Association between phthalate exposure and obesity risk: A meta-analysis of observational studies.

According to epidemiological studies, phthalate exposure is associated with an increased risk of obesity in children and adults; however, these observations remain debatable. Therefore, we performed a systematic review and meta-analysis of the current literature to explore the effects of phthalate exposure on obesity. A systematic search was performed from inception to July 2022 in PubMed, EMBASE, Scopus, and Web of Science. Quality assessment was completed using criteria modified from Newcastle-Ottawa Scale (NOS) for the included studies. Meta-analysis showed that childhood exposure to MnBP, MBP, MEP, MiBP, and MECPP was positively correlated with obesity. In adults, MMP, MEP, and MiBP were positively correlated with adult abdominal obesity, while MEHHP, MECPP, and MCOP were positively correlated with adult general obesity. Subgroup analysis revealed that the positive correlation was particularly significant in women, as well as in Europe and the United States. Overall, a substantial association exists between phthalate exposure and obesity in children and adults. Sex and study site may provide limited sources of heterogeneity.

Di(2-ethylhexyl) phthalate disturbs cholesterol metabolism through oxidative stress in rat liver.

Di(2-ethylhexyl) phthalate (DEHP) is widely used and has been implicated in hepatotoxicity, although the mechanism is unclear. Here, we investigated the effect of DEHP on hepatic cholesterol metabolism in SD rats exposed to 0 and 300 mg/kg/day DEHP for 12 weeks. An RNA-Seq analysis was performed to describe the hepatic responses to long-term DEHP exposure in combination with serological and oxidative stress parameter measurements. DEHP increased the serum levels of total cholesterol (TC), high-density lipoprotein (HDL), and alanine transaminase (ALT). Moreover, DEHP increased the content of malondialdehyde (MDA) and decreased antioxidant enzyme activities in the liver. Transcriptomic results revealed that DEHP dramatically changed the cholesterol metabolism pathway and oxidation-reduction process and depressed gene expression involved in cholesterol efflux and monooxygenase activity. Total antioxidant capacity (T-AOC) positively correlated with Abcg5 and Abcg8. Overall, this study showed the mechanisms underlying hepatotoxicity caused by DEHP, providing new insights into understanding DEHP poisoning.

Integrated metabolomics and transcriptomics reveal di(2-ethylhexyl) phthalate-induced mitochondrial dysfunction and glucose metabolism disorder through oxidative stress in rat liver.

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous pollutant that results in hepatotoxicity. However, an understanding of the systematic mechanism of hepatic injury caused by DEHP remains limited. Here, we performed a comprehensive metabolomics and transcriptomics analyses to describe hepatic responses of rats to long-term DEHP exposure and, together with pathology and functional injury of liver, systematically analyzed the pathogenesis and mechanisms of liver damage. SD rats were exposed to 0 and 600 mg/kg/day DEHP for 12 weeks. Thereafter, biochemical indicators and histopathological changes regarding liver function were detected. Metabolomics and transcriptomics profiles of rat liver samples were analyzed using a UPLC-MS/MS system and Illumina Hiseq 4000, respectively. DEHP induced hepatocyte structural alterations and edema, depressed monooxygenase activity, decreased antioxidant activities, aggravated oxidative damage, blocked the tricarboxylic acid cycle and respiratory chain, and disturbed glucose homeostasis in the liver. These findings indicate that reactive oxygen species play a major role in these events. Overall, this study systematically depicts the comprehensive mechanisms of long-term DEHP exposure to liver injury and highlights the power of metabolomics and transcriptomics platforms in the mechanistic understanding of xenobiotic hepatotoxicity.

Urine Metabonomic Analysis of Interventions Effect of Soy Isoflavones on Rats Exposed to Di-(2-ethylhexyl) Phthalate.

OBJECTIVE: Di-(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant. As an endocrine disruptor, it seriously threatens human health and ecological environmental safety. This study examines the impact of intervention with soybean isoflavones (SIF) on DEHP-induced toxicity using a metabonomics approach. METHODS: Rats were randomly divided into control (H), SIF-treated (A, 86 mg/kg body weight), DEHP-treated (B, 68 mg/kg), and SIF plus DEHP-treated (D) groups. Rats were given SIF and DEHP daily through diet and gavage, respectively. After 30 d of treatment, rat urine was tested using UPLC/MS with multivariate analysis. Metabolic changes were also evaluated using biochemical assays. RESULTS: Metabolomics analyses revealed that p-cresol glucuronide, methyl hippuric acid, N1-methyl-2-pyridone-5-carboxamide, lysophosphatidycholine [18:2 (9Z, 12Z)] {lysoPC [18:2 (9Z, 12Z)]}, lysoPC (16:0), xanthosine, undecanedioic acid, and N6-acetyl-l-lysine were present at significantly different levels in control and treatment groups. CONCLUSION: SIF supplementation partially protects rats from DEHP-induced metabolic abnormalities by regulating fatty acid metabolism, antioxidant defense system, amino acid metabolism, and is also involved in the protection of mitochondria.

Aniline Induces Oxidative Stress and Apoptosis of Primary Cultured Hepatocytes.

The toxicity and carcinogenicity of aniline in humans and animals have been well documented. However, the molecular mechanism involved in aniline-induced liver toxicity and carcinogenesis remains unclear. In our research, primary cultured hepatocytes were exposed to aniline (0, 1.25, 2.50, 5.0 and 10.0 µg/mL) for 24 h in the presence or absence of N-acetyl-l-cysteine (NAC). Levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH), activities of superoxide dismutase (SOD) and catalase (CAT), mitochondrial membrane potential, DNA damage, cell viability, and apoptosis were detected. Levels of ROS and MDA were significantly increased and levels of GSH and CAT, activity of SOD, and mitochondrial membrane potential in hepatocytes were significantly decreased by aniline compared with the negative control group. The tail moment and DNA content of the tail in exposed groups were significantly higher than those in the negative control group. Cell viability was reduced and apoptotic death was induced by aniline in a concentration-dependent manner. The phenomena of ROS generation, oxidative damage, loss of mitochondrial membrane potential, DNA damage and apoptosis could be prevented if ROS inhibitor NAC was added. ROS generation is involved in the loss of mitochondrial membrane potential and DNA injury, which may play a role in aniline-induced apoptosis in hepatocytes. Our study provides insight into the mechanism of aniline-induced toxicity and apoptosis of hepatocytes.

Maternal Genistein Intake Can Reduce Body Weight in Male Offspring.

The study objectives were to investigate the relationship between early exposure to genistein and obesity in young adulthood and to evaluate changes in reproductive health during puberty and adulthood following in utero exposure to genistein. Thirty-two female rats were randomized into four groups; low dose 400 mg genistein/kg diet group (LG), mid-dose 1200 mg genistein/kg diet group (MG), high dose 3600 mg genistein/kg diet group (HG), and control group without genistein diet (CON). Rats were fed genistein at the beginning of pregnancy along with a high-fat diet. Pups were sacrificed at week 4 and week 8 after birth. High performance liquid chromatography (HPLC) results showed a correlation between maternal genistein intake and genistein concentration in pups' plasma. Compared to CON, body weight reduced significantly in male HG group at week 8. No statistical differences were found in plasma estradiol (E2), testosterone (T), interleukin (IL)-6, and C-reactive protein (CRP) levels with early genistein exposure. Furthermore, uterine histopathology showed notable changes in groups HG and MG compared with CON at week 4 and week 8. In conclusion, maternal genistein supplement could reduce body weight in male pups and alter uterine histopathology in female pups.

Influence of soy isoflavone on lindane cumulant in sprague-dawley rats.

Female Sprague-Dawley rats weighing 60-80 g were given different dosages of soy isoflavones and/or lindane for four weeks. Soy isoflavones was added in feed and lindane was given by oral gavage. We found that soy isoflavones could reduce the level of lindane in rat's serum and brain, but might cause the uterus hyperplasia. Lindane could inhibit the effect of soy isoflavones on uterus and significantly decrease the level of estradiol and testosterone in serum. This study indicated that soy isoflavones could reduce the level of lindane in rat's body. Lindane could reduce the level of hormones and decreased the effect of soy isoflavones on rat's uterus.

Soy isoflavone supplementation could reduce body weight and improve glucose metabolism in non-Asian postmenopausal women--a meta-analysis.

OBJECTIVE: The objective of this study was to conduct a systematic review and a meta-analysis to confirm the effects of soy isoflavone supplementation on body weight, fasting glucose, and insulin level in non-Asian postmenopausal women. METHODS: We searched the PubMed, EMBASE, and Cochrane databases up to October 2010 for randomized controlled trials regarding the effects of isoflavone supplementation on body weight, fasting glucose, and insulin level. Pooled estimates and 95% confidence intervals (CIs) were calculated by the fixed-and-random-effects model. RESULTS: Nine studies with 528 participants for body weight, 11 studies with 1182 participants for fasting glucose, and 11 studies with 1142 participants for fasting insulin were included, respectively. Significant reductions were found in body weight [weighted mean difference (WMD), -0.515; 95%CI: -0.895 to -0.134; P = 0.008), glucose level (WMD, -0.189; 95%CI: -0.344 to -0.033), and fasting insulin level (WMD, -0.940; 95%CI: -1.721 to -0.159) with soy isoflavone supplementation compared with placebo control group in non-Asian postmenopausal women after adjusted by unpublished studies. Furthermore, isoflavone supplementation in shorter duration (<6 mo) could significantly reduce body weight (WMD, -0.506; 95%CI: -0.888 to -0.124; P = 0.009) and longer duration (≥ 6 mo) could significantly reduce blood glucose in postmenopausal women (WMD, -0.270; 95%CI: -0.430 to -0.110; P = 0.001). Meanwhile, more reduction in body weight was observed in the lower dose subgroup (dose < 100 mg). Moreover, it is more effective to reduce body weight and fasting insulin level with soy isoflavone supplementation in normal weight (body mass index < 30) than obese (body mass index ≥ 30) women. CONCLUSIONS: This meta-analysis showed soy isoflavone supplementation could be beneficial for body weight reduction, glucose, and insulin control in plasma. Large and well-designed studies are recommended to confirm this conclusion.

Soy isoflavone and its effect to regulate hypothalamus and peripheral orexigenic gene expression in ovariectomized rats fed on a high-fat diet.

OBJECTIVE: To explore the effect of soy isoflavone on obesity in the light of hypothalamus and peripheral orexigenic gene regulation. METHODS: Fifty-four female rats were randomly assigned to 6 groups: one sham-operated group (SHAM), one ovariectomized (OVX) control group, three OVX groups fed with 400 ppm (L-SI), 1200 ppm (M-SI) and 3600 ppm (H-SI) isoflavone respectively, and one OVX group receiving 0.45 ppm diethylstilbestrol (EC). All rats were allowed to take high-fat diet for 4 weeks. Some neuropeptides were measured by RT-PCR. These neuropeptides included NPY, pro-opiomelanocortin (POMC), cocaine and amphetamine regulated transcript (CART), orexin, melanin-concentrating hormone (MCH), melanin-concentrating hormone precursor (P-MCH), ghrelin, and leptin. RESULTS: Compared with the OVX control group, the body weight and food intake in the H-SI group were reduced significantly and there was a significant dose-dependent manner in the 3 isoflavone groups. The results of RT-PCR showed that the NPY level in the 3 isoflavone groups was significantly increased and the POMC/CART gene expression decreased significantly in rats' hypothalamus compared with that in the OVX control group. However, the expression of orexin, MCH and P-MCH had no change. The peripheral grelin mRNA expression was higher in the 3 isoflavone groups, while leptin gene expression in the fat was not consistent. CONCLUSIONS: This research showed that isoflavone could prevent obesity induced by high-fat diet and ovariectomy through regulating hypothalamus and peripheral orexigenic gene expressions associated with food intake.

Isoflavone regulates lipid metabolism via expression of related genes in OVX rats fed on a high-fat diet.

OBJECTIVE: To investigate the effects of isoflavone on body weight, fat mass, and gene expression in relation to lipid metabolism. METHODS: Thirty-six female SD rats were ovariectomized or sham-operated and fed on a high-fat diet. Two months later, abdominal incision was made, blood was collected to separate serum, and the liver and adipose tissue were immediately collected and weighed. Some portions of these tissues were frozen in liquid nitrogen and stored at -80 degrees C. RESULTS: Ovariectomy (OVX) with a high-fat diet could induce obesity in rats, while treatment with isoflavone significantly inhibited the increase in body weight and fat mass in abdomen. Serum total cholesterol and leptin were significantly decreased in isoflavone group, compared with the OVX group. The mRNA expression of liver fatty acid synthase (FAS) in the OVX group was significantly higher than that in sham-operated group, while this difference was not observed in the isoflavone group. The mRNA expression of liver hormone-sensitive lipase (HSL) in the OVX rats tended to be lower than that in the sham-operated rats. Furthermore, a large amount of isoflavone maintained the mRNA expression at a sham level. CONCLUSION: Isoflavone may prevent obesity induced by ovariectomy with a high-fat diet, in part by modulating gene expression related to lipid metabolism.

[Effects of soybean isoflavone on body weight and food utilization rate in ovariectomized rats].

OBJECTIVE: To investigate the inhibitory action of phytoestrogen soybean isoflavone on body weight increasing in ovariectomized rats that imitated postmenopausal women and the effect of decreasing food availability. METHODS: Four-month-old Wistar rats were sham-operated or ovariectomized by abdominal cavity operation and divided into Sham, Ovx, estrogen group(EC) and three isoflavone group and feed 16 weeks. The diet was prepared by ourselves and some contained diethylstilbestrol or different concentration of isoflavone. During the experiment, the rats weight and food intake were recorded. The food utilization rates of each group were calculated. RESULTS: The result showed that high dosage of soybean isoflavone (187.4 mg/kg bw x d) can significantly inhibited OVX induced weight gain and inhibitory action decreased with the dose reduce. Compared with Sham and Ovx group, the food intake of isoflavone group decreased significantly but no different in 3 dosage group and higher than EC group. Compared with Ovx group, the food utilization rates of high isoflavone group decreased significantly but higher than EC group. Isoflavone not influenced the growth and organ/body rates of rats. CONCLUSION: High dosage of isoflavone (187.4mg/kg bw x d) decreased OVX rat's weight gain significantly through reducing food utilization rate.

Blocking effects of genistein on cell proliferation and possible mechanism in human gastric carcinoma.

AIM: To study the blocking effects of genistein on cell proliferation cycle in human gastric carcinoma cells (SGC-7901) and the possible mechanism. METHODS: MTT assay was applied in the detection of the inhibitory effects of genistein on cell proliferation. Flow cytometry was used to analyze the cell cycle distribution. Immunocytochemical technique and Western blotting were performed to detect the protein expression of cyclin D1, cyclin B1 and p21(waf1/cip1). RESULTS: Genistein significantly inhibited the growth and proliferation of human gastric carcinoma cells (SGC-7901). Seven days after treatment with different concentrations of genistein (2.5, 5.0, 10.0, 20.0 microg/mL), the growth inhibitory rates were 11.2%, 28.8%, 55.3%, 84.7% respectively and cell cycles were arrested at the G(2)/ M phase. Genistein decreased cyclin D1 protein expression and enhanced cyclin B1 and p21(waf/cip1) protein expression in a concentration-dependent manner. CONCLUSION: The growth and proliferation of SGC-7901 cells can be inhibited by genistein via blocking the cell cycle, with reduced expression of cyclin D1 and enhanced expression of cyclin B1 and p21(waf/cip1) protein in the concentration range of 0-20 microg/mL.