Association between F2-Isoprostane Metabolites and Weight Change in Older Women: A Longitudinal Analysis.

INTRODUCTION: Theoretically, some metabolic traits may predispose older individuals to weight loss during aging, leading to increased all-cause mortality and many serious health issues. Biomarkers to robustly predict progressive weight loss during aging are, however, lacking. We prospectively assessed if urinary levels of F2-isoprostanes and their peroxisomal ß-oxidation metabolite, 2,3-dinor-5,6-dihydro-15-F2t-isoprostane (F2-IsoP-M), were associated with subsequent weight loss in middle-aged and older women. METHODS: Included in the analysis were 2,066 women aged 40-70 years, a subset of a prospective cohort study. F2-isoprostanes (F2-IsoPs) and its ß-oxidation metabolite, F2-IsoP-M, were measured in urine using gas chromatography-mass spectrometry. Measurements of anthropometry and exposures to major determinants of body weight were performed at baseline and repeated thrice over 15-year follow-up. The longitudinal associations of F2-IsoP-M and the F2-IsoP-M to its parent compound, F2-IsoP, ratio (MPR) with repeatedly measured weight changes were examined using linear mixed-effect models. RESULTS: After adjusting for time-varying covariates: energy intake, physical activity, and comorbidity index, among others, levels of F2-IsoP-M and the MPR were both inversely associated with percentage of weight change. Weight in the highest quartile of these two biomarkers was 1.33% (95% CI = -2.41, -0.24) and 1.09% (95% CI = -2.16, -0.02) lower than those in the lowest quartile group, with p for trend of 0.01 and 0.03, respectively. The inverse association was consistently seen across follow-up periods, although appearing stronger with prolonged follow-up. There was no association between the parent compound, F2-IsoPs, and weight change. CONCLUSION: This study demonstrates the first piece of evidence to associate F2-IsoP metabolism, peroxisomal ß-oxidation, with weight loss in older women. Further investigations into the role of lipid peroxidation and peroxisomal ß-oxidation in weight change among older individuals are warranted.

Associations of maternal and personal smoking with all-cause and cause-specific mortality risk and life expectancy: a prospective cohort study.

OBJECTIVES: The aim of this study was to evaluate the individual and combined effects of maternal smoking during pregnancy (MSDP) and personal smoking on mortality and life expectancy. STUDY DESIGN: A prospective cohort study based on the UK Biobank, with a median follow-up of 12.47 years. METHODS: This study employed multivariate Cox regression to determine the relative risks of mortality from all causes and specific diseases according to maternal and/or personal smoking status and pack-years of smoking (0, 1-20, 21-30, >30). Additionally, this study estimated the additive interaction between the two exposures. Life table analyses were performed using the estimated age-specific mortality rates to forecast life expectancy. RESULTS: Results indicated that MSDP elevated the risk of all-cause mortality (HR = 1.12, 95% CI: 1.09-1.15) and mortality due to neoplasms (HR = 1.10, 95% CI: 1.06-1.12), circulatory (HR = 1.13, 95% CI: 1.06-1.19), respiratory (HR = 1.27, 95% CI: 1.16-1.40) and digestive system diseases (HR = 1.22, 95% CI: 1.08-1.38). Notably, both multiplicative and additive interactions were observed between maternal and personal smoking, with Relative Excess Risk due to Interaction (RERI) values for mortality from all causes, neoplasms, circulatory, and respiratory diseases being 0.21, 0.22, 0.16, and 0.76, respectively. This study also found a trend towards shorter gained life expectancy when maternal smoking and increasing pack-years of personal smoking were combined. CONCLUSIONS: In this cohort study of UK Biobank, MSDP was associated with an increased risk of all-cause mortality and reduced life expectancy, suggesting that quitting smoking during pregnancy might have health and longevity benefits for both generations.

Endogenous sex hormones, aromatase activity and lung cancer risk in postmenopausal never-smoking women.

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never-smoking women. A case-control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Prediagnostic concentrations of sex hormones was quantitated using LC-MS/MS assays in plasma. The product-substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). Multivariable conditional logistic regression models were used to calculate odds ratios (ORs) for lung cancer. Baseline concentrations of estradiol, free testosterone and IAA were inversely associated with subsequent risk of lung cancer in multivariable-adjusted models. When further adjusted for body mass index, the inverse association with estradiol was attenuated and no longer statistically significant, but the association with free testosterone and IAA remained. In analyses confined to participants having never used menopausal hormone therapy in 376 case-control pairs, the inverse association with free testosterone and IAA was slightly strengthened. OR for the highest vs the lowest quartile of free testosterone was 0.55 (95% CI = 0.34-0.90; Ptrend  = .03), and the corresponding OR for IAA was 0.57 (95% CI = 0.34-0.96; Ptrend  = .04). Our study, for the first time, suggests that higher levels of circulating free testosterone and estimated aromatase activity may be associated with lower lung cancer risk in postmenopausal never-smoking women.

Circulating metal concentrations, inflammatory cytokines and gestational weight gain: Shanghai MCPC cohort.

OBJECTIVES: Based on a prospective birth cohort, we aimed to investigate the associations between maternal circulating metals exposure and gestational weight gain (GWG) across pregnancy, and explore whether maternal inflammatory cytokines could contribute to the GWG changes associated with metals exposure. METHODS: A total of 234 pregnant women from the Shanghai Maternal-Child Pairs cohort were enrolled in this panel study. 547 blood and serum samples were collected from pregnant women during three follow-up visits, and the circulating concentrations of 27 metals were determined by using the ICP-MS method. Five inflammatory cytokines in serum samples were measured through multiplexed immunoassays. The linear mixed models were used to estimate the association between each ln-transformed metal concentration and GWG across pregnancy. Robust generalized linear regression models were used to estimate the associations among circulating metals, GWG, and inflammatory cytokines. RESULTS: The GWG during pregnancy was 13.76 ± 1.40 kg. The concentrations Co, Zn, Mo, B, Ag and Te in second or third trimesters were significantly higher than those in early second trimester. The concentration of Mg decreased with the increase of pregnant weeks and no significant statistical differences were found in the concentrations of other metals in different trimesters. Among the detected 26 metals, Li and Sr concentrations were positively associated with GWG in the third trimester. The GWG increased by 0.100 kg (95% CI 0.005, 0.195) and 0.120 kg (95% CI 0.009, 0.232) with each one ln-concentration increase in circulating Li and Sr concentrations, respectively. Concentrations of Li and Sr in the third trimester were positively associated with tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, but negatively associated with growth differentiation factor-15 (GDF-15) significantly. Besides, IL-6 and GDF-15 levels were associated with the increase or decrease of overall pregnancy GWG, respectively. CONCLUSIONS: Results showed that maternal exposure to Li and Sr were associated with increased GWG, in which maternal IL-6 and GDF-15 could contribute to the associations between metal exposures and GWG in pregnant women.

Association between fetal growth restriction and maternal exposure to polybrominated diphenyl ethers.

Humans are exposed to polybrominated diphenyl ethers (PBDEs) via ingestion of food, dust inhalation, and dermal absorption. Exposure to PBDEs via the placenta and breast milk is a special and important pathway in infants. This nested case-control study aimed to investigate the levels of PBDEs in maternal serum and colostrum, and to assess the association between the occurrence of fetal growth restriction (FGR) and prenatal exposure to PBDEs. We recruited 293 mother-newborn pairs, including 98 FGR cases and 195 healthy controls in Wenzhou, China. Maternal serum and colostrum samples were collected during pregnancy and after delivery, respectively, and the levels of PBDEs were measured by gas chromatography-tandem mass spectrometry. The total levels of PBDEs in maternal serum and colostrum were found to be in equilibrium, but congener profiles of PBDEs in these matrices were different. Increased BDE-207, BDE-209, ∑BDE196-209 and ∑PBDEs levels in maternal serum and BDE-99, ∑BDE17-154 and ∑PBDEs levels in colostrum were correlated with decreased birth weight Z score. Increased concentrations of higher brominated BDEs in maternal serum (odds ratio (OR) = 1.010, 95%CI = 1.003-1.018) and low-to moderately brominated BDEs in colostrum (OR = 1.004, 95%CI = 1.000-1.009) were associated with increased risk of FGR, which showed an exposure-response relationship. In addition, infants with FGR were more exposed to PBDEs in colostrum after birth than healthy infants. Longitudinal birth cohort studies are needed to determine the prolonged effect of PBDEs exposure on the growth of FGR infants in the future.

Thiamine deficiency contributes to synapse and neural circuit defects.

BACKGROUND: The previous studies have demonstrated the reduction of thiamine diphosphate is specific to Alzheimer's disease (AD) and causal factor of brain glucose hypometabolism, which is considered as a neurodegenerative index of AD and closely correlates with the degree of cognitive impairment. The reduction of thiamine diphosphate may contribute to the dysfunction of synapses and neural circuits, finally leading to cognitive decline. RESULTS: To demonstrate this hypothesis, we established abnormalities in the glucose metabolism utilizing thiamine deficiency in vitro and in vivo, and we found dramatically reduced dendrite spine density. We further detected lowered excitatory neurotransmission and impaired hippocampal long-term potentiation, which are induced by TPK RNAi in vitro. Importantly, via treatment with benfotiamine, Aß induced spines density decrease was considerably ameliorated. CONCLUSIONS: These results revealed that thiamine deficiency contributed to synaptic dysfunction which strongly related to AD pathogenesis. Our results provide new insights into pathogenesis of synaptic and neuronal dysfunction in AD.

Metabolic health and genetic predisposition in inflammatory bowel disease: Insights from a prospective cohort study.

BACKGROUND: Metabolic disorders exhibit strong inflammatory underpinnings and vice versa. This study aimed to investigate the association between metabolic health status, genetic predisposition, and the risk of inflammatory bowel disease (IBD), and to explore the potential benefits of maintaining ideal metabolic status for individuals with a predetermined genetic risk of IBD. METHOD: This population-based prospective study included 385,820 unrelated European descent participants from the UK Biobank. Using multivariable Cox regression, we assessed the relationship of metabolic phenotypes with risk of IBD and its subtypes. We also developed a polygenic risk score to examine how metabolic health status interacted with genetic risk in relation to IBD risk. RESULTS: During the follow-up period of 4,328,895 person-years, 2,044 newly-diagnosed IBD cases were identified. Higher genetic risk and an increasing number of abnormal metabolic phenotypes were associated with elevated IBD risk (p-trend <0.001). Individuals with high genetic risk and poor metabolic health had a significantly higher risk of IBD (HR=4.56, 95 % CI=3.27-6.36) compared to those with low genetic risk and ideal metabolic health. These results remained consistent for IBD subtypes. Maintaining ideal metabolic status reduced IBD risk within each genetic risk category and jointly decreased subsequent risk by 40 % in high genetic risk individuals. CONCLUSION: Our study reveals a combined impact of poor metabolic health and genetic risk on IBD incidence. Those with low genetic risk and optimal metabolic health exhibit the lowest IBD risk, offering insights into potential management strategies for individuals at predefined genetic risk.

Mixed exposure to phthalates and organic UV filters affects Children's pubertal development in a gender-specific manner.

BACKGROUND: Previous studies showed phthalates and UV filters are endocrine-disruptive and associated with puberty. However, few studies have examined effects of mixed exposure. METHODS: Six phthalate metabolites and 12 organic UV filters were detected among 223 school-age children. Puberty development was evaluated at baseline and after 18 months of follow-up. Ordered logistic regression models, least absolute shrinkage and selection operator (LASSO) regression and quantile-based g-computation (qgcomp) were used to evaluate relationships between phthalate metabolites or UV filters exposure and pubertal development. RESULTS: Six phthalate metabolites and 5 UV filters were detectable in urine samples. In boys, BP-3 and 4'-MAP were negatively associated with genital (ORBP-3 = 0.52, (0.27, 0.93), OR4'-MAP = 0.45, (0.25, 0.74)) and pubic hair development (ORBP-3:0.24, (0.05, 0.76), OR4'-MAP:0.24, (0.05, 0.77)). In girls, MEP levels were associated with advanced breast development (OR: 1.29, (1.04, 1.64)). LASSO regression identified BP-3, 4'-MAP, and OD-PABA for inverse associations with pubertal development in boys. MEP was related to an increase in girls' breast development (OR: 1.64, (1.08, 2.63)). Overall mixture was related to a 70% reduction in boys' genital development stage, with a larger effect size than a single chemical in qgcomp. Mixed exposure was associated with girls' earlier puberty onset (OR: 2.61, (1.06, 6.42)). CONCLUSIONS: Our results suggested higher levels of phthalate metabolites and UV filters were associated with delayed pubertal development in boys but with earlier puberty in girls. Higher effect size of joint exposure than single chemicals suggested phthalates and UV filters might have synergistic effects on puberty and distort adolescent endocrine function together.

Diagnosis and treatment of MN1 C-terminal truncation syndrome.

BACKGROUND: MN1 C-terminal truncation (MCTT) is a rare syndrome; only 27 cases have been reported. We report the first case of an 8-year-old girl with MCTT syndrome complicated with moderate obstructive sleep apnea (OSA). METHODS: MCTT syndrome was diagnosed by whole-exome sequencing (WES) and validated by Sanger sequencing. The patient received 2 years of treatment with continuous positive airway pressure (CPAP) to relieve sleep apnea and hypoxia, and a reverse sector fan-shaped expander for maxillary expansion. RESULTS: WES revealed a de novo MN1 variant, c.3760C>T (p.[Q1254*]). An arachnoid cyst was found in the right occipital brain. The patient presented mild symptoms of classic MCTT syndrome. The patient did not experience hearing loss and only mild intellectual disability. Radiological examinations showed cleft secondary palate, narrow upper arch, narrow upper airway, and mandibular skeletal retrusion. Polysomnography indicated moderate OSA, with an apnea/hypopnea index of 6.8, which decreased to 1 after CPAP during the night. Two-year maxillary expansion widened the upper arch, and the cleft secondary palate became visible. The mandible moved forward spontaneously, resulting in the improvement of profile and upper airway widening. General physical conditions, such as motor delay, muscle weakness, and developmental delay, were significantly improved two years later. CONCLUSION: In conclusion, we discovered a MN1 variant [NM_002430.2: c.3760C>T, p.Q1254*] that causes mild MCTT symptoms compared to other MN1 variants. For patients with MCTT complicated with OSA, multidisciplinary combination therapy can improve maxillofacial development, widen the upper airway and relieve sleep apnea, improving the general physical condition.

Organic UV filters mixture exposure and childhood adiposity: A prospective follow-up study in China.

BACKGROUND: UV filters are emerging contaminants with endocrine disrupting effects, but little is known about their health effects, especially for children. OBJECTIVE: To assess the association between multiple organic UV filters exposure and adiposity measures and by gender in peripubertal children. METHODS: This prospective follow-up study included 327 children aged 7-15 years old. Urinary organic UV filters including benzophenone derivatives (BP-2, BP-3), octyl dimethyl para-aminobenzoic acid (OD-PABA), ethylhexyl methoxycinnamate (EHMC) and its metabolite (4-MCA and 4'-MAP) were quantified. Six adiposity biometrics including height, weight, waist and hip circumferences, and triceps and subscapular skinfold thickness were measured with 1.5-year duration. The Bayesian kernel machine regression method was used to estimate the associations of UV filters mixture with adiposity measurements, and longitudinal analyses were then considered to further evaluate the associations between individual UV filters and trajectories of growth development using linear mixed models or generalized linear mixed models. RESULTS: Exposure to mixture of UV filters was negatively associated with most adiposity measurements, with a reduction of 1.399 kg/m2 (95% CI: -2.246 to -0.551 kg/m2) in BMI, 0.674 (95% CI: -1.045 to -0.304) in BMI z-score, 0.033 BF% (95% CI: -0.053 to -0.013), and 2.301 mm (95% CI: -3.823 to -0.78) in subscapular skinfold thickness at baseline, comparing the 75th percentile to the 25th level of UV filters mixture exposure. Consistent associations were found at follow-up. Both baseline and follow-up results suggested that EHMC was identified as the most important contributor to lower adiposity measurements, which was also confirmed by linear mixed models in longitudinal analyses. No significant effects were found in girls. CONCLUSION: This study found that childhood organic UV filters exposure was negatively associated with adiposity measures in peripubertal boys, but not girls.

Association between lipid peroxidation biomarkers and microRNA expression profiles.

BACKGROUND: In-vitro and animal studies demonstrate that epigenetic regulation may play an important role in lipid peroxidation. No human study to date has directly evaluated microRNAs (miRNAs), as epigenetic modulators, in relation to systemic levels of lipid peroxidation. OBJECTIVES: To evaluate associations between systemic levels of lipid peroxidation and miRNA expression profiles in women. METHODS: Included in the analysis were 92 women aged 40-70 years, a subset of the Shanghai Women's Health Study (SWHS). Lipid peroxidation was assessed by urinary markers F2-isoprostanes (F2-IsoPs), the products of free radical-catalyzed peroxidation of arachidonic acid, and its major metabolite after ß-oxidation, 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M), with GC/NICI-MS assays. Expression levels of 798 miRNAs were quantified in peripheral plasma with NanoString nCounter assays. A multivariable linear regression model was used to examine the association between lipid peroxidation and miRNA expression. RESULTS: After adjusting for potential confounders, 29 miRNAs and 213 miRNAs were associated with F2-IsoPs and F2-IsoP-M, respectively. When further controlling for multiple comparisons, none of these nominally significant associations with F2-IsoPs was retained, whereas 71 of 213 miRNAs associated with F2-IsoP-M remained. The predicted targets of the F2-IsoP-M associated miRNAs were enriched for several lipid peroxidation-related processes such as PI3K/AKT, MAPK, FOXO and HIF-1 signaling pathways. Moreover, 10 miRNAs (miR-93-5p, miR-761, miR-301b-3p, miR-497-5p, miR-141-3p, miR-186-5p, miR-126-3p, miR-200b-3p, miR-520d-3p, and miR-363-3p) exhibited functional interactions with 50 unique mRNAs targets involved in the regulation of ß-oxidation. CONCLUSIONS: To our knowledge, this study, for the first time, provides human data suggesting that miRNA expression may be linked to lipid peroxidation products and their metabolism.

Association between lipid peroxidation and risk of type 2 diabetes in women.

In-vitro and animal studies demonstrate that lipid peroxidation plays an important role in the pathogenesis of type 2 diabetes (T2D). However, human data from prospective studies are limited and contradictory. We used data originally collected in two nested case-control studies of cancer to prospectively evaluate whether systemic levels of lipid peroxidation were associated with incidence of T2D in 1917 women who were 40-70 years old and diabetes-free at baseline. Lipid peroxidation was measured by urinary F2-isoprostanes (F2-IsoPs) and its major metabolite 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M) with GC/NICI-MS assays. The Cox regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident T2D. After a median follow-up of 10.1 years, 187 women were diagnosed with T2D. Urinary concentrations of both F2-IsoPs and F2-IsoP-M were significantly higher in T2D cases than in non-cases. Both biomarkers were positively associated with subsequent risk of T2D in multivariable-adjusted Cox models. When further adjusted for body mass index (BMI), the positive association with F2-IsoP-M was attenuated and no longer statistically significant, whereas the association with F2-IsoPs remained (P for overall significance < 0.001). HR for T2D was 1.68 (95% CI: 1.13, 2.51) for the highest vs the lowest quartile of F2-IsoPs. Moreover, this association appeared more pronounced among women with higher BMI. In summary, our study suggests that F2-IsoPs could be of significance in T2D risk prediction among middle-aged and elderly women.

Prenatal fine particulate matter exposure associated with placental small extracellular vesicle derived microRNA and child neurodevelopmental delays.

BACKGROUND AND AIMS: Prenatal fine particulate matter (PM2.5) exposure has been linked to adverse neurodevelopment. However, epidemiological evidence remains inconclusive and little information about the effects of various PM2.5 components on child neurodevelopment is currently known. The underlying mechanism was also not elucidated. The study aimed to evaluate the effects of PM2.5 and components exposure on child neurodevelopmental delays and the role of placental small extracellular vesicles (sEVs)-derived miRNAs in the associations. METHODS: We included 267 mother-child pairs in this analysis. Prenatal PM2.5 and components (i.e. elements, water-soluble ions, and PAHs) exposure during three trimesters were monitored through personal PM2.5 sampling. Child neurodevelopment at 2, 6, and 12 months old were evaluated by Ages and Stages Questionnaire (ASQ). We isolated sEVs from placental tissue to analyze the change of sEVs-derived miRNAs in response to PM2.5. Associations between the PM2.5-associated miRNAs and child neurodevelopment were evaluated using multivariate linear regression models. RESULTS: The PM2.5 exposure levels in the three trimesters range from 2.51 to 185.21 µg/m3. Prenatal PM2.5 and the components of Pb, Al, V and Ti exposure in the second and third trimester were related to decreased ASQ scores communication, problem-solving and personal-social domains in children aged 2 or 6 months. RNA sequencing identified fifteen differentially expressed miRNAs. The miR-101-3p and miR-520d-5p were negatively associated with PM2.5 and Pb component. miR-320a-3p expression was positively associated with PM2.5 and V component. Meanwhile, the miR-320a-3p was associated with decreased ASQ scores, as reflected by ASQ-T (ß: -2.154, 95 % CI: -4.313, -0.516) and problem-solving domain (ß: -0.605, 95 % CI: -1.111, -0.099) in children aged 6 months. CONCLUSION: Prenatal exposure to PM2.5 and its Pb, Al, V & Ti component were associated with infant neurodevelopmental delays. The placenta sEVs derived miRNAs, especially miR-320a-3p, might contribute to an increased risk of neurodevelopmental delays.

Lipid peroxidation biomarkers associated with height and obesity measures in the opposite direction in women.

OBJECTIVE: This study aimed to investigate whether and how lipid peroxidation markers are associated with height and obesity measures. METHODS: In two independent samples of women (Study 1: n = 1,005; Study 2: n = 1,158), systemic levels of lipid peroxidation were assessed by urinary markers F2 -isoprostanes (F2 -IsoPs) and its major metabolite (F2 -IsoP-M), with gas chromatography/negative ion chemical ionization mass spectrometry assays. Anthropometric parameters were directly measured and genetically estimated, and they were used in the primary analysis and in a Mendelian randomization analysis in relation to lipid peroxidation, respectively, with general linear models. RESULTS: After adjusting for potential confounders, it was found that measured adult height was inversely associated with levels of F2 -IsoPs (ß = -0.89, p < 0.001) and F2 -IsoP-M (ß = -0.71, p = 0.003), whereas obesity measures were positively associated with F2 -IsoP-M (ß = 1.81, p < 0.001 for BMI; and ß = 0.77, p < 0.001 for waist circumference). Results were consistent between the two study samples. The opposite associations were further replicated when using genetically determined measures of height and obesity in the Mendelian randomization analysis. Moreover, analyses mutually adjusted for height and obesity measures suggested that these associations were independent of one another. CONCLUSIONS: This study, for the first time, to our knowledge, reveals that a shared biological process (lipid peroxidation) is associated with both height and obesity measures but in the opposite direction.

Phytoestrogens and lung cancer risk: a nested case-control study in never-smoking Chinese women.

BACKGROUND: Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development. OBJECTIVE: The aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women. METHODS: We conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models. RESULTS: After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk. CONCLUSIONS: This study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.

Quality of dietary carbohydrate is more important than its quantity in lipid peroxidation.

BACKGROUND: High glycemic index (GI) diets have been linked to elevated risk of cardiometabolic diseases. One possible underlying mechanism comes from high GI diet's potential to promote lipid peroxidation. OBJECTIVES: We aim to evaluate whether and to what extent dietary carbohydrate quality and quantity are associated with systemic levels of lipid peroxidation in females. METHODS: In this cross-sectional analysis of 2163 middle-aged women, a subset of the Shanghai Women's Health Study, we measured lipid peroxidation biomarkers F2-isoprostanes (F2-IsoPs) and its metabolite, 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M), in urine. The quality of carbohydrate was defined by dietary GI, assessed using a validated FFQ via in-person interviews. A multivariable linear regression model with restricted cubic spline functions was used to evaluate the association of measured biomarkers with carbohydrate intake and dietary GI. RESULTS: After adjustment for potential confounding factors such as cigarette smoking, BMI, and comorbidities, among others, we found that F2-IsoP-M concentrations were positively associated with both carbohydrate intake and dietary GI. Carbohydrate intake and dietary GI were weakly correlated (r = 0.12). When further mutually adjusted for the 2 factors, the positive association with F2-IsoP-M remained statistically significant for GI (P = 0.004) but not for carbohydrate intake (P = 0.50). Compared with those in the 10th percentile of dietary GI, fold increases (95% CI) in F2-IsoP-M concentrations for those in the 30th, 50th, 70th, and 90th percentiles were 1.03 (1.00, 1.07), 1.06 (1.01, 1.10), 1.09 (1.03, 1.14), and 1.13 (1.05, 1.21), respectively. Moreover, there appeared a threshold regarding the association between dietary GI and F2-IsoP-M concentrations, with the dose-effect slope of GI being 2.3 times greater when GI was ≥75 relative to GI <75. CONCLUSIONS: This study provides evidence that the quality of dietary carbohydrate may be more important than the quantity of the intake with regard to systemic lipid peroxidation.

Prenatal exposure to ambient fine particulate matter and early childhood neurodevelopment: A population-based birth cohort study.

Although previous studies have reported the adverse effect of air pollution exposure during pregnancy on neurodevelopment in children, epidemiological evidence is limited, and the results are inconsistent. This study aimed to explore the association between prenatal ambient fine particulate matter (PM2.5) exposure and early childhood neurodevelopment in a large birth cohort study of 4009 maternal-child pairs. Prenatal daily PM2.5 exposure concentrations at 1 km spatial revolution were estimated using high-performance machine-learning models. Neurodevelopmental outcomes of children at ages 2, 6, 12, and 24 months were assessed using the Ages and Stages Questionnaire (ASQ). Distributed lag nonlinear models were used to identify critical windows of prenatal PM2.5 exposure. General linear mixed models with binomially distributed errors were used to estimate the effect of prenatal PM2.5 exposure on suspected developmental delay (SDD) in five developmental domains based on the longitudinal design. Prenatal PM2.5 exposure was significantly associated with decreased scores for all neurodevelopmental domains of children at ages 2, 6, and 24 months. Each 10-µg/m3 increase in PM2.5 exposure was significantly associated with increased risk of SDD for all subjects (RR: 1.52 95% CI: 1.19, 2.03), specifically, in problem-solving domain for girls (RR: 2.23, 95% CI: 1.22, 4.35). Prenatal PM2.5 exposure in weeks 18 to 34 was significantly associated with both ASQ scores and SDDs. Our study proposed that prenatal PM2.5 exposure affected early childhood neurodevelopment evaluated with the ASQ scale. PM2.5 exposure might increase the risk of SDD for boys and girls, specifically in the problem-solving domain for girls.

Intrauterine antibiotic exposure affected neonatal gut bacteria and infant growth speed.

Although abundant evidence has suggested that early-life antibiotic exposure was associated with adipogenesis later in life, limited data were available on the effect of intrauterine antibiotic exposure on infant growth and growth speed. Additionally, few studies have investigated the role of the neonatal gut microbiota in the above association. In this study, we examined the association between intrauterine cumulative antibiotic exposure and infant growth and explored the potential role of the neonatal gut microbiota in the association. 295 mother-child pairs from the Shanghai Maternal-Child Pairs Cohort (MCPC) study were included, and meconium samples and infant growth measurements were assessed. Z-scores of length-for-age, weight-for-age (weight-for-age), and body mass index (BMI)-for-age (BMI-for-age) were calculated. Eighteen common antibiotics were measured in meconium. Multivariable linear regression models were applied to test the interrelationships between antibiotic exposure, diversity indicators, and the relative abundance of selected bacterial taxa from phylum to genus levels from least absolute shrinkage and selection operator (LASSO) and infant growth indicators. The detection rates of the 18 antibiotics, except for chlortetracycline, penicillin, and chloramphenicol, were below 10 %. Penicillin was found to be positively associated with infant growth at birth and with growth speed from 2 to 6 months. The Pielou and Simpson indexes were negatively associated with meconium penicillin. Nominally significant associations between penicillin and the relative abundances of several bacterial taxa from the phyla Proteobacteria, Bacteroidetes, and Firmicutes were found. The Pielou and Simpson indexes were also found to be negatively associated with infant growth. Among taxa selected from LASSO regression, the relative abundances of the phyla Actinobacteria and Firmicutes and order Bifidobacteriales were found to be significantly associated with weight and BMI growth speeds from 2 to 6 months. In conclusion, intrauterine antibiotic exposure can affect infant growth. The neonatal gut microbiota might play a role in the abovementioned association.

Prenatal fine particulate matter exposure, placental DNA methylation changes, and fetal growth.

This study was designed to examine the impact of prenatal fine particulate matter (PM2.5) exposure on fetal growth and the underlying placental epigenetic mechanism in a cohort of Chinese women. Within the prospective Shanghai Mother-Child Pairs cohort (Shanghai MCPC), 329 women carrying singleton pregnancy with a due date in 2018 were recruited between 2017 and 2018. Maternal PM2.5 exposure levels were estimated using gestational exposure prediction model combining satellite-driven ambient concentrations and personal air sampling. Fetal growth characteristics were evaluated by prenatal ultrasound examinations and anthropometric measurements at birth. In a discovery phase, whole-genome DNA methylation analysis was performed using the Infinium 850 K array. In a validation phase, placental DNA methylation was measured using bisulfite pyrosequencing for five candidate genes that showed the most significant alterations and function relevance in our methylation array screen, including BID (BH3 interacting domain death agonist), FOXN3 (Forkhead box N3), FOXP1 (Forkhead box P1), IGF2 (Insulin-like growth factor 2) and HSD11B2 (Hydroxysteroid 11-beta dehydrogenase 2). Multivariate linear regression models were applied to examine the associations among PM2.5 exposure, fetal growth characteristics and DNA methylation on placental candidate genes. Sobel tests were used to evaluate the mediating role of DNA methylation in multivariable models. After excluding women who withdrew or failed to provide placenta, a total of 287 pregnant women with an average age of 30 entered the final analysis. Increased PM2.5 exposure was significantly associated with reduced biparietal diameter (BPD) (ß: -0.136 mm, 95% CI: -0.228 to -0.043), head circumference (HC) (ß: -0.462 mm, 95% CI: -0.782 to -0.142), femur length (FL) (ß: -0.113 mm, 95% CI: -0.185 to -0.041) and abdominal circumference (AC) (ß: -0.371 mm, 95% CI: -0.672 to -0.071) in the second trimester and birth length (ß: -0.013 cm, 95% CI: -0.025 to -0.001). Prenatal PM2.5 exposure could lead to aberrant changes in DNA methylation profile of placenta genome, which were mainly enriched in reproductive development, energy metabolism and immune response. DNA methylation of IGF2 and BID showed significant associations with PM2.5 exposures during all exposure windows. In addition, BID methylation was negatively correlated with HC (ß: -1.396 mm, 95% CI: -2.582 to -0.209) and BPD (ß: -0.330 mm, 95% CI: -0.635 to -0.026) in the second trimester. Further mediation analysis indicated that BID methylation mediated about 30% of the effects of PM2.5 exposure on HC. These findings collectively suggested that prenatal PM2.5 exposure may cause adverse effects on fetal growth by modifying placental DNA methylation.

Lactational exposure of polybrominated diphenyl ethers and its association with infant developmental measurements.

This study was designed to assess the effect of lactational polybrominated diphenyl ether (PBDE) exposure on early physical development of both healthy and fetal growth restriction (FGR) infants. Z scores of head circumference-for-age (ZHC), length-for-age (ZLEN), weight-for-age (ZWEI) and weight-for-length (ZWFL) were calculated according to the WHO Child Growth Standards. FGR infants had a higher PBDE exposure level and faster growth speed from 42 days to 6 months compared with healthy infants. Exposure of lower brominated BDEs (BDE28∼154) and the sum of 18 BDE congeners (BDE28∼209) negatively associated with ZHC [mean difference estimate (95 % CI): -0.71 (-1.22, -0.22) and -0.81 (-1.31, -0.33)] in FGR boys. Both BDE153 and BDE196 exposure had a significant correlation with ZLEN of boys in FGR group [mean difference estimate (95 % CI): -0.28 (-0.48, -0.07) and -0.52 (-0.91, -0.14)]. Each 10 ng/g lipid increase in the concentrations of BDE154 were respectively associated with 0.16 increase in ZWEI among boys in healthy group. No significant association was found in girls. Lactational PBDE exposure had effects on the early growth of both FGR and healthy infants. The encouragement of breastfeeding should therefore be considered in conjunction with PBDE contamination levels.