Metal exposure and blood lipid biomarkers in early pregnancy: A cross-sectional study.

Recognizing the risk factors for dyslipidemia during pregnancy is crucial for safeguarding the health of both the mothers and the offspring. Growing evidence emerged and suggested links between environmental factors, including metals, and alteration in lipid levels or dyslipidemia in general populations. However, knowledge of the associations during pregnancy remains extremely lacking. Herein, we aimed to explore whether elevated metal exposure constitutes a risk factor for dyslipidemia in pregnant women. Based on the Tongji-Shuangliu Birth Cohort (TSBC), a total of 663 pregnant women were recruited and their urinary levels of 17 metals and blood lipid biomarkers in early pregnancy were measured, namely triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). The multivariable linear regression models revealed that exposure to selected metals during early pregnancy was significantly associated with some important biomarkers. In particular, after natural log-transformed for the levels of lipid biomarkers and metals, copper (Cu) exposure was positively associated with HDL-C (ß = 0.024, 95% CI: 0.001, 0.046), while zinc (Zn) was associated with TG (ß = 0.062, 95% CI: 0.013, 0.110) and selenium with TC (ß = 0.028, 95% CI: 0.004, 0.054). Exposure to rubidium (Rb) was positively associated with multiple lipid biomarkers, including HDL-C (ß = 0.020, 95% CI: 0.002, 0.037) and LDL-C (ß = 0.022, 95% CI: 0.001, 0.042). Mixture exposure analysis further identified significant associations between Cu and HDL-C, Zn and TG, Rb and HDL-C, when multiple metal exposures were considered in the Bayesian kernel machine regression model simultaneously. Our findings showed that exposure to several metals during early pregnancy was associated with an increased prevalence of blood lipid abnormalities in pregnant women. These findings underscore the potential impact of metal combinations on lipid metabolism and increase our understanding of the risk factors associated with abnormal lipid metabolism during pregnancy.

Metal Exposure during Early Pregnancy and Risk of Gestational Diabetes Mellitus: Mixture Effect and Mediation by Phospholipid Fatty Acids.

Despite existing studies exploring the association between metal exposure and gestational diabetes mellitus (GDM), most of them have focused on a single metal or a small mixture of metals. Our prospective work investigated the joint and independent effects of early gestational exposure to 17 essential and nonessential metals on the GDM risk and potential mediation by plasma phospholipid fatty acids (PLFAs) based on a nested case-control study established with 335 GDM cases and 670 randomly matched healthy controls. The Bayesian kernel machine regression (BKMR) and quantile g-computation analyses demonstrated a joint effect from metal co-exposure on GDM risk. BKMR with hierarchical variable selection indicated that the group of essential metals was more strongly associated with GDM than the group of nonessential metals with group posterior inclusion probabilities (PIPs) of 0.979 and 0.672, respectively. Cu (0.988) and Ga (0.570) had the largest conditional PIPs within each group. We also observed significant mediation effects of selected unsaturated PLFAs on Cu-GDM and Ga-GDM associations. KEGG enrichment analysis further revealed significant enrichment in the biosynthesis of unsaturated PLFAs. C18:1 n-7 exhibited the largest proportion of mediation in both associations (23.8 and 22.9%). Collectively, our work demonstrated the joint effect of early gestational metal exposure on GDM risk and identified Cu and Ga as the key species to the joint effect. The findings lay a solid ground for further validation through multicenter investigations and mechanism exploration via laboratory studies.

Target Exposome for Characterizing Early Gestational Exposure to Contaminants of Emerging Concern and Association with Gestational Diabetes Mellitus.

Characterization of gestational exposure to complex contaminants of emerging concern (CECs) is critical to the identification of environmental risk factors for pregnancy complications. However, determination of various CECs with diverse physicochemical properties in biological fluids is technically challenging. In the present study, we developed a target exposome protocol, consisting of simple liquid-liquid extraction-based sample preparation and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, to determine 325 CECs covering 11 subclasses, including poly- and perfluoroalkyl substances, organophosphate esters, ultraviolet (UV) stabilizers, synthetic antioxidants, phthalate esters, and several others. The protocol exhibits exceptional advantages over traditional approaches in the coverage of chemicals, sample volume demand, and time and financial cost. The protocol was applied in a prospective nested gestational diabetes mellitus (GDM) study including 120 cases and 240 matched healthy controls. Thirty-three CECs were detected in >70% of the samples, with a combined concentration of 17.0-484.7 ng/mL. Bayesian kernel machine regression analysis showed that exposure to the CEC mixture was significantly associated with a higher GDM risk. For example, when increasing all CECs in the mixture from 50th percentile to 75th percentile, the estimated probit of GDM incidence had an increase of 92% (95% CI: 56%, 127%). Meanwhile, perfluorohexanesulfonic acid, 1,3-diphenylguanidine, and dibutyl fumarate were identified as the key CECs driving the joint effect. This work demonstrates great potential of our target exposome protocol for environmental risk factor identification in large-scale epidemiology or biomonitoring studies.

BPA and its alternatives BPF and BPAF exaggerate hepatic lipid metabolism disorders in male mice fed a high fat diet.

Alternatives to Bisphenol A (BPA), such as BPF and BPAF, have found increasing industrial applications. However, toxicological research on these BPA analogues remains limited. This study aimed to investigate the effects of BPA, BPF, and BPAF exposure on hepatotoxicity in mice fed with high-fat diets (HFD). Male mice were exposed to the bisphenols at a dose of 0.05 mg per kg body weight per day (mg/kg bw/day) for eight consecutive weeks, or 5 mg/kg bw/day for the first week followed by 0.05 mg/kg bw/day for seven weeks under HFD. The low dose (0.05 mg/kg bw/day) was corresponding to the tolerable daily intake (TDI) of BPA and the high dose (5 mg/kg bw/day) was corresponding to its no observed adverse effect level (NOAEL). Biochemical analysis revealed that exposure to these bisphenols resulted in liver damage. Metabolomics analysis showed disturbances of fatty acid and lipid metabolism in bisphenol-exposed mouse livers. BPF and BPAF exposure reduced lipid accumulation in HFD mouse liver by lowering glyceride and cholesterol levels. Transcriptomics analysis demonstrated that expression levels of genes related to fatty acid synthesis and metabolism were changed, which might be related to the activation of the PPAR signaling pathway. Besides, a feedback regulation mechanism might exist to maintain hepatic metabolic homeostasis. For the first time, this study demonstrated the effects of BPF and BPAF exposure in HFD-mouse liver. Considering the reality of the high prevalence of obesity nowadays and the ubiquitous environmental distribution of bisphenols, this study provides insight and highlights the adverse effects of BPA alternatives, further contributing to the consideration of the safe use of such compounds.

Fusarium graminearum GGA protein is critical for fungal development, virulence and ascospore discharge through its involvement in vesicular trafficking.

Vesicular trafficking is a conserved material transport process in eukaryotic cells. The GGA family proteins are clathrin adaptors that are involved in eukaryotic vesicle transport, but their functions in phytopathogenic filamentous fungi remain unexplored. Here, we examined the only GGA family protein in Fusarium graminearum, FgGga1, which localizes to both the late Golgi and endosomes. In the absence of FgGga1, the fungal mutant exhibited defects in vegetative growth, DON biosynthesis, ascospore discharge and virulence. Fluorescence microscopy analysis revealed that FgGga1 is associated with trans-Golgi network (TGN)-to-plasma membrane, endosome-to-TGN and endosome-to-vacuole transport. Mutational analysis on the five domains of FgGga1 showed that the VHS domain was required for endosome-to-TGN transport while the GAT167-248 and the hinge domains were required for both endosome-to-TGN and endosome-to-vacuole transport. Importantly, the deletion of the FgGga1 domains that are required in vesicular trafficking also inhibited vegetative growth and virulence of F. graminearum. In addition, FgGga1 interacted with the ascospore discharge regulator Ca2+ ATPase FgNeo1, whose transport to the vacuole is dependent on FgGga1-mediated endosome-to-vacuole transport. Our results suggest that FgGga1 is required for fungal development and virulence via FgGga1-mediated vesicular trafficking, and FgGga1-mediated endosome-to-vacuole transport facilitates ascospore discharge in F. graminearum.

BMI and lipidomic biomarkers with risk of gestational diabetes in pregnant women.

OBJECTIVE: The study aimed to identify BMI-related lipids and to explore the role of lipids linking BMI and gestational diabetes mellitus (GDM). METHODS: Plasma lipidome, height, and weight were measured in early pregnancy among 1008 women. Pearson correlation analyses and least absolute shrinkage and selection operator regression (LASSO) were performed to identify BMI-associated lipids. Based on these lipids, a lipid score was created using LASSO, and its association with GDM risk was evaluated by conditional logistic regression. The causal relationships between BMI and lipids were tested by Mendelian randomization analysis with genotyping data. Mediation analysis was conducted to evaluate the mediating effect of lipids on the association of BMI with GDM. RESULTS: Of 366 measured lipids, BMI was correlated with 28 lipids, which mainly belong to glycerophospholipids and glycerolipids. A total of 10 lipid species were associated with BMI, and a lipid score was established. A causal relationship between BMI and lysophosphatidylcholine 14:0 was observed. The lipid score was associated with a 1.69-fold increased risk of GDM per 1-point increment (95% CI: 1.33-2.15). Furthermore, BMI-associated lipids might explain 66.4% of the relationship between BMI and GDM. CONCLUSIONS: Higher BMI in early pregnancy was associated with altered lipid metabolism that may contribute to the increased risk of GDM.

The Endoplasmic Reticulum Cargo Receptor FgErv14 Regulates DON Production, Growth and Virulence in Fusarium graminearum.

Fusarium graminearum is a plant filamentous pathogenic fungi and the predominant causal agent of Fusarium head blight (FHB) in cereals worldwide. The regulators of the secretory pathway contribute significantly to fungal mycotoxin synthesis, development, and virulence. However, their roles in these processes in F. graminearum remain poorly understood. Here, we identified and functionally characterized the endoplasmic reticulum (ER) cargo receptor FgErv14 in F. graminearum. Firstly, it was observed that FgErv14 is mainly localized in the ER. Then, we constructed the FgErv14 deletion mutant (ΔFgerv14) and found that the absence of the FgErv14 caused a serious reduction in vegetative growth, significant defects in asexual and sexual reproduction, and severely impaired virulence. Furthermore, we found that the ΔFgerv14 mutant exhibited a reduced expression of TRI genes and defective toxisome generation, both of which are critical for deoxynivalenol (DON) biosynthesis. Importantly, we found the green fluorescent protein (GFP)-tagged FgRud3 was dispersed in the cytoplasm, whereas GFP-FgSnc1-PEM was partially trapped in the late Golgi in ΔFgerv14 mutant. These results demonstrate that FgErv14 mediates anterograde ER-to-Golgi transport as well as late secretory Golgi-to-Plasma membrane transport and is necessary for DON biosynthesis, asexual and sexual reproduction, vegetative growth, and pathogenicity in F. graminearum.

Low-level alternative halogenated flame retardants (AHFRs) in indoor dust from Adelaide, South Australia decades since national legislative control on polybrominated diphenyl ethers (PBDEs).

Since commercial polybrominated diphenyl ethers (PBDEs) have been globally banned or restricted in 2000s, alternative halogenated flame retardants (AHFRs) appear increasingly dominant over PBDEs in many countries/regions. In this study, low levels of AHFRs were unexpectedly observed in the indoor dust from Adelaide, South Australia. Anti-dechlorane plus (anti-DP) was the most frequently detected AHFR with a median concentration of 1.28 ng/g, while other AFHRs were less detected (detection frequency < 50%). The levels of ΣPBDEs (496 ng/g, median) and ΣAHFRs (160 ng/g) and the ratio of ΣAHFRs/ΣPBDEs (0.32) were much lower than those investigated in Australian indoor dust previously. The findings were different to the trend for PBDEs and AHFRs from other countries over the past two decades. No significant correlation was determined between DP and PBDE congeners, indicating their different sources in dust. The human exposure assessment suggested that dust ingestion was the predominant pathway of PBDEs and AHFRs exposure for toddlers, while dermal absorption may be the dominant pathway for adults. The estimated daily intake (EDI) suggested low health risks via dust ingestion and dermal contact for general populations in Adelaide. This study contributes to the knowledge on region-specific FR contamination in indoor environments and related human exposure risk.

A Prospective Study of Early-pregnancy Thyroid Markers, Lipid Species, and Risk of Gestational Diabetes Mellitus.

CONTEXT: While the associations between thyroid markers and gestational diabetes mellitus (GDM) have been extensively studied, the results are inconclusive and the mechanisms remain unclear. OBJECTIVE: We aimed to investigate the prospective associations of thyroid markers in early gestation with GDM risk, and examine the mediating effects through lipid species. METHODS: This study included 6068 pregnant women from the Tongji-Shuangliu Birth Cohort. Maternal serum thyroid markers (free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone, thyroid peroxidase antibody, and thyroglobulin antibody) were measured before 15 weeks. Deiodinase activity was assessed by fT3/fT4 ratio. Plasma lipidome were quantified in a subset of 883 participants. RESULTS: Mean age of the participants was 26.6 ± 3.7 years, and mean gestational age was 10.3 ± 2.0 weeks. Higher levels of fT4 were associated with a decreased risk of GDM (OR = 0.73 comparing the extreme quartiles; 95% CI 0.54, 0.98, Ptrend = .043), while higher fT3/fT4 ratio was associated with an increased risk of GDM (OR = 1.43 comparing the extreme quartiles; 95% CI 1.06, 1.93, Ptrend = .010) after adjusting for potential confounders. Multiple linear regression suggested that fT3/fT4 ratio was positively associated with alkylphosphatidylcholine 36:1, phosphatidylethanolamine plasmalogen 38:6, diacylglyceride 18:0/18:1, sphingomyelin 34:1, and phosphatidylcholine 40:7 (false discovery rate [FDR] adjusted P < .05). Mediation analysis indicated 67.9% of the association between fT3/fT4 ratio and GDM might be mediated through the composite effect of these lipids. CONCLUSION: Lower concentration of serum fT4 or higher fT3/fT4 ratio in early pregnancy was associated with an increased risk of GDM. The association of fT3/fT4 ratio with GDM was largely mediated by specific lipid species.

Quantitative fatty acid signature analysis (QFASA) in indoor dust: Implication for tracking indoor source accumulation of organic pollutant exposure.

Indoor dust has been used as a proxy for estimating human indoor pollutant exposure risks, yet source identification remains challenging. This study tentatively investigated whether quantitative fatty acid signature analysis (QFASA) of dust, could be applied to indicate sources and their respective contributions for a major class of indoor organic pollutants organophosphate flame retardants (OPFRs). We observed significant correlations between OPFR concentrations and lipid content (p < 0.05) in house dusts. Using 15 signature fatty acids (FAs) in various indoor sources and the QFASA model, we found that clothing (39.1% in Australia and 36.5% in China) was the predominant contributing vector of dust OPFR followed by cooking oil and pet hair. Among these sources, clothing materials were proposed to be important vectors introducing organic pollutants to the indoor environment. Our QFASA contribution estimation analyses allowed for accurate prediction of most OPFR concentrations in clothing, validating our findings that clothing materials may serve as important carrier for OPFRs in indoor migration. This is the first study attempting to identify sources of organic pollutants using QFASA in an indoor setting and will provide important insight into the transfer of organic pollutants in indoor environment.

Plasma lipidomics in early pregnancy and risk of gestational diabetes mellitus: a prospective nested case-control study in Chinese women.

BACKGROUND: Lipid metabolism plays an important role in the pathogenesis of diabetes. There is little evidence regarding the prospective association of the maternal lipidome with gestational diabetes mellitus (GDM), especially in Chinese populations. OBJECTIVES: We aimed to identify novel lipid species associated with GDM risk in Chinese women, and assess the incremental predictive capacity of the lipids for GDM. METHODS: We conducted a nested case-control study using the Tongji-Shuangliu Birth Cohort with 336 GDM cases and 672 controls, 1:2 matched on age and week of gestation. Maternal blood samples were collected at 6-15 wk, and lipidomes were profiled by targeted ultra-HPLC-tandem MS. GDM was diagnosed by oral-glucose-tolerance test at 24-28 wk. The least absolute shrinkage and selection operator is a regression analysis method that was used to select novel biomarkers. Multivariable conditional logistic regression was used to estimate the associations. RESULTS: Of 366 detected lipids, 10 were selected and found to be significantly associated with GDM independently of confounders: there were positive associations with phosphatidylinositol 40:6, alkylphosphatidylcholine 36:1, phosphatidylethanolamine plasmalogen 38:6, diacylglyceride 18:0/18:1, and alkylphosphatidylethanolamine 40:5 (adjusted ORs per 1 log-SD increment range: 1.34-2.86), whereas there were inverse associations with sphingomyelin 34:1, dihexosyl ceramide 24:0, mono hexosyl ceramide 18:0, dihexosyl ceramide 24:1, and phosphatidylcholine 40:7 (adjusted ORs range: 0.48-0.68). Addition of these novel lipids to the classical GDM prediction model resulted in a significant improvement in the C-statistic (discriminatory power of the model) to 0.801 (95% CI: 0.772, 0.829). For every 1-point increase in the lipid risk score of the 10 lipids, the OR of GDM was 1.66 (95% CI: 1.50, 1.85). Mediation analysis suggested the associations between specific lipid species and GDM were partially explained by glycemic and insulin-related indicators. CONCLUSIONS: Specific plasma lipid biomarkers in early pregnancy were associated with GDM in Chinese women, and significantly improved the prediction for GDM.

Postnatal exposure to DINP was associated with greater alterations of lipidomic markers for hepatic steatosis than DEHP in postweaning mice.

The toxicity of the endocrine disruptor di(2-ethylhexyl) phthalate (DEHP) has been extensively studied for its hormonal dysregulation, obesogenic effect and associated metabolic diseases. DEHP's primary substitute di-isononyl phthalate (DINP), however, although increased in annual production globally, requires better understanding of its health effect. Our previous work reported disruptions in plasma lipid profiles, but the metabolic responses following phthalate exposure in the liver, particularly the entire hepatic lipidome, have been lacking. A targeted lipidomic technique was applied to accurately quantify a total of 363 lipid species in the liver of neonatal mice after exposure to a daily dose of 4.8 mg/kg body weight/day from birth throughout lactation. Distinct patterns of disruption for each sum of lipid classes or sub-classes between the genders were the most noticeable. Following DINP administration, female pups were subject to greater changes in phosphatidylethanolamines, bis(monoacylglycero)phosphate and ceramides. In contrast, the males exhibited less changes in the phosphoglycerol backbone-based molecules, whereas glycerol and cholesterol esters were more disrupted by DINP. DEHP, however, induced less changes overall compared to DINP. These findings highlighted the predominant lipidomic disruption of DINP on glycerol (diacylglycerides and triacylglycerides) and/or cholesterol (in ester or free form) molecules in neonatal mice across genders, suggesting the genesis of hepatic steatosis occurring at as early as post weaning. Collectively, these findings question the suitability of DINP as a safe DEHP substitute and warrant further investigation on longer-term exposure to elucidate its effect on chronic liver diseases.

Lipidomic Changes in Banana (Musa cavendish) during Ripening and Comparison of Extraction by Folch and Bligh-Dyer Methods.

Banana (Musa cavendish) is one of the most popular fruits globally and is an important foodstuff in many regions, attributed to its high nutritional value. Contrast to its high consumption volume, relatively little research has been conducted on banana lipidome. In this study, two classic lipid extraction methods, Folch and Bligh-Dyer, were compared for studying the banana lipidome in both the peel and pulp by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Lipidomic profiles were also investigated to understand the changes of lipid molecules during three ripening stages (unripe, ripe, and overripe), and differences in lipids from different origins were also compared. This study suggested that although both Folch and Bligh-Dyer methods allow lipidome investigation, the latter demonstrated advantage in rendering higher extraction efficiency for the majority of lipid molecules in banana samples, particularly in the pulp. In peel, there were differences in the trends of each lipid classes at various stages of maturity, while the majority of lipid classes in pulp reached the highest levels with reduced desaturation at ripe stage, consistent with previous studies. Moreover, the lipidomic profiles of bananas in different habitats differed significantly according to partial least-squares discriminant analysis. This study for the first time provided comprehensive atlas of lipidomic changes of Musa cavendish during maturity and in different origins. These findings will facilitate better understanding of biochemical changes in banana and offer new tools for food chemical analyses in the understanding of mechanisms underlying lipid metabolism.

A broad range of organophosphate tri- and di-esters in house dust from Adelaide, South Australia: Concentrations, compositions, and human exposure risks.

This study aimed to investigate the occurrences of a suite of thirty-one organophosphate tri-esters (tri-OPEs) and six di-esters (di-OPEs) in house dust collected from Adelaide, South Australia. The results demonstrate ubiquitous presence of most OPEs in Adelaide house dust, with median concentration of 40,200 and 5260 ng/g dry weight for ∑tri-OPEs and ∑di-OPEs, respectively. A number of emerging OPEs with chemical structures resembling that of triphenyl phosphate (TPHP), including bisphenol A bis(diphenyl phosphate) (BPA-BDPP), cresyl diphenyl phosphate (CDP), isodecyl diphenyl phosphate (IDDPP), resorcinol-bis(diphenyl)- phosphate (RDP), as well as a suite of isopropylated or tert-butylated triarylphosphate ester isomers (ITPs or TBPPs), were frequently detected with combined levels surpassing that of TPHP. The investigated di-OPEs, predominated by DPHP, consisted of approximately 13% of the ∑tri-OPEs concentrations. Median concentration ratios of diphenyl phosphate (DPHP) and bis(2-ethylhexyl) phosphate (BEHP) to their respective tri-OPEs [i.e., TPHP and tris(2-ethylhexyl) phosphate (TEHP)] were determined to be 1.8 and 2.0, respectively, indicating possible commercial applications for these two di-OPEs. The estimated human intakes of dust-associated OPEs via dust ingestion and dermal contact were much lower than the reference doses. However, the risks of human exposure to OEPs may be complicated by quickly expanding family of OPEs containing various analogues and isomers as well as additional exposure pathways. Therefore, elucidation of human exposure to OPEs and associated risks requires extensive efforts in analytical, environmental, toxicological, and epidemiological investigations.

DEHP and DINP Induce Tissue- and Gender-Specific Disturbances in Fatty Acid and Lipidomic Profiles in Neonatal Mice: A Comparative Study.

Di-isononyl phthalate (DINP) is considered one of the main industrial alternatives to di(2-ethylhexyl)phthalate (DEHP), a well-known chemical with various toxic effects including the disruption with lipid metabolism. However, the potential effects of DINP on lipid metabolism have rarely been investigated in mammals. Our study demonstrated that exposure of neonatal mice to DEHP and DINP at a daily dose of 0.048 or 4.8 mg/kg from postnatal day 0 (PND0) to PND21 caused nonmonotonic as well as tissue- and gender-specific alterations of total fatty acid (FA) compositions in plasma, heart, and adipose tissues. However, the patterns of disruption differed between DEHP- and DINP-treated groups. On the basis of targeted lipidomic analyses, we further identified gender-specific alterations of eight lipid classes in plasma following DEHP or DINP exposure. At the higher dose, DEHP induced decreases in total phosphatidylcholines and phosphatidylinositol (PI) in females and increases in phosphatidylethanolamines (PEs) and triglycerides in males. By contrast, DINP at the higher dose caused alterations of PEs, PIs, phosphatidylserines, and cholesterols exclusively in male mice, but no changes were observed in female pups. Although the most significant dysregulation of lipid metabolism was often observed for the higher dose, the lower one could also disrupt lipid profiles and sometimes its effects may even be more significant than those induced by the higher dose. Our study for the first time identified tissue- and gender-specific disruptions of FA compositions and lipidomic profiles in mice neonatally exposed to DINP. These findings question the suitability of DINP as a safe DEHP substitute and lay a solid foundation for further elucidation of its effects on lipid metabolism and underlying mechanisms.