Gestational exposure to ambient fine particulate matter disrupts maternal hepatic lipid metabolism.

Pregnancy is a unique physiological stage for females as well as a vulnerable period for pollutant exposure. The effect of gestational ambient fine particulate matter (PM2.5) exposure on maternal lipid metabolism during pregnancy is rarely observed, and the mechanism is unknown. In the current study, pregnant C57BL/6 mice were randomly assigned to either ambient PM2.5 or filtered air exposure chambers since gestational day (GD) 0. Meanwhile, non-pregnant female mice were housed as controls in each exposure chamber. PM2.5 exposure exerted no significant effect on body weight gain or the body composition during pregnancy. Pregnant mice exposed to PM2.5 demonstrated improved glucose tolerance, whereas non-pregnant mice showed an increased fasting blood glucose level after PM2.5 exposure with no alterations in glucose tolerance. PM2.5 exposure exerted no significant effect on total lipid content in serum during pregnancy, while an increased serum total lipid level was found in non-pregnant mice exposed to PM2.5. PM2.5 exposure had no effect on total liver lipid levels, it increased several triacylglycerol (TAG) species and total cholesterol esters (CEs) in pregnant mice but lowered a considerable amount in non-pregnant mice' livers. Furthermore, gestational exposure to PM2.5 enhanced the expression of key enzymes in fatty acid uptake, de novo lipid synthesis, and ß oxidation, and inhibited molecules for lipid export in mice liver. Conversely, PM2.5 exposure upregulated proteins involved in hepatic lipolysis and lipid export in non-pregnant mice. These results suggest that the interference of PM2.5 exposure during pregnancy on the lipid metabolism, particularly the hepatic lipid metabolism, differs from that during non-pregnancy. This study provides toxicological evidence that PM2.5 exposure during pregnancy disrupts the lipid metabolism of the liver and provides a basis for protecting vulnerable populations.

Sex difference in effects of intermittent heat exposure on hepatic lipid and glucose metabolisms.

Global climate warming has drawn worldwide attention. However, the health impact of heat exposure is still controversial. This study aimed to explore the exact effects and sex differential vulnerability under intermittent heat exposure (IHE) patterns and tried to elucidate the potential mechanisms by which IHE modulated hepatic lipid and glucose homeostasis. Both female and male C57BL/6 N mice were randomly allocated to control group (22 ± 1 °C) or intermittent heat group (37 ± 1 °C for 6 h) for 9 consecutive days followed by 4-day recovery at 22 ± 1 °C in a whole-body exposure chamber. Male mice, but not female, being influenced by IHE with decreased body weight, improved insulin sensitivity and glucose tolerance. Next, the levels of hepatic triglyceride (TG) were decreased and free fatty acid (FFA) increased in male mice exposed to intermittent heat, accompanied with upregulated expression of anti-oxidative enzymes in the liver. In addition, IHE led to enhanced lipid catabolism in male mice by inducing fatty acid uptake, lipid lipolysis, mitochondrial/peroxisomal fatty acid oxidation and lipid export. And glycolysis and glucose utilization were induced by IHE in male mice as well. Mechanically, heat shock protein 70 (HSP70)/insulin receptor substrate 1 (IRS1)/AMPKα pathways were activated in response to IHE. These findings provide new evidence that IHE sex-dependently enhanced the metabolism of lipid and glucose in male mice through HSP70/IRS1/AMPKα signaling.

Lipidomics and transcriptomics insight into impacts of microplastics exposure on hepatic lipid metabolism in mice.

Microplastics (MPs), the emerging environmental pollutants, have attracted global attention due to the potential public health challenge and ecological security risk. Recent studies suggested liver as a vulnerable organ to MPs exposure, evidenced by abnormal hepatic lipid metabolism upon MPs intake in multiple animal species. However, the specific changes of lipid metabolism in mammalian livers, as well as the underlying mechanisms, remain to be elucidated. In the present study, C57BL/6 mice were randomly assigned to normal drinking water or drinking water containing 100 µg L-1 or 1000 µg L-1 polystyrene (PS) MPs for 8 weeks. MPs exposure exerted no significant effect on body weight, serum triglyceride or total cholesteryl esters. However, mice showed impaired glucose tolerance and hepatic lipid deposition in response to high-dose MPs administration. Further lipidomic analysis showed significant alteration in hepatic lipid species particularly with free fatty acids (FFAs) and triacylglycerols (TAGs) in mice exposed to MPs. Meanwhile, the liver transcriptional profile indicated MPs exposure-induced differentially expressed genes (DEGs) were enriched in pathways of lipid metabolism and unfolded protein response. Furthermore, most altered lipid species were significantly correlated with DEGs enriched in lipid metabolic signaling. These findings provide lipidomic and transcriptional signatures of liver in response to MPs exposure, which will shed light on further understanding of the metabolic toxicity of MPs.

Ambient fine particulate matter exposure disrupts placental autophagy and fetal development in gestational mice.

Recent studies have shown that some adverse pregnancy outcomes, especially intrauterine growth restriction (IUGR), are associated with gestational exposure to ambient fine particulate matter (PM2.5). However, potential mechanism remains to be elucidated. In the present study, pregnant C57BL/6 mice were randomly assigned to be exposed to either filtered air or ambient PM2.5 in the gestation period via a concentrated whole-body exposure system. We found that gestational PM2.5 exposure exerted no effect on implantation, preterm delivery, as well as fetal resorption and death. However, in utero fetal exposure to PM2.5 showed a significant reduction in body weight and crown-rump length on GD13 and GD18. Meanwhile, maternal blood sinusoid in placenta was markedly reduced along with abnormal expression of placental nutrient transporters and growth hormone in dams exposed to PM2.5. Additional tests showed gestational PM2.5 exposure decreased autophagy-related protein levels and inhibited autophagy flux mainly on GD15. Correspondingly, AMPK/mTOR signaling pathway, a critical negative regulator of autophagy, was activated in placenta on GD15 by PM2.5 exposure as well. These findings provide evidences that placental developmental disorder caused by autophagy inhibition might be an important mechanism for the growth restriction caused by PM2.5 exposure.

Effect of GEN1 interference on the chemosensitivity of the breast cancer MCF-7 and SKBR3 cell lines.

Chemotherapy is a notable method for the treatment of breast cancer. Numerous genes associated with the sensitivity of cancer to chemotherapy have been found. In recent years, evidence has suggested that a particular structure termed Holliday junction (HJ) plays a crucial role in cancer chemosensitivity. Targeting HJ resolvases, such as structure-specific endonuclease subunit SLX4 (Slx4) and MUS81 structure-specific endonuclease subunit (Mus81), significantly increases the chemosensitivity of tumor cells. Flap endonuclease GEN homolog 1 (GEN1) is a HJ resolvase that belongs to the Rad2/xeroderma pigmentosum complementation group G nuclease family. Whether GEN1 affects the chemosensitivity of tumor cells in a similar manner to Slx4 and Mus81 remains unknown. The aim of the present study was to determine the effect of GEN1 interference on the chemosensitivity of breast cancer cell lines. The investigation of the function of GEN1 was performed using MCF-7 and SKBR3 cells. Short hairpin RNA was used to suppress the expression of GEN1, and western blot analysis and reverse transcription-quantitative polymerase chain reaction were used to detect gene expression. In addition, a cell counting kit-8 assay was performed to detect the viability of cells and flow cytometry was performed to test apoptosis levels. Suppression of GEN1 in SKBR3 cells effectively increased the sensitivity to the chemotherapeutic drug 5-fluorouracil (5-FU), while MCF-7 cells showed no significant change in sensitivity following GEN1 suppression. However, when GEN1 was targeted in addition to Mus81, the MCF-7 cells also demonstrated a significantly increased sensitivity to 5-FU. In addition, when the level of Mus81 was low, GEN1 expression was increased under a low concentration of 5-FU. The present results suggest that GEN1 may play different roles in different breast cancer cell lines. The function of GEN1 may be affected by the level of Mus81 in the cell line. In addition, GEN1 interference may improve the sensitivity to chemotherapy induced by targeting Mus81 alone.

Inhibition of Mus81 by siRNA enhances sensitivity to 5-FU in breast carcinoma cell lines.

PURPOSE: One of the most challenging aspects of breast carcinoma chemotherapy is the rapid acquirement of drug resistance. Improving the sensitivity to chemotherapeutic drugs is very important for successful treatment. Mus81 plays an important role in maintaining the stability of the genome and DNA repair. However, recent studies suggested that Mus81 expression levels correlate well with resistance to DNA-damaging drugs. The present study aimed to investigate the role of Mus81 on the chemosensitivity of breast carcinoma cells in response to 5-fluorouracil (5-FU), a chemotherapeutic drug that is widely used for treatment of breast malignancies. METHODS: The expression of Mus81 in MCF-7 and T47D cells was suppressed by small interfering RNA (siRNA). mRNA and protein levels of Mus81 were analyzed by quantitative real-time polymerase chain reaction and Western blot. Cell viability and colony survival were determined by Cell Counting Kit-8 and plate colony formation assay, respectively. Cell cycle and apoptosis were detected by flow cytometry. RESULTS: 5-FU inhibited the cell viability of MCF-7 and T47D cells in a concentration-dependent manner. We found that the Mus81-silenced MCF-7 and T47D cells exhibited decreased cell viability and clonogenic survival, but increased G2 accumulation, in response to 5-FU. In addition, Mus81 deficiency resulted in increased apoptosis and p53 expression in MCF-7 after 5-FU treatment. However, Mus81 deficiency did not affect the apoptosis of T47D cells with 5-FU. CONCLUSION: Taken together, our data suggest that Mus81 inhibition significantly increased the chemosensitivity of MCF-7 and T47D cells in response to 5-FU. Thus, Mus81 siRNA is potentially a useful adjuvant strategy for breast cancer chemotherapy.

A comparison of biochars from lignin, cellulose and wood as the sorbent to an aromatic pollutant.

Biochars' performance as the sorbent to pollutants is dependent on their compositions and surface characteristics, which are then related to the feedstock used for biochar preparation. The objective of this work is to probe the feedstock's influence on biochar's sorption property through a comparative study on biochars from lignin, cellulose and wood prepared at 400°C and 600°C, respectively. Elemental and spectral analyses demonstrated that the wood biochar had a composition and carbonization degree close to the cellulose biochar but much different from the lignin biochar prepared at the same temperature, suggesting that lignin is not dominant to properties of plant-derived biochars. The lignin biochar showed a sorption capacity comparable to both cellulose and wood biochars as the sorbent to nitrobenzene, with a higher partition contribution to the total sorption due to the lower carbonization of lignin. In general, the lignin biochar is a good candidate of sorbent to aromatic pollutants, and is advantageous over the other two species with its efficient carbon utilization.