had detectable levels in greater than 94% of the sample. Higher protein, sodium and refined grain intake during pregnancy were correlated with lower POPs in newborn DBS. We found that high concentrations of perfluorooctanesulfonate (unstandardized coefficient [B]: −0.62, 95% confidence interval [CI]: −0.96 to −0.29) and perfluorohexanesulfate (B: −0.65, 95% CI: −0.99 to −0.31) were related to lower birth weight z-scores compared to those with low concentrations. We did not find associations between PBDEs, OCPs, and the other PFASs with birth weight z-scores, or between any POPs and weight status at 18 months. In conclusion, two PFASs were associated with lower birth weight, an important indicator of child health and growth, although direct associations with infant overweight status were not found. Whether neonatal POPs exposures contribute to economic and ethnic disparities in early obesity remains unclear.
Показать больше [+] Меньше [-]Perfluorooctane sulfonic acid (PFOS) inhibits vessel formation in a human 3D co-culture angiogenesis model (NCFs/HUVECs)
2022
Forsthuber, Martin | Widhalm, Raimund | Granitzer, Sebastian | Kaiser, Andreas Marius | Moshammer, Hanns | Hengstschläger, Markus | Dolznig, Helmut | Gundacker, Claudia
Perfluorooctane sulfonic acid (PFOS) is a ubiquitous environmental pollutant. In humans, PFOS exposure has been associated with a number of adverse health outcomes, including reduced birth weight. Whether PFOS is capable of affecting angiogenesis and thus possibly fetal development is unknown. Therefore, we investigated 1) the metabolic activity of PFOS-exposed endothelial cells (human umbilical vein endothelial cells, HUVECs), fibroblasts (normal colon fibroblasts, NCFs), and epithelial cells (human colorectal carcinoma cells, HCT116), 2) PFOS-specific inhibition of vascular endothelial growth factor receptor (VEGFR)2 stimulation in KDR/NFAT-RE HEK293 cells, and 3) the antiangiogenic potential of PFOS in a 3D in vitro angiogenesis model of HUVECs and NCFs. In terms of metabolic activity, endothelial cells (HUVECs) were much more sensitive to PFOS than fibroblasts (NCFs) or epithelial cells (HCT116). VEGFR2 signaling in KDR/NFAT-RE HEK293 cells decreased with increasing PFOS concentrations. In co-culture (angiogenesis assay), PFOS treatment resulted in a dose-dependent reduction in tip and branch formation, tip length (μm), and total structural area (μm²) with stable metabolic activity of HUVECs up to high concentrations. We conclude that PFOS possesses antiangiogenic properties. Inhibition of VEGFR2 signaling indicates a possible mechanism of action that can be linked to an existing Adverse Outcome Pathway (AOP43) containing the AO reduced birth weight. Further studies are needed to confirm PFOS-specific adverse effects on angiogenesis, placental perfusion, and fetal growth.
Показать больше [+] Меньше [-]Early pregnancy PM2.5 exposure and its inorganic constituents affect fetal growth by interrupting maternal thyroid function
2022
Zhou, Yuhan | Zhu, Qingqing | Wang, Pengpeng | Li, Jialin | Luo, Ranran | Chao, Winston | Zhang, Liyi | Shi, Huijing | Zhang, Yunhui
Early pregnancy is crucial for fetal growth. Maternal thyroid hormone is critical for fetal growth and can be disturbed under exogenous exposure. However, it's uncertain whether exposure to PM₂.₅ and inorganic constituents during early pregnancy can affect TH and fetal growth. We focused on the associations of early-pregnancy PM₂.₅ and inorganic constituents with fetal growth and maternal THs. PM₂.₅ concentration was estimated using a satellite-based spatiotemporal model. Fetal biparietal diameter (BPD), head circumference (HC), femur length (FL), and humerus length (HL) were measured by ultrasonography at median 15.6, 22.2, and 33.1 gestational weeks. Levels of 28 PM₂.₅ constituents were measured in a sub-group of 329 pregnancies. Maternal serum free thyroxine (fT4), free triiodothyronine, and thyroid-stimulating hormone levels were measured at 14 weeks of gestation. Mixed-effect models and multiple linear regression were applied to evaluate the associations of PM₂.₅ and its constituents with fetal growth measures. Mediation analysis was used to examine the mediating role of the THs. Results showed that each 10 μg/m³ increase in PM₂.₅ was associated with 0.20 mm reductions in BPD (95%CI: 0.33, −0.01), 0.27 mm decreases in FL (95%CI: 0.40, −0.13), and 0.36 decreases in HL (95%CI: 0.49, −0.23). Per 10 μg/m³ increment in PM₂.₅ was correlated with 5.82% decreases in the fT4 level (95% CI: 8.61%, −2.96%). FT4 accounted for 14.3% of PM₂.₅ exposure-induced change in BPD at first follow-up. Al (β = −2.91, 95%CI: 5.17, −0.66), Si (β = −1.20, 95%CI: 2.22, −0.19), K (β = −3.09, 95%CI: 5.41, −0.77), Mn (β = −47.20, 95%CI: 83.68, −10.79) and Zn (β = −3.02, 95%CI: 5.55, −0.49) were associated with decreased fetal BPD, especially in first follow-up. Zn (β = −38.12%, 95% CI: 58.52%, −8.61%) was also associated with decreased fT4 levels. Overall, early pregnancy exposure to PM₂.₅ and its constituents was associated with fetal growth restriction and decreased maternal fT4 levels might mediate the effect of PM₂.₅.
Показать больше [+] Меньше [-]Associations of exposure to cadmium, antimony, lead and their mixture with gestational thyroid homeostasis
2021
Margetaki, Katerina | Vafeiadi, Marina | Kampouri, Mariza | Roumeliotaki, Theano | Karakosta, Polyxeni | Daraki, Vasiliki | Kogevinas, Manolis | Hu, Howard | Kippler, Maria | Chatzi, Leda
Maintaining thyroid homeostasis during pregnancy is vital for fetal development. The few studies that have investigated associations between metal exposure and gestational thyroid function have yielded mixed findings. To evaluate the association of exposure to a mixture of toxic metals with thyroid parameters in 824 pregnant women from the Rhea birth cohort in Crete, Greece. Concentrations of three toxic metals [cadmium (Cd), antimony (Sb), lead (Pb)] and iodine were measured in urine using inductively coupled plasma mass spectrometry and thyroid hormones [Thyroid Stimulating Hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3)] were measured in serum in early pregnancy. Associations of individual metals with thyroid parameters were assessed using adjusted regression models, while associations of the metal mixture with thyroid parameters were assessed using Bayesian Kernel Machine Regression (BKMR).Women with high (3rd tertile) concentrations of urinary Cd, Sb and Pb, respectively, had 13.3 % (95%CI: 2.0 %, 23.2 %), 12.5 % (95%CI: 1.8 %, 22.0 %) and 16.0 % (95%CI: 5.7 %, 25.2 %) lower TSH compared to women with low concentrations (2nd and 1st tertile). In addition, women with high urinary Cd had 2.2 % (95%CI: 0.0 %, 4.4 %) higher fT4 and 4.0 % (95%CI: −0.1 %, 8.1 %) higher fT3 levels, and women with high urinary Pb had 4 % (95%CI: 0.2 %, 8.0 %) higher fT3 levels compared to women with low exposure. The negative association of Cd with TSH persisted only when iodine sufficiency was unfavorable. BKMR attested that simultaneous exposure to toxic metals was associated with decreased TSH and increased fT3 and revealed a potential synergistic interaction of Cd and Pb in association with TSH. The present results suggest that exposure to toxic metals even at low levels can alter gestational thyroid homeostasis.
Показать больше [+] Меньше [-]Associations of maternal soy product consumption and urinary isoflavone concentrations with neonatal anthropometry: A prospective cohort study
2021
Chen, Yao | Li, Tao | Ji, Honglei | Wang, Xin | Sun, Xiaowei | Miao, Maohua | Wang, Yan | Wu, Qian | Liang, Hong | Yuan, Wei
Isoflavones (ISOs) are naturally occurring endocrine-disrupting compounds. Few human studies have evaluated the effects of ISO exposure on neonatal anthropometry. This study aimed to examine the associations of maternal soy product consumption and urinary ISO concentrations, including genistein, daidzein, glycitein, and equol, with neonatal anthropometry, based on a Chinese cohort study. In Shanghai-Minhang Birth Cohort Study, pregnant women at 12–16 weeks of gestation were recruited, and they completed a structured questionnaire to assess soy product consumption during pregnancy. They also provided a single spot urine sample for the ISO assay. Neonatal anthropometric indices (birth weight; arm, waist, and head circumference; and triceps, back, and abdominal skinfold thickness) were measured at birth. Multivariable linear regression analysis was performed among the 1188 mother-infant pairs to examine the associations between maternal soy product consumption and neonatal anthropometry. The same statistical model was applied to examine the associations between maternal ISO exposure and neonatal anthropometry among 480 mother-infant pairs. Neonate girls born to mothers who “sometimes” and “frequent” consumed soy products had 169.1 g (95% confidence interval [CI], −68.9–407.1) and 256.5 g (95% CI, 17.1–495.8) higher birth weight, respectively, than those born to mothers who “never” consumed soy products during pregnancy. We observed consistent associations between higher maternal urine ISO concentrations and increased anthropometric indices (birth weight, arm and waist circumference, and triceps and abdominal skinfold thickness) in neonate girls, while no association was observed among boys. The findings suggested that maternal dietary ISO intake during pregnancy is associated with fetal development in a sex-specific pattern. In addition, follow-up studies are required to evaluate whether the observed changes in anthropometric indices at birth are associated with health conditions later in life.
Показать больше [+] Меньше [-]Maternal prenatal urinary bisphenol A level and child cardio-metabolic risk factors: A prospective cohort study
2020
Ouyang, Fengxiu | Zhang, Guang-Hui | Du, Kun | Shen, Lixiao | Ma, Rui | Wang, Xia | Wang, Xiaobin | Zhang, Jun
Exposure to endocrine disrupting chemicals during the first 1000 days of life may have long-lasting adverse effects on cardio-metabolic risk in later life. This study aimed to examine the associations between maternal prenatal Bisphenol A (BPA) exposure and child cardio-metabolic risk factors at age 2 years in a prospective cohort. During 2012–2013, 218 pregnant women were enrolled at late pregnancy from Shanghai, China. Urinary BPA concentration was measured in prenatal and child 2-year spot urine samples, and classified into high, medium and low tertiles. Child adiposity anthropometric measurements, random morning plasma glucose, serum insulin, and lipids (high-density lipoprotein, low-density lipoprotein, cholesterol, triglyceride), systolic (SBP) and diastolic blood pressure (DBP) were measured. Linear regression was used to evaluate the associations between prenatal BPA and each of the cardio-metabolic risk factors in boys and girls, respectively, adjusting for pertinent prenatal, perinatal and postnatal factors. BPA was detectable (>0.1 μg/L) in 98.2% of mothers prenatally and 99.4% of children at age 2 years. Compared to those with low prenatal BPA, mean SBP was 7.0 (95%CI: 2.9–11.2) mmHg higher, and DBP was 4.4 (95%CI: 1.2–7.5) mmHg higher in girls with high prenatal BPA levels, but these associations were not found in boys. In boys, medium maternal prenatal BPA level was associated with 0.36 (95% CI: 0.04–0.68) mmol/L higher plasma glucose. No associations were found between prenatal BPA and child BMI, skinfold thicknesses, serum lipids, or insulin in either girls or boys. There were no associations between concurrent child urinary BPA and cardio-metabolic risk factors. These results support that BPA exposure during prenatal period, susceptible time for fetal development, may be associated with increase in child BP and plasma glucose in a sex-specific manner. Further independent cohort studies are needed to confirm the findings.
Показать больше [+] Меньше [-]Triclosan and triclocarbon in maternal-fetal serum, urine, and amniotic fluid samples and their implication for prenatal exposure
2020
Bai, Xueyuan | Zhang, Bo | He, Yuan | Hong, Danhong | Song, Shiming | Huang, Yingyan | Zhang, Tao
Triclosan (TCS) and Triclocarbon (TCC) are chlorinated synthetic antimicrobial agents formaternal urinelated in quantities of consumer products. However, the biomonitoring of direct exposure reflection for fetuses are rare. In this study, we determine the concentrations of TCS and TCC in paired maternal serum, cord serum, maternal urine, and amniotic fluid samples collected from a cohort of 95 expecting mother-fetal pairs in Southern China. TCS and TCC are detected widely (detection rates: >76.9%) in maternal serum, cord serum, maternal urine, and amniotic fluid samples. TCS is found to be the predominant antimicrobial agent with median concentrations in maternal serum (1.5 ng/mL) and cord serum (1.8 ng/mL) that are one order of magnitude higher than those of tcc in maternal serum (0.085 ng/mL) and cord serum (0.052 ng/mL), respectively. Cord serum concentrations of tcs and tcc correlated well with the concentrations in maternal serum, which reflect the mothers’ contribution to fetal exposure. The higher median ratio of cord serum/maternal serumTCS (0.95) compared to that of cord serum/maternal serumTCC (0.53) indicates high placental transmission ability of TCS. Moreover, the facility to penetrate the placental barrier and hard to depurate characteristics lead to the long residence of TCS in the fetal environment, causing great concern over the prenatal exposure risks during the critical window of fetal development. This study provides a novel contribution by increasing existing knowledge on the exposure assessment of TCS and TCC during pregnancy through the exploration of matched maternal-fetal samples.
Показать больше [+] Меньше [-]Microcystin-LR exposure decreased the fetal weight of mice by disturbance of placental development and ROS-mediated endoplasmic reticulum stress in the placenta
2020
Zhao, Sujuan | Zhong, Shengzheng | Wang, Fang | Wang, Honghui | Xu, Dexiang | Li, Guangyu
The placenta is essential for sustaining the growth of the fetus. The aim of this study was to investigate the role of the placenta in MCLR-induced significant reduction in fetal weight, especially the changes in placental structure and function. Pregnant mice were intraperitoneally injected with MCLR (5 or 20 μg/kg) from gestational day (GD) 13 to GD17. The results showed MCLR reduced fetal weight and placenta weight. The histological specimens of the placentas were taken for light and electron microscopy studies. The internal space of blood vessels decreased obviously in the placental labyrinth layer of mice treated with MCLR. After the ultrastructural examination, the edema and intracytoplasmic vacuolization, dilation of the endoplasmic reticulum and corrugation of the nucleus were observed. In addition, maternal MCLR exposure caused a reduction of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) expression in placentae, a critical regulator of fetal development. Several genes of placental growth factors, such as Vegfα and Pgf and several genes of nutrient transport pumps, such as Glut1 and Pcft were depressed in placentas of MCLR-treated mice, however nutrient transporters Fatp1 and Snat4 were promoted. Moreover, significant increases in malondialdehyde (MDA) revealed the occurrence of oxidative stress caused by MCLR, which was also verified by remarkable decrease in the glutathione levels, total antioxidant capacity (T-AOC) as well as the activity of antioxidant enzymes. Real-time PCR and western blot analysis revealed that GRP78, CHOP, XBP-1, peIF2α and pIRE1 were remarkable increased in placentas of MCLR-treated mice, indicating that endoplasmic reticulum (ER) stress pathway was activated by MCLR. Furthermore, oxidative stress and ER stress consequently triggered apoptosis which contributed to the impairment of placental development. Collectively, these results suggest maternal MCLR exposure results in reduced fetal body weight, which might be associated with ROS-mediated endoplasmic reticulum stress and impairment in placental structure and function.
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