Endocrine toxicity of atrazine and its underlying mechanisms.

Atrazine (ATR) is one of the most widely utilized herbicides globally and is prevalent in the environment due to its extensive use and long half-life. It can infiltrate the human body through drinking water, ingestion, and dermal contact, and has been recognized as an environmental endocrine disruptor. This study aims to comprehensively outline the detrimental impacts of ATR on the endocrine system. Previous research indicates that ATR is harmful to various bodily systems, including the reproductive system, nervous system, adrenal glands, and thyroi d gland. The toxic effects of ATR on the endocrine system and its underlying molecular mechanisms are summarized as follows: influencing the expression of kisspeptin in the HPG axis, consequently affecting steroid synthesis; disrupting DNA synthesis and meiosis, as well as modifying DNA methylation levels, leading to reproductive and developmental toxicity; impacting dopamine by altering Nurr1, VMAT2, and DAT expression, consequently affecting dopamine synthesis and transporter expression, and influencing other neurotransmitters, resulting in neurotoxicity; and changing adipose tissue synthesis and metabolism by reducing basal metabolism, impairing cellular oxidative phosphorylation, and inducing insulin resistance. Additionally, a compilation of natural products used to mitigate the toxic effects of ATR has been provided, encompassing melatonin, curcumin, quercetin, lycopene, flavonoids, vitamin C, vitamin E, and other natural remedies. It is important to note that existing research predominantly relies on in vitro and ex vivo experiments, with limited population-based empirical evidence available.

DEHP induces apoptosis and autophagy of the thyroid via Rap1 signaling pathway: In vivo and in vitro study.

OBJECTIVE: DEHP has thyroid toxicity and affects thyroid function. However, the mechanism is unclear. METHODS: The offspring of SD rats were gavaged with different doses of DEHP from in utero to 8 or 12 weeks old. We observed the thyroid morphology with HE and autophagosomes with TEM. The THs levels were tested with ELISA. The apoptosis level was tested by flow cytometry. The levels of apoptosis-related genes, autophagy-related genes and Rap1 pathway genes, were measured with qRT-PCR and Western blot. We established an MEHP-treated Nthy-ori 3-1 cell model and inhibited the Rap1 to verify the mechanism. RESULTS: DEHP could cause pathological damage and ultrastructure damage of thyroids in offspring rats. After DEHP exposure, the THs levels were altered, the apoptosis levels increased, and autophagosomes appeared. DEHP significantly affected the levels of apoptosis-related genes and autophagy-related genes. DEHP also affected the levels of Rap1 pathway, which was correlated with the levels of apoptosis and autophagy. After inhibiting Rap1 in Nthy-ori 3-1 cells, the THs levels were altered. Rap1 pathway was inhibited and the levels of apoptosis and autophagy were down-regulated. CONCLUSION: DEHP could induce the apoptosis and autophagy of the thyroid, and Rap1 signaling pathway may play a significant role.

ATR induces hepatic lipid metabolism disorder in rats by activating IRE1α/XBP1 signaling pathway.

Atrazine (ATR) is a widely used herbicide and due to its persistence in environment and bioaccumulation, it can cause harmful impacts on human health. ATR exposure can lead to disorders of lipid metabolism in the liver, but its underlying mechanism is still unclear. 40 eight-week-old rats were given different doses of ATR (0, 0.5, 5 and 50 mg/kg/d) for 90 days. The liver tissue and serum were collected for histological observation and biochemical analysis. The levels of lipid and oxidative stress were assessed using colorimetry. Changes in MMP and ROS of liver cells were observed through flow cytometry. The expression of mRNA and protein was detected using Real-Time PCR and western blot. The results showed that TC and HDL-C levels in both the liver and serum were increased in the ATR-treated groups. The levels of MDA were accumulated, while the levels of SOD and GSH were depleted in the liver with ATR exposure. The expression of liver lipid metabolism related genes (SCD1, DGAT2, ACC1, PPARγ) was elevated. The liver ERS was activated and the gene expression of IRE1α/XBP1 signal pathway and GRP78, GRP94 in the liver was increased. There was a correlation between the levels of ERS and the levels of lipid metabolism. These results suggested that ATR can activate ERS and promote the expression of IRE1α/XBP1 signaling pathway, and further lead to lipid metabolism disorders in rat liver. This study can provide valuable insights as a reference for the prevention and control of hazards associated with agricultural residues.

Role of COX-2/PGE2 signaling pathway in the apoptosis of rat ovarian granulosa cells induced by MEHP.

OBJECTIVE: MEHP, as the metabolite of DEHP, is a widely used environmental endocrine disruptor. Ovarian granulosa cells participate in maintaining the function of ovary and COX2/PGE2 pathway may regulate the function of granulosa cells. We aimed to explore how COX-2/PGE2 pathway affects cell apoptosis in ovarian granulosa cells caused by MEHP. METHODS: Primary rat ovarian granulosa cells were treated with MEHP (0, 200, 250, 300 and 350 µM) for 48 h. Adenovirus was used for over-expression of COX-2 gene. The cell viability was tested with CCK8 kits. The apoptosis level was tested by flow cytometry. The levels of PGE2 were tested with ELISA kits. The expression levels of COX-2/PGE2 pathway related genes, ovulation-related genes and apoptosis-related genes, were measured with RT-qPCR and Western blot. RESULTS: MEHP decreased the cell viability. After MEHP exposure, the cell apoptosis level increased. The level of PGE2 markedly decreased. The expression levels of COX-2/PGE2 pathway related genes, ovulation-related genes and anti-apoptotic genes decreased; the expression levels of pro-apoptotic genes increased. The apoptosis level was alleviated after over-expression of COX-2, and the level of PGE2 slightly increased. The expression levels of PTGER2 and PTGER4, and the levels of ovulation-related genes increased; the levels of pro-apoptotic genes decreased. CONCLUSION: MEHP can cause cell apoptosis by down-regulating the levels of ovulation-related genes via COX-2/PGE2 pathway in rat ovarian granulosa cells.

Di-(2-ethylhexyl) phthalate (DEHP) promoted hepatic lipid accumulation by activating Notch signaling pathway.

Di-(2-ethylhexyl) phthalate (DEHP) and mono-2-ethylhexyl phthalate (MEHP) can induce hepatic lipid metabolism disorders, while the molecular mechanism still remain unknown. We aim to explore the underlying mechanism of Notch signaling pathway on hepatic lipid accumulation induced by DEHP/MEHP. A total of 40 male wistar rats were exposed to DEHP (0, 5, 50, and 500 mg/kg/d) for 8 weeks, BRL-3A hepatocytes were exposed to MEHP (0, 10, 50, 100, and 200 µM) for 24 h. About 50 µM DAPT and 100 µg/mL Aspirin were used to inhibit Notch pathway and prevent inflammation, respectively. Real-Time PCR was performed to detect the mRNA expression, western blot and immunofluorescence were used to detect the protein expression. Lipids and inflammatory factors levels were determined by commercial kits. The results showed that DEHP/MEHP promoted the expression of Notch pathway molecules and lipids accumulation in rat livers/BRL-3A cells. The up-regulated Notch receptors were correlated with the TG levels in the rat liver. MEHP increased the levels of IL-8 and IL-1ß. The lipids levels were reduced after anti-inflammation. The inhibition of Notch pathway reversed the elevation of inflammation and lipid accumulation caused by MEHP. In conclusion, this study demonstrated that DEHP/MEHP led to lipid accumulation in hepatocytes by up-regulating Notch pathway and the inflammation might play a key role in the process.

PM2.5 induces the abnormal lipid metabolism and leads to atherosclerosis via Notch signaling pathway in rats.

PM2.5 can affect the lipid metabolism and cause atherosclerosis. Abnormal lipid metabolism is a sever risk factor of atherosclerosis and the underlying molecular mechanism still remains unclear. In this study, GPL16956 Agilent-045997 Arraystar human lncRNA microarray V3 (Probe Name Version) platform was used to detect the different genes of lipid metabolism between the normal arterial intima and advanced atherosclerotic plaque, which were downloaded from GEO database. A high-fat diet and vitamin D3 were administered to Wistar rats to establish the atherosclerotic model and another normal healthy 56 rats were used as the non-atherosclerotic exposure groups. The atherosclerotic rats and non-atherosclerotic rats were randomly divided into 4 PM2.5 groups (0, 1.5, 7.5, 37.5 mg/kg), respectively. The results of bioinformatics showed changes in the Notch1, Dll1, Hes1, LDLR and ABCG1 levels. PM2.5 exposure could produce damage to the physiological structure of the aorta, and aggravate atherosclerosis in rats from both non-atherosclerotic and atherosclerotic groups. With the increase of the exposure dose, the levels of TC and TG significantly increased. PM2.5 exposure significantly affected the expression levels of PPARγ, ABCA1, LDLR, CD36, SR-BI and SREBP2. PM2.5 exposure could also affect the expression levels of the Notch signaling pathways which was significantly correlated with the levels of TC and TG. The results proved that PM2.5 exposure could induce and aggravate the atherosclerosis in rats by disrupting lipid metabolism in which Notch signaling pathway may play a significant role.

Nanoplastics and Microplastics May Be Damaging Our Livers.

Plastics in the environment can be degraded and even broken into pieces under the action of natural factors, and the degraded products with a particle size of less than 5 mm are called microplastics (MPs). MPs exist in a variety of environmental media that come into contact with the human body. It can enter the body through environmental media and food chains. At present, there are many studies investigating the damage of MPs to marine organisms and mammals. The liver is the largest metabolizing organ and plays an important role in the metabolism of MPs in the body. However, there is no available systematic review on the toxic effects of MPs on the liver. This paper summarizes the adverse effects and mechanisms of MPs on the liver, by searching the literature and highlighting the studies that have been published to date, and provides a scenario for the liver toxicity caused by MPs.

Effect of Acute Cold Exposure on Energy Metabolism and Activity of Brown Adipose Tissue in Humans: A Systematic Review and Meta-Analysis.

Background: The benefit of cold exposure for humans against obesity has brought the energy metabolism and activity of brown adipose tissue (BAT) induced by cold into focus. But the results are inconsistent. This review is aimed to systematically explore the effect of cold exposure on the activity of BAT and energy metabolism in humans. Methods: We searched relevant papers that were published from 1990 to 2021 and were cited in PubMed Central, Web of science, Embase and Cochrane Library databases to conduct this systematic review and meta-analysis. Energy metabolism, BAT volume, BAT activity and non-esterified fatty acids (NEFA) data reported in eligible researches were extracted. Meta-analysis was applied to combine the mean difference or standard mean difference with their 95% confidence intervals (95%CI). RevMan 5.3 software was used for meta-analysis and evaluating the risk of bias. Stata 16.0 was used for evaluating the publication bias. Results: Ten randomized controlled trials were included in meta-analysis. Compared with human exposed in room temperature at 24°C, the energy expenditure (EE) was increased after acute cold exposure at 16∼19°C (Z = 7.58, p < 0.05, mean different = 188.43kal/d, 95% CI = 139.73-237.13); BAT volume (Z = 2.62, p < 0.05; standard mean different = 0.41, 95% CI = 0.10-0.73); BAT activity (Z = 2.05, p = 0.04, standard mean difference = 1.61, 95% CI = 0.07-3.14) and the intake of BAT NEFA (Z = 2.85, p < 0.05; standard mean different = 0.53, 95% CI = 0.17-0.90) also increased. Conclusion: Acute cold exposure could improve the energy expenditure and BAT activity in adults, which is beneficial for human against obesity.

Ginsenoside Rg1 ameliorates reproductive function injury in C57BL/6J mice induced by di-N-butyl-phthalate.

With the aggravation of environmental pollution, the incidence of infertility is increasing. Ginsenoside Rg1 is a monomer component extracted from Panax ginseng. It has been found that Ginsenoside Rg1 is able to prevent premature ovarian failure and delay testicular senescence. Therefore, we speculate Ginsenoside Rg1 may have great potential to prevent and treat infertility. The aim of this work is to explore whether Ginsenoside Rg1 plays a protective role in the dinbutyl phthalate (DBP)-induced reproductive function injury mice, and to elucidate the potential mechanism. C57BL/6J male mice were administered by DBP with or without Ginsenoside Rg1 treatment and serum, testis and epididymis were collected for further analysis. Sperm analysis, hematoxylin and eosin staining, and serum hormone detection indicated that Ginsenoside Rg1 treatment improved the sperm density and sperm motility, reduced the testicular tissue damage, increased the serum testosterone and luteinizing hormone levels, and decreased the serum follicle-stimulating hormone level in DBP-induced mice. Furthermore, Ginsenoside Rg1 treatment upregulated expression levels of spermatogenesis-related protein, Cx43, E-cadherin, p-PI3K, p-Akt, and mTOR in the mice treated by DBP, observed by using a immunohistochemistry assay, a real-time quantitative PCR assay, and a western blot analysis. The present study reveals that Ginsenoside Rg1 may exert anti-DBP-induced reproductive function injury in C57BL/6J mice. In addition, the protect role of Ginsenoside Rg1 in spermatogenesis may be associated with the regulation of reproductive hormones, upregulation of spermatogenic associated proteins expression, restoration of the gap junctions, and the activation of PI3K/Akt/mTOR signaling pathways.

Intrauterine exposure to low-dose DBP in the mice induces obesity in offspring via suppression of UCP1 mediated ER stress.

Dibutyl phthalate (DBP) is recognized as an environmental endocrine disruptor that has been detected in fetal and postnatal samples. Recent evidence found that in utero DBP exposure was associated with an increase of adipose tissue weight and serum lipids in offspring, but the precise mechanism is unknown. Here we aimed to study the effects of in utero DBP exposure on obesity in offspring and examine possible mechanisms. SPF C57BL/6J pregnant mice were gavaged with either DBP (5 mg /kg/day) or corn oil, from gestational day 12 until postnatal day 7. After the offspring were weaned, the mice were fed a standard diet for 21 weeks, and in the last 2 weeks 20 mice were selected for TUDCA treatment. Intrauterine exposure to low-dose DBP promoted obesity in offspring, with evidence of glucose and lipid metabolic disorders and a decreased metabolic rate. Compared to controls, the DBP exposed mice had lower expression of UCP1 and significantly higher expression of Bip and Chop, known markers of endoplasmic reticulum (ER) stress. However, TUDCA treatment of DBP exposed mice returned these parameters nearly to the levels of the controls, with increased expression of UCP1, lower expression of Bip and Chop and ameliorated obesity. Intrauterine exposure of mice to low-dose DBP appears to promote obesity in offspring by inhibiting UCP1 via ER stress, a process that was largely reversed by treatment with TUDCA.