Associations among perfluorooctanesulfonic/perfluorooctanoic acid levels, nuclear receptor gene polymorphisms, and lipid levels in pregnant women in the Hokkaido study.
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ABSTRACT:
SUBMITTER: Kobayashi S
PROVIDER: S-EPMC8113244 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), chemicals present in a multitude of consumer products, are persistent organic pollutants. Both compounds induce hepatotoxic effects in rodents, including steatosis, hepatomegaly and liver cancer. The mechanisms of PFOA- and PFOS-induced hepatic dysfunction are not completely understood. We present evidence that PFOA and PFOS induce their hepatic effects via targeting hepatocyte nuclear factor 4-alpha (HNF4α). Human hepatocytes treated with PFOA and PFOS at a concentration relevant to occupational exposure caused a decrease in HNF4α protein without affecting HNF4α mRNA or causing cell death. RNA sequencing analysis combined with Ingenuity Pathway Analysis of global gene expression changes in human hepatocytes treated with PFOA or PFOS indicated alterations in the expression of genes involved in lipid metabolism and tumorigenesis, several of which are regulated by HNF4α. Further investigation of specific HNF4α target gene expression revealed that PFOA and PFOS could promote cellular dedifferentiation and increase cell proliferation by down regulating positive targets (differentiation genes such as CYP7A1) and inducing negative targets of HNF4α (pro-mitogenic genes such as CCND1). Furthermore, in silico docking simulations indicated that PFOA and PFOS could directly interact with HNF4α in a similar manner to endogenous fatty acids. Collectively, these results highlight HNF4α degradation as novel mechanism of PFOA and PFOS-mediated steatosis and tumorigenesis in human livers.
| S-EPMC5367386 | biostudies-literature
Project description:BACKGROUND:Studies on the associations of the adenosine triphosphate-binding cassette transporter A1 gene (ABCA1) rs2230806, rs2230808, and rs2066714 polymorphisms with plasma lipid levels have reported apparently conflicting findings. This meta-analysis aimed to clarify the relationships between the 3 polymorphisms and fasting lipid levels. METHODS:A comprehensive search of the literature was carried out by using the databases including Medline, Google Scholar, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and VIP. The studies that presented mean lipids and standard deviations or standard errors according to the rs2230806, rs2230808, and/or rs2066714 genotypes were examined and included. The random effects model was used. Standardized mean difference and 95% confidence interval were used to assess the differences in lipid levels between the genotypes. Heterogeneity among studies was tested by Cochran's ?-based Q-statistic, and Galbraith plots were used to detect the potential sources of heterogeneity. Publication bias was assessed by Begg's rank correlation test as well as funnel plots. RESULTS:Sixty-two studies (48,452 subjects), 12 studies (9853 subjects) and 14 studies (10,727 subjects) were identified for the rs2230806, rs2230808, and rs2066714 polymorphisms, respectively. A dominant model was used for all the polymorphisms in this meta-analysis. The A allele carriers of the rs2230806 polymorphism had higher levels of high-density lipoprotein cholesterol (HDL-C) (P?<.001), and lower levels of low-density lipoprotein cholesterol (LDL-C) (P?=.03) and triglycerides (TG) (P?<.01) than the non-carriers. The A allele carriers of the rs2230808 polymorphism had higher levels of total cholesterol (TC) (P?<.001) than the non-carriers. The G allele carriers of the rs2066714 polymorphism had higher levels of TC (P?<.01) and HDL-C (P?=?.02) than the non-carriers. CONCLUSION:The ABCA1 rs2230806, rs2230808, and rs2066714 polymorphisms are significantly associated with plasma lipid levels in the present meta-analysis.
| S-EPMC6320104 | biostudies-literature
Project description:Several epidemiological cross-sectional studies have found positive associations between serum concentrations of lipids and perfluorooctanoic acid (PFOA, or C8). A longitudinal study should be less susceptible to biases from uncontrolled confounding or reverse causality.We investigated the association between within-individual changes in serum PFOA and perfluorooctanesulfonic acid (PFOS) and changes in serum lipid levels (low-density lipoprotein [LDL] cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglycerides) over a 4.4-year period. The study population consisted of 560 adults living in parts of Ohio and West Virginia where public drinking water had been contaminated with PFOA. They had participated in a cross-sectional study in 2005-2006, and were followed up in 2010, by which time exposure to PFOA had been substantially reduced.Overall serum concentrations of PFOA and PFOS fell by half from initial geometric means of 74.8 and 18.5 ng/mL, respectively, with little corresponding change in LDL cholesterol (mean increase 1.8%, standard deviation 26.6%). However, there was a tendency for people with greater declines in serum PFOA or PFOS to have greater LDL decrease. For a person whose serum PFOA fell by half, the predicted fall in LDL cholesterol was 3.6% (95% confidence interval = 1.5-5.7%). The association with a decline in PFOS was even stronger, with a 5% decrease in LDL (2.5-7.4%).Our findings from this longitudinal study support previous evidence from cross-sectional studies of positive associations between PFOA and PFOS in serum and LDL cholesterol.
| S-EPMC4724201 | biostudies-literature
Project description:BackgroundPregnancy is an important stimulus of bone lead release. Elevated blood lead levels (BLLs) may cause adverse pregnancy outcomes for mothers and harmful lead effects on fetuses. However, the reports about maternal BLL changes during pregnancy are conflicting to some extent. This article is to explore the variations in BLLs among pregnant women. The relationships of BLLs with methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms, which are associated with bone resorption, were also studied. A total of 973 women, including 234, 249, and 248 women in their first, second, and third trimesters, respectively, and 242 non-pregnant women, were recruited at the Wuhan Women and Children Medical Health Center.MethodsBLLs were determined using a graphite furnace atomic absorption spectrometer. Single-nucleotide polymorphisms of MTHFR were identified with the TaqMan probe method.ResultsThe geometric mean (geometric standard deviation) of BLLs was 16.2 (1.78) ?g/L for all participants. All the studied MTHFR alleles were in Hardy-Weinberg equilibrium. Multiple-linear regression analysis revealed the following results. Among the pregnant women, those that carried MTHFR 677CC (i.e. wild-genotype homozygote) and 1298CC (i.e. mutant-genotype homozygote) exhibited higher BLLs than those that carried 677CT/TT (standardized ? = 0.074, P = 0.042) and 1298AC/AA (standardized ? = 0.077, P = 0.035) when other covariates (e.g., age, no. of children, education and income, etc.) were adjusted. The BLLs of pregnant women consistently decreased during the pregnancy and these levels positively correlated with BMI (standard ? = 0.086-0.096, P<0.05).ConclusionsThe 1298CC mutant-type homozygote in the MTHFR gene is a risk factor for high BLLs among low-level environmental lead-exposed Chinese pregnant women, whose BLLs consistently decreased during gestation.
| S-EPMC4344240 | biostudies-literature
Project description:Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are man-made chemicals that are used for the fabrication of many products with water- and dirt-repellent properties. The toxicological potential of both substances is currently under debate. In a recent Scientific Opinion, the European Food Safety Authority (EFSA) has identified increased serum total cholesterol levels in humans as one major critical effect being associated with exposure to PFOA or PFOS. In animal studies, both substances induced a decrease of serum cholesterol levels, and the underlying molecular mechanism(s) for these opposed effects are unclear so far. In the present study, we examined the impact of PFOA and PFOS on cholesterol homoeostasis in the human HepaRG cell line as a model for human hepatocytes. Cholesterol levels in HepaRG cells were not affected by PFOA or PFOS, but both substances strongly decreased synthesis of a number of bile acids. The expression of numerous genes whose products are involved in synthesis, metabolism and transport of cholesterol and bile acids was strongly affected by PFOA and PFOS at concentrations above 10 µM. Notably, both substances led to a strong decrease of CYP7A1, the key enzyme catalyzing the rate-limiting step in the synthesis of bile acids from cholesterol, both at the protein level and at the level of gene expression. Moreover, both substances led to a dilatation of bile canaliculi that are formed by differentiated HepaRG cells in vitro. Similar morphological changes are known to be induced by cholestatic agents in vivo. Thus, the strong impact of PFOA and PFOS on bile acid synthesis and bile canalicular morphology in our in vitro experiments may allow the notion that both substances have a cholestatic potential that is connected to the observed increased serum cholesterol levels in humans in epidemiological studies.
| S-EPMC8241792 | biostudies-literature
Project description:BackgroundImpaired kidney function and earlier menopause were associated with perfluorooctanoic acid (PFOA) serum levels in previous cross-sectional studies. Reverse causation, whereby health outcomes increase serum PFOA, may underlie these associations.ObjectiveWe compared measured (subject to reverse causation) versus modeled (unaffected by reverse causation) serum PFOA in association with these outcomes to examine the possible role of reverse causation in these associations.MethodsIn cross-sectional analyses, we analyzed PFOA in relation to self-reported menopause among women (n = 9,192) 30-65 years old and in relation to kidney function among adults > 20 years old (n = 29,499) in a highly exposed Mid-Ohio Valley cohort. Estimated glomerular filtration rate (eGFR, a marker of kidney function) and serum PFOA concentration were measured in blood samples collected during 2005-2006. Retrospective year-specific serum PFOA estimates were modeled independently of measured PFOA based on residential history and plant emissions. Using measured and modeled PFOA in 2005 or 2006 (predictor variables), cross-sectional associations were assessed for eGFR and menopause (yes/no). We also analyzed measured PFOA (dependent variable) in relation to the number of years since menopause.ResultsMenopause and eGFR were significantly associated with measured (trend tests: p = 0.013, p = 0.0005, respectively) but not with modeled serum PFOA (p = 0.50, p = 0.76, respectively). Measured PFOA levels increased for the first 7 years after menopause (trend test, p < 0.0001), providing further evidence that the observed association between measured PFOA and menopause is subject to reverse causation for this outcome.ConclusionOur results support the conjecture that in previous studies, earlier menopause and reduced kidney function are the causes rather than the results of increased measured serum PFOA. These results suggest caution in using biomarkers in cross-sectional studies. Citation: Dhingra R, Winquist A, Darrow LA, Klein M, Steenland K. 2017. A study of reverse causation: examining the associations of perfluorooctanoic acid serum levels with two outcomes. Environ Health Perspect 125:416-421; http://dx.doi.org/10.1289/EHP273.
| S-EPMC5332181 | biostudies-literature
Project description:IntroductionObjectives: low vitamin D during pregnancy is common and could adversely affect health outcomes. This study evaluated vitamin D status during pregnancy and early in life, and its association with glucose metabolism. Methods: maternal serum 25(OH)D, glucose, and insulin levels were measured longitudinally during pregnancy in Hispanic women with overweight/obesity (n = 31) and their infants at birth and 4 months. Results: insulin and HOMA-IR levels were higher among women with vitamin D below adequate levels compared to those with adequate levels in pregnancy (p < 0.05). Late in pregnancy, as vitamin D increased by one unit (ng/mL), insulin decreased by 0.44 units and HOMA-IR by 0.09 units. Maternal vitamin D late in pregnancy was correlated with infant vitamin D levels at birth (r = 0.89; p < 0.01) and 4 months (r = 0.9; p = 0.04), and with glucose (r = 0.79; p = 0.03) and insulin (r = 0.83; p = 0.04) at 4 months. Conclusion: maternal vitamin D status was associated with maternal and infant glucose metabolism in this sample.
| S-EPMC9015214 | biostudies-literature
Project description:BackgroundThe prevalence of gestational hypertension and diabetes in pregnancy is increasing worldwide. Diet is a modifiable factor that may influence these conditions, but few studies have examined the association between diet quality and blood pressure and glucose profiles among pregnant women. Data are especially scarce for women in low- and middle-income countries (LMICs), where 90% of global pregnancies occur, and in urban settings. We, therefore, assessed these associations among 174 pregnant women in the Asian megacity of Jakarta in a cross-sectional study of the Brain Probiotic and LC-PUFA Intervention for Optimum Early Life (BRAVE) project.MethodsTrained field-enumerators collected socio-demographic characteristics, measured Mid-Upper Arm Circumference (MUAC), and assessed diet by two 24-hour recalls, which were used to calculate the Alternate Healthy Eating Index for Pregnancy (AHEI-P). Blood pressure was measured by automated sphygmomanometer, and fasting blood glucose by capillary glucometer. General linear models were used to identify associations.ResultsThe median AHEI-P score was 47.4 (IQR 19.1-76.6). The middle tertile of the AHEI-P score (39.59-56.58) was associated with a 0.4 SD (standardized effect size, 95% CI -0.7 to -0.06; p = 0.02) lower diastolic blood pressure compared with the lowest tertile (<39.59), after adjustment for level of education, smoking status, MUAC, gestational age, history of hypertension, and family history of hypertension. However, no associations were found between the AHEI-P score and systolic blood pressure and blood glucose.ConclusionHigher diet quality was associated with lower diastolic blood pressure among pregnant women in an urban LMIC community, but not with systolic blood pressure and blood glucose. A behavioral change intervention trial would be warranted to confirm the influence of diet quality on blood pressure and glucose levels and among pregnant women, and even before pregnancy.
| S-EPMC7688158 | biostudies-literature
Project description:Perfluoroalkyl substances (PFAS) are persistent bio-accumulative chemicals that impact the health of pregnant women and their children. PFAS derive from environmental and consumer products, which depend on human lifestyle, socioeconomic characteristics, and time variation. Here, we aimed to explore the temporal trends of PFAS in pregnant women and the characteristics related to maternal PFAS concentration. Our study is part of the Hokkaido Study on Environment and Children's Health, the Hokkaido large-scale cohort that recruited pregnant women between 2003 and 2011. Blood samples were acquired from pregnant women during the third trimester to measure PFAS and cotinine concentrations. Maternal basic information was collected with a baseline structured questionnaire. Eleven PFAS were measured from 2123 samples with ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. Eight PFAS were above 80% detection rate and were included in the final analysis. We used multivariable linear regression to analyze the association of pregnant women characteristics with the levels of eight PFAS. The temporal trend of PFAS was observed in two periods (August 2003 to January 2006 and February 2006 to July 2012). The concentration of perfluorooctane sulfonate (PFOS) significantly decreased from August 2003 to January 2006 and from February 2006 to July 2012. The concentrations of perfluorododecanoic acid (PFDoDA), perfluoroundecanoic acid (PFUnDA), and perfluorotridecanoic acid (PFTrDA) increased significantly between August 2003 and January 2006, whereas they decreased significantly between February 2006 and July 2012. Women with pre-pregnancy body mass index (BMI) >25 kg/m² had lower PFUnDA, PFDoDA, and PFTrDA levels than did those with normal BMI (18.5?24.9 kg/m²). Pregnant women, who were active smokers (cotinine > 11.49 ng/mL), had higher PFOS than the non-smokers (cotinine < 0.22 ng/mL). Lower levels of PFHxS, PFOS, PFOA, PFNA, and PFDA were observed in women, who had given birth to more than one child. There were also significant positive associations between PFAS levels and annual income or maternal education. PFAS levels varied in women with higher pre-pregnancy BMI, active smoking status, higher education level and annual income. The causes of the individual PFAS differences should be explored in an independent study.
| S-EPMC5982028 | biostudies-literature
Project description:Our goal was to examine the associations of the 388A>G and 521T>C polymorphisms in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene with hepatic function, baseline lipid levels, and the lipid-lowering efficiency of simvastatin. We recruited 542 patients with hyperlipidemia. The 388A>G and 521T>C polymorphisms were genotyped. Serum alanine aminotransferase (ALT) and aspartate transaminase (AST), Serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were measured before and after an oral 20-mg dose of simvastatin. Individuals with the 388AA genotype had higher ALT and AST levels than those with the 388AG or 388GG genotypes (P = .037 and P = .002, respectively). Individuals with both the 388AA and the 521TT genotypes had the highest levels of ALT and AST (P = .001 and P = .001, respectively). Moreover, we divided all patients into normal and abnormal subgroups based on elevated ALT and AST values (≥ 40 U/L), participants in the abnormal subgroup had a higher frequency of the 388A/521T haplotype and a lower frequency of the 388G/521T haplotype compared to those in the normal subgroup. In addition, compared to 388G allele and 521C allele carriers, individuals with the 388G allele and 521TT genotype carriers had greater TC and LDL-C reduction in response to simvastatin after 4 weeks of treatment. Our conclusion suggests that the interaction between the SLCO1B1 388A>G and 521T>C polymorphisms could be an important genetic determinant of hepatic function and the therapeutic efficiency of simvastatin in Chinese patients with hyperlipidemia.
| S-EPMC6714829 | biostudies-literature