Toxicological Research最新文献

In this study, the adsorption of toxic difenoconazole pesticide was investigated by using chitosan. In the first phase of the study, chitosan was extracted from deep-water pink shrimp (Parapenaeus longirostris) shells, by deacetylation of the chitin, which is separated and disposed of after meat extraction in processing facilities in Turkey. The deacetylation degree, molecular weight, viscosity, moisture, and crude-ash values of the extracted chitosan were determined. Chitosan, having a high deacetylation degree (90.21%), was used as the adsorbent. In the second phase of the study, the effects of pH, temperature, and pesticide concentration on the adsorption were investigated. The optimum pH level for pesticide adsorption was determined as 5. It was observed that the adsorption increases as the temperature increases. A rapid increase was observed within the first 5 min of the 60-minute adsorption process in difenoconazole concentrations of 5, 15, and 25 µg/L, and after 10 min, the adsorption rate was stable. The Langmuir isotherm parameters regarding the adsorption were determined as aL = 0.635, kL = 15.10, and the Q_max value was calculated as 23.77 mg/g. In the evaluation of overall study results, it was determined that the chitosan biopolymer is a suitable adsorbent for difenoconazole pesticide adsorption.

This study investigated the potential effects of China dust (CD) exposure on cyclophosphamide (CP)-induced testicular toxicity in mice, focusing on spermatogenesis and oxidative damage. CP treatment reduced testicular and epididymal weight and sperm motility and enhanced sperm abnormality. Histopathological examination presented various morphological alterations in the testis, including increased exfoliation of spermatogenic cells, degeneration of early spermatogenic cells, vacuolation of Sertoli cells, a decreased number of spermatogonia/spermatocytes/spermatids, along with a high number of apoptotic cells. In addition, the testis exhibited reduced glutathione (GSH) levels and glutathione reductase (GR) activity and enhanced malondialdehyde (MDA) concentration. Meanwhile, CD exposure exacerbated testicular histopathological alterations induced by CP. CD exposure also aggravated oxidative damage by increasing the lipid peroxidative product MDA and decreasing GSH levels and antioxidant enzyme activities in the testis. These results suggest that CD exposure exacerbates CP-induced testicular toxicity in mice, which might be attributed to the induction of lipid peroxidation and reduced antioxidant activity.

Cigarette smoke (CS) is a dominant carcinogenic agent in a variety of human cancers. CS exposure during pregnancy can adversely affect the fetus. Non-alcoholic fatty liver disease (NAFLD) is considered as a hepatic manifestation of a metabolic disorder, and ranges from simple steatosis to cirrhosis leading to hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is a more severe phase of NAFLD. Recently, there is increasing apprehension about the CS-related chronic liver diseases. Therefore, we examined whether maternal CS exposure could affect the pathogenesis of NASH in offspring. Mainstream CS (MSCS) was exposed to pregnant C57BL/6 mice via nose-only inhalation for 2 h/day, 5 days/week for 2 weeks from day 6 to 17 of gestation at 0, 300, or 600 μg/L. Three-week-old male offspring mice were fed methionine and choline-supplemented (MCS) diet or methionine and choline-deficient including high-fat (MCDHF) diet for 6 weeks to induce NASH. Maternal MSCS exposure increased the severity of NASH by increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic total cholesterol (TC) and triglyceride (TG) levels, pro-inflammation, fibrosis, and steatosis in offspring mice. Especially, maternal MSCS exposure significantly downregulated the phosphorylation of AMP-activated protein kinase (AMPK) in MCDHF diet-fed offspring mice. Subsequently, the protein levels of sterol regulatory element-binding protein (SREBP)-1c and stearoyl-CoA desaturase-1 (SCD1) were upregulated by maternal MSCS exposure. In conclusion, maternal MSCS exposure exacerbates the progression of NASH by modulating lipogenesis on offspring mice.

Supplementary information: The online version contains supplementary material available at 10.1007/s43188-022-00153-1.

2,4,3',5'-Tetramethoxystilbene (TMS) is a selective inhibitor of cytochrome P450 1B1 to block the conversion from estradiol to 4-OH-estradiol. Several studies suggested that TMS may act as a potent anti-cancer agent for hormone-related cancer including cervical cancer. Nutlin-3a is a cis-imidazoline analog that interferes with the interaction between mouse double minute 2 homolog (MDM2) and the tumor suppressor p53. The purpose of the study was to compare the cytotoxic effect of TMS and nutlin-3a treatment individually and in combination in HeLa cells. To assess the potential synergistic effects between TMS and nutlin-3a, low concentrations of TMS and nutlin-3a were simultaneously treated in HeLa cells. Based on cell viability, apoptosis assays, and the increase in cleaved caspase-3 and poly (ADP-ribose) polymerase cleavage, it was demonstrated that the combination with TMS and nutlin-3a exerts a synergistic effect on cancer cell death. Isobologram analysis of HeLa cells noted synergism between TMS and nutlin-3a. The combined treatment increased the expression of mitochondrial pro-apoptotic factors such as Bax and Bak, and decreased the expression of the XIAP. In addition, combination treatment significantly enhanced the translocation of AIF to the nucleus in HeLa cells. In conclusion, the results demonstrate that the combination of TMS and nutlin-3a induces synergistic apoptosis in HeLa cells, suggesting the possibility that this combination can be applied as a novel therapeutic strategy for cervical cancer.

Melanocyte cell death can lead to various melanocyte-related skin diseases including vitiligo and leukoderma. Melanocytotoxic chemicals are one of the most well-known causes of nongenetic melanocyte-related diseases, which induce melanocyte cell death through apoptosis. Various chemicals used in cosmetics, medicine, industry and food additives are known to induce melanocyte cell death, which poses a significant risk to the health of consumers and industrial workers. This review summarizes recently reported melanocytotoxic chemicals and their mechanisms of toxicity in an effort to provide insight into the development of safer chemicals.

Lung cancer is the leading cause of cancer death. Although docetaxel has been used as a second- or third-line treatment for non-small cell lung cancer (NSCLC), the objective response rate is less than 10%. Hence, there is a need to improve the clinical efficacy of docetaxel monotherapy; combination therapy should be considered. Here, we show that CKD-516, a vascular disruption agent, can be combined with docetaxel to treat epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant NSCLC. CKD-516 was orally bioavailable; neither CKD-516 nor docetaxel affected the mean plasma concentration-time profile or pharmacokinetic parameters of the other drug. CKD-516 and docetaxel synergistically inhibited the growth of H1975 (with an L858R/T790M double mutation of EGFR) and A549 (with a KRAS mutation) lung cancer cell lines. In addition, docetaxel plus CKD-516 delayed tumor growth in-and extended the lifespan of-tumor-bearing mice. Thus, combination CKD-516 and docetaxel therapy could be used to treat EGFR-TKI-resistant NSCLC.

Animal and human studies suggest that thyroid hormone may have critical roles in the development of the ovary. For example, thyroid deficiency disrupts the ovarian microarchitecture and menstrual cycle in neonate and adult women, respectively. Therefore, it is conceivable that thyroid deficiency might disrupt sexual maturation during the peri-pubertal period. To investigate the impact of radioactive iodine-induced thyroid deficiency on reproductive organs throughout puberty, immature female rats were given water containing radioactive iodine (0.37 MBq/g body weight) twice, on postnatal days 22 and 29. Radioactive iodine-induced hypothyroidism was revealed by low free thyroxin levels. Thyroid deficiency delayed the onset of vaginal opening, reduced ovarian weight and the number of medium-sized follicles and led to elongated uteri. However, there was no effect on the estrous cycle or absolute uterus weight. We conclude that radioactive iodine-induced thyroid deficiency delays sexual maturation and alters normal ovarian growth in peri-pubertal rats.

Febrile seizure (FS) is one of the most prevalent etiological events in childhood affecting 2-5% of children from 3 months to 5 years old. Debates on whether neurodevelopmental consequences rise in later life following a febrile seizure or not are still ongoing however there is limited evidence of its effect, especially in a laboratory setting. Moreover, the comparative study using both male and female animal models is sparse. To examine the effect of FS on the behavioral features of mice, both sexes of ICR mice were induced with hyperthermic seizures through exposure to an infrared heat lamp. The mice were divided into two groups, one receiving a single febrile seizure at postnatal day 11 (P11) and one receiving three FS at P11, P13, and P15. Starting at P30 the FS-induced mice were subjected to a series of behavioral tests. Mice with seizures showed no locomotor and motor coordination deficits, repetitive, and depressive-like behavior. However, the FS-induced mice showed impulsive-like behavior in both elevated plus maze and cliff avoidance tests, which is more prominent in male mice. A greater number of mice displayed impaired CAT in both males and females in the three-time FS-induced group compared to the single induction group. These results demonstrate that after induction of FS, male mice have a higher susceptibility to consequences of febrile seizure than female mice and recurrent febrile seizure has a higher chance of subsequent disorders associated with decreased anxiety and increased impulsivity. We confirmed the dysregulated expression of impulsivity-related genes such as 5-HT1A and tryptophan hydroxylase 2 from the prefrontal cortices of FS-induced mice implying that the 5-HT system would be one of the mechanisms underlying the increased impulsivity after FS. Taken together, these findings are useful in unveiling future discoveries about the effect of childhood febrile seizure and the mechanism behind it.

The aim of the present study is to investigate the preventive effect of water extract of Mori Ramulus (MRWE) on oxidative stress-mediated cellular damages in rat skeletal L6 myoblasts. Our results demonstrated that MRWE pretreatment markedly improved cell survival and suppressed cell cycle arrest at the G2/M phase and apoptosis in hydrogen peroxide (H₂O₂)-treated L6 cells. H₂O₂-triggered DNA damage was also notably reduced by MRWE, which since it was correlated with protection of reactive oxygen species (ROS) production. Additionally, H₂O₂ stimulated cytosolic release of cytochrome c and up-regulation of Bax/Bcl-2 ratio, whereas MRWE suppressed these changes following by H₂O₂. Moreover, MRWE inhibited the cleavage of poly(ADP-ribose) polymerase as well as the activity of caspase-3 by H₂O₂. Furthermore, MRWE enhanced H₂O₂-mediated expression of nuclear factor erythroid 2-associated factor 2 (Nrf2) and its representative downstream enzyme, heme oxygenase-1 (HO-1). However, the protective effects of MRWE on H₂O₂-induced ROS production, cell cycle arrest and apoptosis were significantly attenuated by HO-1 inhibitor. In conclusion, our present results suggests that MRWE could protect L6 myoblasts from H₂O₂-induced cellular injury by inhibiting ROS generation along with Nrf2-mediated activation of HO-1, indicating this finding may expand the scope of application of Mori Ramulus in medicine.

Cosmetics, especially rinse-off personal care products (PCPs), such as shampoo, facial cleanser, and body wash, are composed of various chemicals and are one of the sources of chemicals released into aquatic ecosystems. Therefore, the cosmetic industry strives to reduce the impact of their products on the aquatic environment. In this study, we proposed an algorithm based on persistence, bioaccumulation potential, and toxicity (PBT) for the environmental risk assessment of cosmetics. PBT features are generally used in the evaluation of the environmental impact of chemicals. Based on the PBT assessment, it is possible to predict the short- and long-term effects of chemicals on the environment. Our algorithm derives substance and product scores from PBT features, allowing for the risk assessment of each ingredient in the product. Furthermore, we proposed a criterion for the environmental impact grade through which each component can be classified. We intend to use this grade and factors determined through the algorithm to manufacture products with low environmental impact.