Associations of perfluoroalkyl substances with adipocytokines in umbilical cord serum: A mixtures approach.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), a kind of emerging environmental endocrine disruptors, may interfere with the secretion of adipokines and affect fetal metabolic function and intrauterine development. However, the epidemiological evidence is limited and inconsistent. We examined the associations of single and multiple PFAS exposures in utero with adipocytokine concentrations in umbilical cord serum. METHODS: This study included 1111 mother-infant pairs from Sheyang Mini Birth Cohort Study (SMBCS), and quantified 12 PFAS and two adipokine in umbilical cord serum. Generalized linear models (GLMs) and Bayesian Kernel Machine Regression (BKMR) models were applied to estimate the associations of single- and mixed- PFAS exposure with adipokines, respectively. Furthermore, sex-stratification was done in each model to assess the sexually dimorphic effects of PFAS. RESULTS: 10 PFAS were detected with median concentrations (µg/L) ranging from 0.04 to 3.97, (except 2.7% for PFOSA and 1.7% for PFDS, which were excluded). In GLMs, for each doubling increase in PFBS, PFHpA, PFHxS, PFHpS, PFUnDA and PFDoDA, leptin decreased between 14.04% for PFBS and 22.69% for PFHpS (P < 0.05). PFAS, except for PFNA, were positively associated with adiponectin, and for each doubling of PFAS, adiponectin increased between 3.27% for PFBS and 12.28% for PFHxS (P < 0.05). In addition, infant gender modified the associations of PFAS with adipokines, especially the associations of PFBS, PFOA and PFHxS with adiponectin. Similarly, significant associations of PFAS mixtures with leptin and adiponectin were observed in the BKMR models. PFDA, PFOS, PFNA and PFHpS were identified as important contributors. In the sex-stratified analysis of BKMR models, the associations between PFAS mixtures and adipokines were more pronounced in males. CONCLUSIONS: PFAS levels were significantly associated with adipokines in cord serum, suggesting that intrauterine mixture of PFAS exposure may be related to decreased fetal leptin level but increased fetal adiponectin level and the associations may be sex-specific.

Mediating effect of endocrine hormones on association between per- and polyfluoroalkyl substances exposure and birth size: Findings from sheyang mini birth cohort study.

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been reported to affect fetus growth, but current results were inconsistent and their mechanism remained unclear. OBJECTIVES: We aimed to evaluate the associations of prenatal exposure to single and/or multiple PFAS with birth size and to elucidate whether thyroid hormones and reproductive hormones mediate these associations. METHODS: A total of 1087 mother-newborn pairs from Sheyang Mini Birth Cohort Study were included in the present cross-sectional analysis. 12 PFAS, 5 thyroid hormones and 2 reproductive hormones were measured in cord serum. Multiple linear regression models and Bayesian kernel machine regression (BKMR) models were used to examine the associations of PFAS with either birth size or endocrine hormones. One-at-a-time pairwise mediating effect analysis was applied to estimate the mediating effect of single hormone in the association between individual chemical and birth size. High-dimensional mediation approach including elastic net regularization and Bayesian shrinkage estimation were further performed to reduce exposure dimension and figure out the global mediation effects of joint endocrine hormones. RESULTS: Perfluorononanoic acid (PFNA) exposure was positively associated to weight for length z score [WLZ, per log10-unit: regression coefficient (ß) = 0.26, 95% confidence intervals (CI): 0.04, 0.47] and ponderal index (PI, ß = 0.56, 95% CI: 0.09, 1.02), and PFAS mixture results fit by BKMR model showed consistent consequences. High-dimensional mediating analyses revealed that thyroid stimulating hormone (TSH) explained 6.7% of the positive association between PFAS mixtures exposure and PI [Total effect (TE) = 1.499 (0.565, 2.405); Indirect effect (IE) = 0.105 (0.015, 0.231)]. Besides, 7.3% of the PI variance was indirectly explained by 7 endocrine hormones jointly [TE = 0.810 (0.802, 0.819); IE = 0.040 (0.038, 0.041)]. CONCLUSIONS: Prenatal PFAS mixtures exposure, especially PFNA, was positively associated to birth size. Such associations were partly mediated by cord serum TSH.

Low dose PFDA induces DNA damage and DNA repair inhibition by promoting nuclear cGAS accumulation in ovarian epithelial cells.

Per- and polyfluoroalkyl substances (PFAS), the versatile anthropogenic chemicals, are popular with the markets and manufactured in large quantities yearly. Accumulation of PFAS has various adverse health effects on human. Albeit certain members of PFAS were found to have genotoxicity in previous studies, the mechanisms underlying their effects on DNA damage repair remain unclear. Here, we investigated the effects of Perfluorodecanoic acid (PFDA) on DNA damage and DNA damage repair in ovarian epithelial cells through a series of in vivo and in vitro experiments. At environmentally relevant concentration, we firstly found that PFDA can cause DNA damage in primary mouse ovarian epithelial cells and IOSE-80 cells. Moreover, nuclear cGAS increased in PFDA-treated cells, which leaded to the efficiency of DNA homologous recombination (HR) decreased and DNA double-strand breaks perpetuated. In vivo experiments also verified that PFDA can induce more DNA double-strand breaks lesions and nuclear cGAS in ovarian tissue. Taken together, our results unveiled that low dose PFDA can cause deleterious effects on DNA and DNA damage repair (DDR) in ovarian epithelial cells and induce genomic instability.

Alterations of selenium level and speciation during milling and cooking in different wheat cultivars.

BACKGROUND: Selenium (Se) deficiency is a recognized problem that threatens the health of people worldwide, and wheat is grown worldwide and is one of the major sources of dietary Se. Since there are few studies that have investigated the changes in Se content and speciation of different varieties of Se-enriched wheat from primary to deep processing, we studied four naturally Se-enriched kinds of wheat and two Se-fertilized kinds of wheat. RESULTS: Glutenin- and albumin-bound Se accounted for the highest proportion of protein-bound Se in refined wheat flour (7.29 ± 0.19 to 10.82 ± 0.50% and 6.16 ± 0.34 to 8.45 ± 0.07%); water-soluble polysaccharide-bound Se accounted for the highest proportion of polysaccharide-bound Se in refined wheat flour (12.02 ± 0.54 to 24.62 ± 1.87%). Coarse bran Se content was significantly higher than refined wheat flour (137.94 ± 7.80 to 174.55 ± 5.09% for unpeeled wheat, 147.27 ± 10.96 to 187.72 ± 17.70% for peeled wheat). The peeling and processing of wheat into flour had different effects on Se the content and speciation dependent on the particular wheat variety. Whole wheat flour enabled better retention of selenomethionine (101.64 ± 2.32 to 138.41 ± 2.84% for unpeeled wheat, 158.59 ± 13.72 to 250.20 ± 4.94% for peeled wheat). The cooking process had no significant effect on Se content, but Se species were possibly interconverted. CONCLUSION: The organic Se content of different varieties of Se-enriched wheat was different, but the milling and cooking process retained the total Se and Se speciation better, which could be used for daily Se supplementation for Se-deficient people. © 2022 Society of Chemical Industry.

PFDA promotes cancer metastasis through macrophage M2 polarization mediated by Wnt/ß-catenin signaling.

Perfluoroundecanoic acid (PFDA) is extensively utilized in the textile and food processing industries and may have a tumor-promoting effect by modulating the tumor microenvironment. Macrophages play crucial roles in tumor microenvironment as key regulators of tumor immunity. However, further investigation is needed to elucidate how PFDA interacts with macrophages and contributes to tumor progression. In this study, we treated the macrophage cell line RAW264.7 with various concentrations of PFDA and found that RAW264.7 transitioned into an M2 tumor-promoting phenotype. Through bioinformatic analysis and subsequent verification of molecular assays, we uncovered that PFDA could activate ß-catenin and enhance its nuclear translocation. Additionally, it was also observed that inhibiting ß-catenin nuclear translocation partly attenuated RAW264.7 M2 polarization induced by PFDA. The conditioned medium derived from PFDA-pretreated RAW264.7 cells significantly promoted the migration and invasion abilities of human ovarian cancer cells. Furthermore, in vivo studies corroborated that PFDA-pretreated RAW264.7 could promote tumor metastasis, which could be mitigated by pretreatment with the ß-catenin inhibitor ICG001. In conclusion, our study demonstrated that PFDA could promote cancer metastasis through regulating macrophage M2 polarization in a Wnt/ß-catenin-dependent manner.

Association between Different Types of Tea Consumption and Risk of Gynecologic Cancer: A Meta-Analysis of Cohort Studies.

Plenty of studies have shown that tea has an effect of inhibiting gynecologic tumors. However, there still remained controversy of the association between tea and gynecologic tumors in epidemiological studies. In this study, PubMed, Embase, and Cochrane Database were used to search the literature from 1 January 1960 to 26 December 2022 to investigate the association between tea intake and gynecologic cancer risk. In total, 19 cohort studies with 2,020,980 subjects and 12,155 gynecological tumor cases were retrieved. The pooled relative risk (RR) of gynecologic tumor for tea intake was 1.00 (95% CI: 0.96-1.04). RRs were 0.94 (95% CI: 0.88-1.01) for ovarian cancer, 1.02 (95% CI: 0.97-1.07) for endometrial cancer, and 1.06 (95% CI: 0.91-1.23) for cervical cancer. Subgroup analyses were adopted based on the tea type and geographic location. Interestingly, significant preventive impact of non-herbal tea on ovarian cancer (pooled relative risk: 0.67; 95% CI: 0.55-0.81) was found, especially for black tea (pooled relative risk: 0.64; 95% CI: 0.51-0.80). Dose-response analysis indicated that although it is not statistically significant, a decreasing trend of ovarian cancer risk could be observed when the tea consumption was 1.40 to 3.12 cups/day. In conclusion, our findings suggested that ovarian cancer, but not other gynecologic cancers, could possibly be prevented by drinking non-herbal tea. In addition, the preventive impact of green tea on gynecologic cancer seemed to be relatively weak and needs further cohorts to validate it.

Low-dose BPA and its substitute BPS promote ovarian cancer cell stemness via a non-canonical PINK1/p53 mitophagic signaling.

The environmental toxicity of bisphenol A (BPA) and its analog like bisphenol S (BPS) have drawn wide attention, but their roles in cancer progression remain controversial. Here, we investigated the effect of BPA/BPS on the development of ovarian cancer. Human internal BPA/BPS exposure levels were analyzed from NHANES 2013-2016 data. We treated human ovarian cancer cells with 0-1000 nM BPA/BPS and found that 100 nM BPA/BPS treatment significantly increased Cancer Stem Cell (CSC) markers expression including OCT4, NANOG and SOX2. Cancer cell stemness evaluation induced by BPA/BPS was notably attenuated by the knockdown of PINK1 or Mdivi-1 treatment. The activation of PINK1 initiated mitophagy by inhibiting p-p53 nuclear translocation in a non-canonical manner. In vivo studies validated that BPA/BPS-exposed mice have higher tumor metastasis incidence compared with the control group, while mitophagy inhibition blocked such a promotion effect. In addition, CSC markers such as SOX2 had been found to be overexpressed in the tumor tissues of BPA/BPS exposure group. Taken together, the findings herein first provide the evidence that environmentally relevant BPA/BPS exposure could enhance ovarian cancer cell stemness through a non-canonical PINK1/p53 mitophagic pathway, raising concerns about the potential population hazards of BPA and other bisphenol analogs.

Per- and polyfluoroalkyl substances in umbilical cord serum and body mass index trajectories from birth to age 10 years: Findings from a longitudinal birth cohort (SMBCS).

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to low birth weight but higher childhood weight and obesity. However, little is known regarding the associations between PFAS exposure and dynamic body mass index (BMI) trajectories, particularly from birth through preadolescence. OBJECTIVE: To evaluate the associations of cord serum PFAS concentrations with BMI trajectories from birth to age 10 years and longitudinal BMI in different periods. METHODS: Based on 887 mother-child pairs in the longitudinal prospective birth cohort, we measured 12 PFAS congeners in cord serum and calculated BMI with anthropometric indicators at 9 follow-up time points from birth to age 10 years. The BMI trajectories were identified using group-based trajectory model (GBTM). To estimate the associations of cord serum PFAS levels with BMI trajectories and longitudinal changes in BMI, logistic regression models, linear mixed models, Bayesian kernel machine regression, and quantile-based g-computation models (QGC) were used. RESULTS: The median concentrations of 10 PFAS congeners included in statistical analysis ranged from 0.047 to 3.623 µg/L. Two BMI trajectory classes were identified by GBTM, characterized by high group and low group. In logistic regression models, five PFAS congeners (PFBA, PFHpA, PFHxS, PFHpS, and PFDoDA) were associated with the higher probability of being in high BMI trajectory group (odds ratio, OR: 1.21 to 1.74, p < 0.05). Meanwhile, higher PFAS mixture were related to elevated odds for the high group in both BKMR models and QGC models, with PFHpA and PFHpS being the two most important drivers jointly. In the sex-stratified analysis, the positive associations remained significant exclusively among males. In the longitudinal analysis, PFUnDA and PFDoDA were associated with increased BMI from birth to age 10 years. Furthermore, PFBS and PFHpA were negatively related to BMI throughout infancy and toddlerhood (from birth to age 3 years), whereas PFDoDA confirmed a positive association with mid-childhood (from age 6 to 10 years) BMI. CONCLUSIONS: Prenatal PFAS exposure was positively associated with BMI trajectories from birth to preadolescence and longitudinal BMI in various periods. Future research could use better trajectory modeling strategies to shape more complete growth trajectories and explore the relationship between BMI trajectories and adulthood health.

Prenatal exposure to parabens in association with cord serum adipokine levels and offspring size at birth.

BACKGROUND: Paraben exposure is linked to the release of adipokine such as leptin and adiponectin, and both paraben and adipokine may affect fetal growth. The present study aimed to explore the associations among maternal paraben exposure, adipokine level and offspring size. METHODS: 942 mother-newborn pairs from the Sheyang Mini Birth Cohort Study (SMBCS) were enrolled. Data of birth weight, length, head circumference and ponderal index (PI) were obtained from medical records. Maternal urinary parabens were determined by gas chromatography tandem mass spectrometry. Cord serum leptin and adiponectin were measured using ELISA assay. Generalized linear regression was applied to explore the associations among parabens, adipokines and offspring size. RESULTS: The median levels of leptin and adiponectin were 13.13 µg/L and 161.82 µg/mL. Benzylparaben level was positively associated with leptin (regression coefficient (ß) = 0.06, 95% confidence interval (CI): 0.03-0.09; p < 0.01). Leptin level was positively associated with neonatal weight (ß = 84.11, 95% CI: 63.22-105.01; p < 0.01), length (ß = 0.25, 95% CI: 0.14-0.37; p < 0.01), head circumference (ß = 0.15, 95% CI: 0.07-0.22; p < 0.01) and PI (ß = 0.23, 95% CI: 0.08-0.39; p < 0.01). Adiponectin was positively associated with neonatal weight (ß = 75.94, 95% CI: 29.65-122.23; p < 0.01) and PI (ß = 0.43, 95% CI: 0.09-0.77; p = 0.01). Urinary propylparaben concentration (ß = -0.10, 95% CI: -0.17 to -0.02; p = 0.01) was negatively associated with head circumference. Sex-stratified analyses indicated the negative association of propylparaben and head circumference was only remained in male neonates. CONCLUSIONS: Prenatal paraben exposure might affect cord serum leptin levels. Both paraben and adipokine levels may affect fetal growth, and sex-specific differences may exist.

Associations of Diet with Urinary Trimethylamine-N-Oxide (TMAO) and Its Precursors among Free-Living 10-Year-Old Children: Data from SMBCS.

Trimethylamine-N-oxide (TMAO), a diet-derived cometabolite linked to cardiometabolic disease, has been associated with elevated dietary status, particularly in people with kidney failure and adults with dietary modulations. However, the influence of the current diet on TMAO levels in free-living children has not been adequately described. This study was to explore associations of food compositions and dietary diversity with urinary TMAO and its precursor concentrations. Urinary TMAO and its precursor concentrations of 474 healthy children from the Sheyang Mini Birth Cohort were quantified by ultra-performance liquid chromatography−Q Exactive high-resolution mass spectrometer (UPLC-Q Exactive HRMS). Individual food compositions from 24 h dietary recall data were classified into 20 groups and diversity scores were calculated according to the guidelines of the Food and Agriculture Organization of the United Nations (FAO). Associations of urinary TMAO and its precursors with food compositions and dietary diversity scores were assessed by generalized linear regression models. In models adjusted for potential confounders, urinary TMAO was significantly associated with intakes of fish (ß, regression coefficient = 0.155, p < 0.05) and vegetables (ß = 0.120, p < 0.05). Eggs intake showed positive associations with TMAO's precursors (trimethylamine: ß = 0.179, p < 0.05; choline: ß = 0.181, p < 0.05). No association between meat intake and TMAO was observed, whereas meat and poultry intakes were related to the levels of acetyl-L-carnitine and L-carnitine (ß: 0.134 to 0.293, p < 0.05). The indicators of dietary diversity were positively correlated to TMAO concentration (ß: 0.027 to 0.091, p < 0.05). In this free-living children-based study, dietary factors were related to urinary TMAO and its precursors, especially fish, meat, and eggs. As such, dietary diversity was positively related to the level of TMAO.

The emerging role of ferroptosis in inflammation.

Ferroptosis is a newly discovered type of cell death triggered by intracellular phospholipid peroxidation that is morphologically, biologically and genetically distinct from other types of cell death. Ferroptosis is classified as regulated necrosis and is more immunogenic than apoptosis. To date, compelling evidence indicates that ferroptosis plays an important role in inflammation, and several antioxidants functioning as ferroptosis inhibitors have been shown to exert anti-inflammatory effects in experimental models of certain diseases. Our review provides an overview of the link between ferroptosis and inflammation; a better understanding of the mechanisms underlying ferroptosis and inflammation may hasten the development of promising therapeutic strategies involving ferroptosis inhibitors to address inflammation.