Gender associations between phthalate exposure and biomarkers of oxidative stress: A prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p < .05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children.

The effect of phthalates exposure during pregnancy on asthma in infants aged 0 to 36 months: a birth cohort study.

This cohort study sought to investigate the effects of phthalates exposure during pregnancy on offspring asthma and its association with placental stress and inflammatory factor mRNA expression levels. A total of 3474 pregnant women from the China Ma'anshan birth cohort participated in this study. Seven phthalate metabolites were detected in urine samples during pregnancy by solid phase extraction-high-performance liquid chromatography tandem mass spectrometry. Placenta stress and inflammation mRNA expression were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Early pregnancy may be the critical period when phthalates exposure increases the risk of asthma in infants and young children, and there is a certain gender difference in the risk of asthma in infants and young children. Moreover, through the placenta stress and inflammatory factor associated with infant asthma found anti-inflammatory factor of interleukin-10 (IL-10) mRNA expression will reduce the risk of 36-month-old male infant asthma. The expression of interleukin-4(IL-4) and macrophage (M2) biomarker cluster of differentiation 206(CD206) mRNA reduced the risk of asthma in 18-month-old female infants. Placental stress and inflammatory response were analyzed using mediating effects. Tumor necrosis factor-α (TNFα) showed a complete mediating effect between mono-benzyl phthalate (MBzP) exposure in early pregnancy and asthma in 12-month-old males, and IL-10 also showed a complete mediating effect between mono-n-butyl phthalate (MBP) exposure in early and late pregnancy and asthma in 36-month-old males. In summary, exposure to phthalates during pregnancy may contribute to the development of asthma in infants, which may be associated with placental stress and inflammation.

Bmal1 inhibits phenotypic transformation of hepatic stellate cells in liver fibrosis via IDH1/α-KG-mediated glycolysis.

Hepatic stellate cells (HSCs) play an important role in the initiation and development of liver fibrogenesis, and abnormal glucose metabolism is increasingly being considered a crucial factor controlling phenotypic transformation in HSCs. However, the role of the factors affecting glycolysis in HSCs in the experimental models of liver fibrosis has not been completely elucidated. In this study, we showed that glycolysis was significantly enhanced, while the expression of brain and muscle arnt-like protein-1 (Bmal1) was downregulated in fibrotic liver tissues of mice, primary HSCs, and transforming growth factor-ß1 (TGF-ß1)-induced LX2 cells. Overexpression of Bmal1 in TGF-ß1-induced LX2 cells blocked glycolysis and inhibited the proliferation and phenotypic transformation of activated HSCs. We further confirmed the protective effect of Bmal1 in liver fibrosis by overexpressing Bmal1 from hepatic adeno-associated virus 8 in mice. In addition, we also showed that the regulation of glycolysis by Bmal1 is mediated by the isocitrate dehydrogenase 1/α-ketoglutarate (IDH1/α-KG) pathway. Collectively, our results indicated that a novel Bmal1-IDH1/α-KG axis may be involved in regulating glycolysis of activated HSCs and might hence be used as a therapeutic target for alleviating liver fibrosis.

Aluminum and magnesium status during pregnancy and placenta oxidative stress and inflammatory mRNA expression: China Ma'anshan birth cohort study.

The aim of this study was to explore the impact of prenatal Al and Mg on placental oxidative stress and inflammatory mRNA expression. A total of 2519 pregnant women from the China Ma'anshan birth cohort participated in this study. Al and Mg levels were measured by inductively coupled plasma mass spectrometry (ICP-MS). Placental stress and inflammatory mRNA expression were assessed by RT-PCR. The median Al levels in the first and second trimesters of pregnancy and in cord blood were higher than the corresponding median Mg levels. Predictors of lower Al and Mg levels included Han ethnicity and high education according to a mixed linear model. Multiple linear regression analysis revealed that Al and Al/Mg levels had a positive association with inflammatory mRNA expression and placental oxidative stress in the second trimester of pregnancy. A negative association existed between Al and Al/Mg levels and inflammatory mRNA expression and placenta oxidative stress in the cord blood, with the exception of IL-1ß expression. In conclusion, prenatal Al and Mg status was associated with placental oxidative stress and inflammatory mRNA expression. More preclinical studies are needed to confirm the relevant mechanism.

Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation.

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl4)-induced acute liver injury. Mice were intraperitoneally injected with CCl4 (0.15ml/kg). In CCl4+OCA group, mice were orally with OCA (5mg/kg) 48, 24 and 1h before CCl4. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl4-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl4-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl4-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl4-induced hepatic pro-inflammatory gene Tnf-α and Il-1ß. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl4-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl4-induced acute liver injury. These results suggest that OCA protects against CCl4-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury.

[Multivariate factors analysis on length of stay in Lushan earthquake victims].

OBJECTIVE: To clarify the factors associate with the length of stay (LOS) in Lushan Earthquake victims. METHODS: We retrospectively analyzed the medical information of 263 traumatic patients admitted to West China Hospital, Sichuan University after the Lushan Earthquake. Ten variables extracted for the analysis, including gender, age, injuried time, multiple injury, infection, comorbidities, Injury Severity Score (ISS), Revised Trauma Score (RTS) CRAMS score, and Prehospital Index (PHI). Univariable analysis using multiple stepwise regression analysis was performed to identify the factors associated with extended LOS. RESULTS: Infection, ISS score, and Pre-hospital Time were associated with extended LOS, and infection was the most weighted factor. The regression equation is: LOS (h) = 498.36 + 671.41 x Infection + 43.87 x ISS score - 5.12 x Pre-hospital Time. CONCLUSION: This study demonstrated that trauma patients with infections and high ISS scores were at increased risk for extended LOS and pre-hospital time decreased the risk.

Effects of stand ages on soil enzyme activities in Chinese fir plantations and natural secondary forests.

Forest type and stand age are important biological factors affecting soil enzyme activities. However, the changes in soil enzyme activities across stand ages and underlying mechanisms under the two forest restoration strate-gies of plantations and natural secondary forests remain elusive. In this study, we investigated the variations of four soil enzyme activities including cello-biohydrolase (CBH), ß-1,4-glucosidase (ßG), acid phosphatase (AP) and ß-1,4-N-acetylglucosaminidase (NAG), which were closely associated with soil carbon, nitrogen, and phosphorus cycling, across Cunninghamia lanceolata plantations and natural secondary forests (5, 8, 21, 27 and 40 years old). The results showed that soil enzyme activities showed different patterns across different forest types. The acti-vities of AP, ßG and CBH in the C. lanceolata plantations were significantly higher than those in the natural secon-dary forests, and there was no significant difference in the NAG activity. In the plantations, AP activity showed a decreasing tendency with the increasing stand ages, with the AP activity in the 5-year-old plantations significantly higher than other stand ages by more than 62.3%. The activities of NAG and CBH decreased first and then increased, and ßG enzyme activity fluctuated with the increasing stand age. In the natural secondary forests, NAG enzyme activity fluctuated with the increasing stand age, with that in the 8-year-old and 27-year-old stand ages being significantly higher than the other stand ages by more than 14.9%. ßG and CBH enzyme activities increased first and then decreased, and no significant difference was observed in the AP activity. Results of the stepwise regression analyses showed that soil predictors explained more than 34% of the variation in the best-fitting models predicting soil enzyme activities in the C. lanceolata plantations and natural secondary forests. In conclusion, there would be a risk of soil fertility degradation C. lanceolata plantations with the increasing stand age, while natural secondary forests were more conducive to maintaining soil fertility.

Phenylbutyric acid protects against carbon tetrachloride-induced hepatic fibrogenesis in mice.

A recent report showed that the unfolded protein response (UPR) signaling was activated in the pathogenesis of carbon tetrachloride (CCl(4))-induced hepatic fibrosis. Phenylbutyric acid (PBA) is a well-known chemical chaperone that inhibits endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling. In the present study, we investigated the effects of PBA on CCl(4)-induced hepatic fibrosis in mice. All mice were intraperitoneally (i.p.) injected with CCl(4) (0.15 ml/kg BW, twice per week) for 8 weeks. In CCl(4)+PBA group, mice were i.p. injected with PBA (150 mg/kg, twice per day) from the beginning of CCl(4) injection to the end. As expected, PBA significantly attenuated CCl(4)-induced hepatic ER stress and UPR activation. Although PBA alleviated, only to a less extent, hepatic necrosis, it obviously inhibited CCl(4)-induced tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-ß). Moreover, PBA inhibited CCl(4)-induced hepatic nuclear factor kappa B (NF-κB) p65 translocation and extracellular signal-regulated kinase (ERK) and c-Jun N-terminal Kinase (JNK) phosphorylation. Interestingly, CCl(4)-induced α-smooth muscle actin (α-SMA), a marker for the initiation phase of HSC activation, was significantly attenuated in mice pretreated with PBA. Correspondingly, CCl(4)-induced hepatic collagen (Col)1α1 and Col1α2, markers for the perpetuation phase of HSC activation, were inhibited in PBA-treated mice. Importantly, CCl(4)-induced hepatic fibrosis, as determined using Sirius red staining, was obviously attenuated by PBA. In conclusion, PBA prevents CCl(4)-induced hepatic fibrosis through inhibiting hepatic inflammatory response and HSC activation.

Effects of common afforestation tree species on soil bacterial community and microbial functional guilds in subtropical forests.

To understand the effects of common afforestation tree species on soil microbial community in subtropical forests, seven different tree species were selected as the research object, including Pinus massoniana, Mytilaria laosensis, Liquidambar formosana, Ilex chinensis, Michelia macclurei, Quercus acutissima and Betula luminifera. Based on 16S rRNA high-throughput sequencing and real-time quantitative PCR techniques, we explored the effects of different tree species on soil bacterial community composition, diversity and microbial functional guilds. The results showed that Acidobacteria, Proteobacteria, and Actinobacteria were the dominant bacterial phyla, and that there was no significant difference in bacterial diversity or richness index among different tree species. Results of redundancy analysis suggested that soil bulk density, soil C/N, litter nitrogen content, and litter C/N were the predominant factors determining soil bacterial community composition. The afforestation tree species had significant effects on functional gene abundances of ammonia oxidizing archaea, ammonia oxidizing bacteria and complete ammonia oxidation. Comammox were dominant in abundance. Ammonia oxidizing archaea amoA gene was the only type whose abundance showed significant correlation with soil nitrate content, suggesting that ammonia oxidizing archaea could play a dominant role in the autotrophic nitrification in the acidic subtropical forest soils. The afforestation tree species had significant effects on functional gene abundances of ammonia oxidizing microorganisms. Results of correlation analysis showed that litter nitrogen content was the driving factor for the abundance of ammonia oxidizing microorganisms. Our study provided strong evidence that the responses of soil microbial functional guilds to tree species were more sensitive than bacterial community composition. Future studies should explore the mechanisms of tree plantations on forest ecosystem functioning from the perspective of microbial functional guilds.

Effects of elevated carbon dioxide (CO2)and ozone (O3)concentrations on ectoenzyme activities in rice rhizospheric soil.

Rising atmospheric carbon dioxide (CO2) and ozone (O3) concentrations are the main global change drivers. Soil ectoenzymes play an important role in maintaining soil ecosystem services. Exploring the responses of soil ectoenzymes to elevated CO2 and O3 concentrations is important for combating global climate change. In this study, we simulated elevated CO2 concentrations (+200 µmol·mol-1, eCO2), elevated O3 concentrations (0.04 µmol·mol-1, eO3), and their combination (eCO2+eO3) in open-top chambers (OTCs), and investigated the responses of rhizospheric soil ectoenzyme activities. The results showed that eCO2 significantly increased the ß-D-Glucosidase (ßG) activity by 73.0%, and decreased that of polyphenol oxidase (PHO), peroxidase (PEO), and acid phosphatase (AP) by 48.9%, 46.6% and 72.9% respectively, but did not affect that of cellulose hydrolase (CBH) and ß-N-Acetylglucosaminidase (NAG). eO3 significantly reduced the activities of CBH and AP by 34.2% and 30.4%, respectively. The activities of PHO and AP were reduced by 87.3% and 32.3% under the eCO2+eO3 compared with the control, respectively. Results of the principal coordinate analysis, permutation multivariate analysis of variance and redundancy analysis showed that both elevated CO2 and O3 significantly affected soil ectoenzyme activities, with stronger effects of elevated CO2 than elevated O3. Root nitrogen content, root carbon to nitrogen ratio, soil microbial biomass carbon and nitrate nitrogen were the main drivers of soil ectoenzyme activities under elevated CO2 and O3. Elevated O3 could partially neutralize the effects of elevated CO2 on soil ectoenzyme activities. In conclusion, elevated CO2 and O3 restrained the activities of most soil ectoenzyme, suggesting that climate change would threat soil ecosystem services and functions in the agroecosystem.

Combined effects of prenatal phthalate exposure on cardiometabolic risk score among 4- to 7-year-old children: MABC study.

There is currently no consensus about the impact of prenatal phthalate exposure on blood pressure and glycolipids in children. Few studies consider the health effects as an integrated indicator. The combined effect of multiple phthalate exposures is often ignored. Based on the Ma'anshan Birth Cohort, 2298 woman-child pairs were included in this study. Maternal urine was collected in each trimester to analyze 6 phthalate metabolites. The overall cardiometabolic risk (CMR) score was calculated based on serum glycolipids and blood pressure for children aged 4-7 years. A higher score represents a less favorable CMR profile. The restricted cubic spline model was used to explore the relationship between prenatal phthalate exposure and childhood CMR score. In addition, the quantile g-computation and the Bayesian kernel machine regression were used to evaluate the combined effect. The MBP exposure in the 1st trimester (MBP-1st) and the MEP-2nd were non-linearly associated with the CMR score (Fnonlinear = 3.28 and 5.60, Pnonlinear = 0.0378 and 0.0038, respectively). The MBP-3rd (Flinear = 5.31, Plinear = 0.0012) and the ∑LMWP-3rd (Flinear = 4.37, Plinear = 0.0045) were negatively associated with the score in a linear manner. The phthalate mixture in the 2nd trimester increased the score (psil = 0.1747, 95% CI = 0.0077-0.3416), with the MEP being the most common [weights = 0.5290; posterior inclusion probability (PIP) = 0.40]. The phthalate mixture in the 3rd trimester decreased the score (psil = -0.2024, 95% CI = -0.4097－0.0048), with the MEHP (weights = -0.5101; PIP = 0.14) and the MBP (weights = -0.3993, PIP = 1.00) being the greatest contributors. In conclusion, the MBP-1st and the MEP-2nd are non-linearly associated with the cardiometabolic risk in children. The MBP-3rd and the ∑LMWP-3rd decrease the childhood risk. The combined exposure to phthalate mixture in the second and third trimester elevates and decreases the risk of childhood cardiometabolism, respectively.

Protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats.

AIM: To study the protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats. METHODS: Male Sprague-Dawley rats were given a high-fat diet for 10 weeks. The rats were administered tiopronin (20 mg/kg) or a positive control drug ursodeoxycholic acid (UDCA, 15 mg/kg) via gavage daily from week 5 to week 10. After the rats were sacrificed, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), free fatty acids (FFA), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C), and liver homogenate FFA, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured using commercial analysis kits. The expression levels of CYP2E1 mRNA and protein were determined using RT-PCR and immunoblot assays, respectively. RESULTS: Tiopronin significantly lowered both the serum ALT and AST levels, while only the serum ALT level was lowered by UDCA. Tiopronin significantly decreased the serum and liver levels of TG, TC and FFA as well as the serum LDL-C level, and increased the serum HDL-C level, while UDCA decreased the serum and liver TC levels as well as the serum LDL-C level, but did not change the serum levels of TG, FFA and HDL-C. Tiopronin apparently ameliorated the hepatocyte degeneration and the infiltration of inflammatory cells in the livers, but UDCA did not affect the pathological features of the livers. Both tiopronin and UDCA ameliorated the mitochondrial abnormality in the livers. The benefits of tiopronin were associated with increased SOD and GSH-Px activities, and with decreased MDA activity and CYP2E1 expression in the livers. CONCLUSION: Tiopronin exerts protective effects against non-alcoholic steatohepatitis in rats, which may be associated with its antioxidant properties and regulation of lipid metabolism.

Phthalate exposure and lung disease: the epidemiological evidences, plausible mechanism and advocacy of interventions.

Phthalates are a kind of synthetic plasticizers, which extensively used as plastic productions to improve their plasticity and flexibility. However, exposure to phthalates has been proved an increased risk of respiratory disease, because by they affect the development and functions of the lung and immune system. Here, we attempt to review respiratory health of phthalate exposure. Firstly, we describe the relationship between phthalates and lung function and airway inflammation. Then, the role of phthalates in asthma, lung cancer, rhinitis, and respiratory tract infections and the possible mechanisms of action are discussed. Finally, possible effective measures to reduce exposure to phthalates are proposed, and health care workers are called upon to provide educational resources and advocate for informed public health policies. Overall, the evidence for association between phthalate exposure and respiratory disease is weak and inconsistent. Therefore, thorough implementation in large populations is needed to produce more consistent and robust results and to enhance the overall understanding of the potential respiratory health risks of phthalate in long-term exposure.

Mediation Effects of Placental Inflammatory Transcriptional Biomarkers on the Sex-Dependent Associations between Maternal Phthalate Exposure and Infant Allergic Rhinitis: A Population-Based Cohort Study.

Objective: Prenatal phthalate exposure has been associated with placental inflammatory factors and infant allergic rhinitis (AR). However, the results are inconclusive. We designed a population-based cohort study to examine the effects of placental inflammatory biomarkers on the sex-dependent associations between maternal phthalate exposure and infant AR. Methods: A total of 2,348 pregnant women from Ma'anshan, Anhui Province, China, who were screened before antenatal visits and met the inclusion criteria, were included in the present study. We assessed AR in their offspring aged 36 months with a questionnaire. Quantitative PCR was performed to measure placental inflammatory factor mRNAs. The independent samples t-test and multivariable logistic regression were used to determine the associations between infant AR and maternal phthalates. Results: Childhood AR may be related to education and family monthly income ( P = 0.01). The phthalate metabolites, mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyl) phthalate (MEHHP), in pregnant women were associated with a significantly increased risk for infant AR in males [ P < 0.05; odds ratio ( OR): 1.285; 95% confidence interval ( CI): 1.037-1.591, and OR: 1.232, 95% CI: 1.008-1.507, respectively], but not females. Additionally, irritably-increased expression levels of HO-1 and IL-4 were associated with AR in male infants ( OR: 1.175; 95% CI: 1.038-1.329 and OR: 1.181; 95% CI: 1.056-1.322, respectively). The association between maternal urinary MEHHP and placental HO-1 was marginally significant according to mediation analysis. Conclusion: The associations of maternal MEHHP and MEOHP levels with fetal AR in males were significant. Placental HO-1 was a fractional mediator in the associations between MEHHP and AR. Thus, the placenta should be further investigated as a potential mediator of maternal exposure-induced disease risk in children.

10-Ethyl-10H-phenothia-zine-3-carbaldehyde.

In the title mol-ecule, C(15)H(13)NOS, the two benzene rings of the tricyclic fused-ring system are inclined at 21.1 (1)°. In the crystal, weak C-H⋯O hydrogen bonds link the mol-ecules into chains along [001]. The crystal packing also exhibits π-π inter-actions with a distance of 3.801 (5) Šbetween the centroids of the benzene rings of neighbouring mol-ecules.

Research mechanisms of and pharmaceutical treatments for ferroptosis in liver diseases.

Regulated cell death (RCD) is a universal process in living organisms that is essential for tissue homeostasis or to the restoration of biological equilibrium following stress. Ferroptosis is a specific nonapoptotic cell death that is dependent on iron and is very different from other forms of RCD. Ferroptosis can affect the development of liver diseases such as drug-induced liver injury (DILI), liver fibrosis, and hepatocellular carcinoma (HCC) by regulating the level of intracellular iron, the production of intracellular reactive oxygen species, and lipid peroxides. In this review, we summarize the current knowledge of ferroptosis, in terms of discovery, history, characteristics, mechanism, and the factors regulating liver diseases. We discuss how these factors and signaling pathways change in the context of liver disease. Furthermore, we focus on delineating the roles of effective therapeutic drugs or compounds in liver disease. In summary, we discuss the role of ferroptosis in liver disease, providing a strategy and new ideas for preventing liver disease, finding new therapeutic targets, and reducing liver damage.

Adverse pregnancy outcomes for women with endometriosis: a systematic review and meta-analysis.

OBJECTIVES: This study aimed at assessing the adverse outcomes of pregnancy in women with endometriosis. MATERIAL AND METHODS: The Cochrane, Embase and PubMed databases were searched for identifying the required studies published before June 2019. Meta-analyses of relative risk (RR) were performed under the random-effects model to estimate the risk of selected adverse outcomes of pregnancy in females with endometriosis. RESULTS: Twenty-eight studies (53,141 women with and 2,355,923 women without endometriosis data) were selected for meta-analysis. Endometriosis bearing females had a significantly higher risk placenta previa (RR 3.92 [95% CI 2.48-6.20]), miscarriage (RR 1.31 [95% CI 1.06-1.61), gestational hypertension (RR 1.30 [95% CI 1.02-1.65]), cesarean section (RR 1.48 [95% CI 1.33-1.65]) and preeclampsia (RR 1.18 [95% CI 1.09-1.28]). The incidence of placental abruption was not statistically significant between the groups (RR 3.62 [95% CI [0.99-13.28]). CONCLUSIONS: Women suffering from endometriosis are at higher risks of miscarriage, preterm birth, gestational hypertension, placenta previa, cesarean section, and preeclampsia.

Urinary concentrations of phthalate metabolites during gestation and intrahepatic cholestasis of pregnancy: a population-based birth cohort study.

Phthalates, a class of widely used endocrine-disrupting chemicals (EDCs), are toxic to various organ systems in animals and humans. Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver dysfunction causing cholestasis in late pregnancy. Evidence on the associations between exposure to phthalates and ICP is still lacking. In the present study, we investigated the relationships between urinary concentrations of phthalate metabolites and the risk of ICP in a Chinese population-based birth cohort. Pregnant women participated in the Ma'anshan Birth Cohort (MABC) study in China. Seven phthalate metabolites were detected in a urine sample in early pregnancy. Chemical concentrations were grouped by quartiles, and associations with outcomes were examined using logistic regression with adjustment for urine creatinine, race, education, poverty status, smoking status, alcohol consumption, maternal age, prepregnancy body mass index (BMI), parity, twin pregnancy, and pregnancy-related liver complications. Of 3474 women recruited into the Ma'anshan Birth Cohort, 2760 met the inclusion criteria and contributed to further analysis and biomonitoring data. Elevated odds ratios (ORs) of ICP were observed in the highest quartiles of monomethyl phthalate (MMP) exposure (OR = 1.59, 95% confidence intervals (CI) = 1.01-2.51) and monobutyl phthalate (MBP) exposure (OR = 1.82, 95% CI = 1.16-2.85) in the adjusted analyses. Our findings add to the evidence that supports the role of maternal phthalate exposure in the first trimester of gestation as a risk factor for ICP.

The protective effect of obeticholic acid on lipopolysaccharide-induced disorder of maternal bile acid metabolism in pregnant mice.

The disorder of bile acid metabolism is a common feature during pregnancy, which leads to adverse birth outcomes and maternal damage effects. However, the cause and therapy about the disorder of bile acid metabolism are still poor. Microbial infection often occurs in pregnant women, which can induce the disorder of bile acid metabolism in adult mice. Here, this study observed the acute effect of lipopolysaccharide (LPS) on maternal bile acid of pregnant mice at gestational day 17 and the protective effect of obeticholic acid (OCA) pretreatment, a potent agonist of bile acid receptor farnesoid X receptor (FXR). The results showed LPS significantly increased the level of maternal serum and disordered bile acids components of maternal serum and liver, which were ameliorated by OCA pretreatment with obviously reducing the contents of CA, TCA, DCA, TCDCA, CDCA, GCA and TDCA in maternal serum and DCA, TCA, TDCA, TUDCA, CDCA and TCDCA in maternal liver. Furthermore, we investigated the effects of OCA on LPS-disrupted bile acid metabolism in maternal liver. LPS disrupted maternal bile acid profile by decreasing transport and metabolism with hepatic tight junctions of bile acid in pregnant mice. OCA obviously increased the protein level of nuclear FXR and regulated its target genes involving in the metabolism of bile acid, which was characterized by the lower expression of bile acid synthase CYP7A1, the higher expression of CYP3A and the higher mRNA level of transporter Mdr1a/b. This study provided the evidences that LPS disrupted bile acid metabolism in the late stage of pregnant mice and OCA pretreatment played the protective role on it by activating FXR.