Transplacental transport of per- and polyfluoroalkyl substances (PFAS): Mechanism exploration via BeWo cell monolayer model.

Per- and polyfluoroalkyl substances (PFAS) have received global concern on adverse effects on pregnancy outcomes. Although human studies have reported fetal exposure to PFAS, the underlying mechanisms driving transplacental transfer of PFAS have not been sufficiently understood. The present study aimed to investigate chemical-specific transplacental transfer of PFAS and potential mechanisms based on a BeWo cell monolayer model. The findings of concentration- and time-dependent transport, asymmetry in bidirectional transport, molecular docking and transporter inhibition experiments indicate that passive diffusion and membrane transporter-involved active transport could collectively determine transplacental transport of PFAS. Membrane transporters could play important roles in chemical-specific transport. The inhibition of OAT transporter resulted in promotion of trans-monolayer transport for most PFAS, while an opposite trend was observed when P-gp, BCRP and MRP transporters were prohibited. By contrast, inhibition of OCT resulted in inhibitory effects on the transport of some PFAS (i.e., PFHxA, PFHpA, PFOA, and PFNA), and promotive effects on the other substances (i.e., PFUdA, PFHpS, PFOS, 6:2 Cl-PFESA and PFOSA). Therefore, simultaneous involvement of diverse membrane transporters in utero could result in complicated influence on transplacental transport. Our work constitutes a solid ground for further exploration of the effects of gestational PFAS exposure on birth outcomes.

Large polystyrene microplastics results in hepatic lipotoxicity in mice.

Like small microplastics (MPs), recent studies reveal that large MPs could cause health risks in mice, even if they are not enriched in tissues. However, potential hepatoxicity following large MPs exposure and the underlying mechanisms have not been thoroughly investigated. In the present study, we explored the disruption of hepatic lipid metabolism and potential underlying toxic mechanisms in mice caused by long-term exposure to large polystyrene MPs (40-100 µm) based on a multi-omic approach. After 21 weeks of feeding foods containing MPs (50 and 500 mg/kg food), lipidomic revealed that environmentally relevant and higher doses MP exposures resulted in significant changes in a total of 20 lipid classes. Ceramide (Cer) and dihydroceramide (dhCer) were significantly reduced, while cholesteryl ester (CE), lysoalkylphosphatidylcholine (LPCO), lysophosphatidylethanolamine (LPE) and total glyceride (TG) were all elevated by MPs. The transcriptomic and other physiological data suggested that the potential toxic mechanisms may be related to disorders of fatty acid and cholesterol synthesis and metabolism disorders, and transporting of TG. Our findings demonstrate the hepatic lipotoxicity following exposure to environmentally relevant and higher doses of large MPs, calling for future research and management of the environmental risks of MPs with relatively large particle sizes.

Individual and joint effects of phthalates exposure on the risk of early miscarriage.

BACKGROUND: The exposure levels of phthalates in humans have dropped dramatically. Little is known about the individual and joint effects of phthalates exposure at low levels on the risk of early miscarriage. OBJECTIVE: To examine the association between exposure to phthalates individually or as a mixture and early miscarriage. METHODS: A case-control study was conducted in Shanghai, China during 2019-2020. A total of 291 women seeking medical services due to miscarriage (cases) and 308 women planning to terminate an unintended pregnancy (controls) within 12 gestational weeks were recruited. Urinary concentrations of eight phthalate metabolites were determined by ultra-performance liquid chromatography. We included 534 women in the main analysis who had available data on both phthalates exposure and complete information on potential confounders. We used logistic regression and Bayesian kernel machine regression (BKMR) to examine the associations of concentrations of phthalates with miscarriage. RESULTS: Among the phthalate metabolites, mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) had the highest concentration (8.10 ng/mL), followed by mono(2-ethyl-5-oxohexyl) phthalate (MEOHP, 2.68 ng/mL) and monobutyl phthalate (MBP, 2.24 ng/mL). Higher concentrations of MBP, mono(2-ethylhexyl) phthalate (MEHP), MEHHP, MEOHP and the molar sum of di(2-ethylhexyl) phthalate (DEHP) metabolites (∑DEHPm) were associated with an increased risk of miscarriage exhibiting a dose-response relationship. The most evident association of miscarriage was found with ∑DEHPm, with adjusted odds ratio (95% confidence interval) of 1.94 (1.14, 3.31) for the second quartile, 2.83 (1.67, 4.79) for the third quartile and 4.28 (2.49, 7.37) for the fourth quartile compared to the first quartile. Consistently, the phthalate mixture was positively associated with the risk of miscarriage and DEHP was the predominant contributor to the joint effect in BKMR model. IMPACT: Phthalates are a family of synthetic chemicals mainly used as plasticizers, solvents and additives in a large variety of industrial and consumer products, including food packing materials, toys, gloves, medical devices and personal care products. Although exposure levels of phthalates of pregnant women have declined sharply over the past few decades, phthalates exposure was still associated with an increased risk of early miscarriage. Our findings suggest that future researchers and policy makers might need to take low-dose effects of phthalates into account regarding the reproductive toxicity of phthalates exposure in humans. SIGNIFICANCE: Our findings contribute to the awareness of the reproductive toxic potential of phthalates at low levels in humans and support the ongoing efforts to further reduce exposure to phthalates.

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.

Gestational exposure to organophosphate esters and adiposity measures of children up to 6 years: Effect modification by breastfeeding.

Organophosphate esters (OPEs) are synthetic chemicals used in various commercial products. Accumulating evidence has shown that they may act as metabolic disruptors. However, no study has investigated the long-term effects of gestational OPEs exposure on childhood adiposity. Breast milk represents the optimal nutritional form of feeding for infants and may protect against the adverse effects of gestational OPEs exposure on offspring development. Using data from the Shanghai-Minhang birth cohort study, we investigated the associations of gestational OPEs exposure with adiposity measures in children up to 6 years of age, and whether breastfeeding could modify these associations. A total of 733 mother-child pairs with available data on OPE concentrations and child anthropometry were included. Eight OPE metabolites were assessed in maternal urine samples collected at 12-16 weeks of pregnancy. Information on children's weight, height, arm circumference, and waist circumference was collected at birth and 0.5, 1, 4, and 6 years of age. Weight-for-age and body mass index-for-age z scores were calculated. The duration of children's breastfeeding was categorized as ≤4 months or >4 months. The generalized estimate equation and Bayesian Kernel Machine Regression models were used to examine the associations of OPEs exposure with children's adiposity measures. Selected OPEs exposure was associated with higher children's adiposity measures. Particularly, we found stronger associations of bis(1-chloro-2-propyl) phosphate (BCIPP), bis(2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), and di-o-cresyl phosphate and di-p-cresyl phosphate (DCP) with higher adiposity measures in children breastfed for ≤4 months, while little evidence of associations was found among those breastfed for >4 months. Our study suggested that gestational OPEs exposure could alter children's adiposity measures, but the potential effects were attenuated if children were breastfed for >4 months.

Prenatal exposure to organophosphate esters is associated with decreased anogenital distance in offspring.

BACKGROUND: Evidence from in vitro and rodent studies suggests that organophosphate esters (OPEs) may disrupt sex steroid hormone homeostasis, but no human studies, to date, have examined the effects of in utero exposure to OPEs on offspring reproductive development. OBJECTIVE: Anogenital distance (AGD) is a sensitive biomarker of fetal hormonal milieu and has been used to assess reproductive toxicity. We evaluated the longitudinal effects of prenatal exposure to OPEs on the AGD of offspring from birth to 4 years. METHODS: Based on Shanghai-Minhang Birth Cohort Study, pregnant women provided urine samples at a gestational age of 12-16 weeks, which were analyzed for eight OPE metabolites. AGD was measured in offspring at birth and 0.5, 1, and 4 years of age. We used generalized estimating equations (GEE) and Bayesian kernel machine regression (BKMR) models to estimate the associations of prenatal exposure to individual OPE metabolites and OPE mixtures with AGD stratified by sex. RESULTS: A total of 733 mother-infant pairs were analyzed. Prenatal exposure to diphenyl phosphate and bis-(2-ethylhexyl) phosphate was associated with decreased AGD in boys in GEE models. Bis-(1-chloro-2-propyl) phosphate (BCIPP) showed a similar but marginally significant effect. Prenatal exposure to most OPE metabolites was associated with decreased AGD in girls, with the most profound association observed for bis (2-butoxyethyl) phosphate (BBOEP) and alkyl-OPEs. The OPE mixture was also inversely associated with AGD in both sexes. The single-exposure effects of BKMR models were largely consistent with those observed in the GEE models. In addition, alkyl-OPEs, particularly BBOEP, contributed the most to the decreased AGD in girls, while BCIPP contributed the most to the decreased AGD in boys. CONCLUSIONS: This study provides the first human evidence that prenatal exposure to OPEs is associated with decreased AGD in offspring. The magnitude of these effects may vary depending on the structure of OPEs.

Long-Term Exposure to Environmentally Relevant Doses of Large Polystyrene Microplastics Disturbs Lipid Homeostasis via Bowel Function Interference.

The question of whether long-term chronic exposure to microplastics (MPs) could induce dose- and size-dependent adverse effects in mammals remains controversial and poorly understood. Our study explored potential health risks from dietary exposure to environmentally relevant doses of polystyrene (PS) MPs, through a mouse model and integrated analyses of the interruptions of fecal microbial metagenomes and plasma lipidomes. After 21 weeks of exposure to the MPs (40-100 µm), mice mainly exhibited gut microbiota dysbiosis, tissue inflammation, and plasma lipid metabolism disorder, although no notable accumulation of MPs was observed in the gut or liver. The change of the relative abundance of microbiota was strongly associated with the exposure dose and size of MPs while less significant effects were observed in gut damage and abnormal lipid metabolism. Moreover, multiomics data suggested that the host abnormal lipid metabolism was closely related to bowel function disruptions, including gut microbiota dysbiosis, increased gut permeability, and inflammation induced by MPs. We revealed for the first time that even without notable accumulation in mouse tissues, long-term exposure to MPs at environmentally relevant doses could still induce widespread health risks. This raises concern on the health risks from the exposure of humans and other mammals to environmentally relevant dose MPs.

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.

Exposure to bisphenol analogues interrupts growth, proliferation, and fatty acid compositions of protozoa Tetrahymena thermophila.

A number of bisphenol A (BPA) analogues are increasingly used as its industrial alternatives. However, their effects on aquatic organisms at both individual and population levels have not been well understood. In this study, effects of five bisphenol analogues (i.e., BPA, BPAF, BPB, BPE and BPS) were investigated by using the unicellular eukaryote Tetrahymena thermophila as a model organism. All of them inhibited individual growth and population proliferation at a concentration of 2.6 µM or 13.0 µM during the 60-h exposure period, with the population suppression capacify ranked as: BPB > BPA ≈ BPAF > BPE > BPS. These analogues also exhibited chemical-specific disruption of fatty acid profiles in single-cell eukaryotes and the transcriptional levels of enzymes involved in fatty acid metabolism/biosynthesis. For example, exposure to BPA and BPE significantly increased the ratio of saturated fatty acids to unsaturated fatty acids, contrary to the desaturation effects exhibited by BPAF and BPB. Overall, our results clearly indicated that these bisphenol analogues could pose chemical-specific effects on low-trophic level aquatic organisms, particularly disruption of endogenous metabolic balances. Selected analogues (i.e., BPB and BPAF) could result in effects similar to or even greater than that of BPA.

Comparative analysis of surface water quality prediction performance and identification of key water parameters using different machine learning models based on big data.

The water quality prediction performance of machine learning models may be not only dependent on the models, but also dependent on the parameters in data set chosen for training the learning models. Moreover, the key water parameters should also be identified by the learning models, in order to further reduce prediction costs and improve prediction efficiency. Here we endeavored for the first time to compare the water quality prediction performance of 10 learning models (7 traditional and 3 ensemble models) using big data (33,612 observations) from the major rivers and lakes in China from 2012 to 2018, based on the precision, recall, F1-score, weighted F1-score, and explore the potential key water parameters for future model prediction. Our results showed that the bigger data could improve the performance of learning models in prediction of water quality. Compared to other 7 models, decision tree (DT), random forest (RF) and deep cascade forest (DCF) trained by data sets of pH, DO, CODMn, and NH3-N had significantly better performance in prediction of all 6 Levels of water quality recommended by Chinese government. Moreover, two key water parameter sets (DO, CODMn, and NH3-N; CODMn, and NH3-N) were identified and validated by DT, RF and DCF to be high specificities for perdition water quality. Therefore, DT, RF and DCF with selected key water parameters could be prioritized for future water quality monitoring and providing timely water quality warning.

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.