Exposure of Bisphenol A (BPA) is closely associated with an increased prevalence of obesity-related metabolic syndrome. However, the potential mechanism of BPA-induced adipogenesis remains to be fully elucidated. Herein, potential mechanisms of BPA-induced adipogenesis in 3T3-L1 preadipocytes were evaluated using RNA-Seq. Then, using an early-life BPA exposure model, we further evaluated the effects of BPA exposure on lipid and glucose homeostasis. The results showed that lipid content in 3T3-L1 adipocytes was significantly increased after BPA exposure (p < 0.01) and male C57BL/6 mice with the dose of 500 μg/kg/day BPA by once-a-day oral administration for 8 weeks displayed a NAFLD-like phenotype. RNA-Seq analysis of preadipocytes showed that BPA exposure affected multiple biological processes including glycosphingolipid biosynthesis, regulation of lipolysis in adipocytes, PPAR signaling pathway and fatty acid metabolism. The dysregulation in a series of genes of mice was associated to de novo lipogenesis and lipid transport, which was linked to obesity. Importantly, we also found a significant expression increase of stearoyl-CoA desaturase 1 (SCD1) and a significant decrease of apolipoprotein D (APOD) in both fat (p < 0.01) and livers (p < 0.01) of male mice. Besides, the dysregulation of pro-inflammatory genes (TNF-α,IL-6 and SAA3) showed that BPA exposure promoted progression of hepatic inflammation. In conclusion, this study elucidated a novel mechanism in which obesity associated with BPA exposure by targeting SCD1. Exposure to BPA should be carefully examined in the chronic liver metabolic diseases.

An increasing body of evidence has linked greenspace and various health outcomes in children and adolescents, but the conclusions were inconsistent. For this review, we comprehensively summarized the measurement methods of greenspace, resultant health outcomes, and potential mechanisms from epidemiological studies in children and adolescents (aged ≤19 years). We searched for studies published and indexed in MEDLINE and EMBASE (via Ovid) up to April 11, 2022. There were a total of 9,291 studies identified with 140 articles from 28 countries finally assessed and included in this systematic review. Over 70% of the studies were conducted in highly urbanised countries/regions, but very limited research has been done in low-and middle-income countries and none in Africa. Measures of greenspace varied. Various health outcomes were reported, including protective effects of greenspace exposure on aspects of obesity/overweight, myopia, lung health, circulatory health, cognitive function, and general health in children and adolescents. The associations between greenspace exposure and other health outcomes were inconsistent, especially for respiratory health studies. We pooled odds ratios (OR) using random-effects meta-analysis for health outcomes of asthma (OR = 0.94, 95%CI: 0.84 to 1.06), allergic rhinitis (OR = 0.95; 95% CI: 0.73 to 1.25), and obesity/overweight (OR = 0.91, 95%CI: 0.84 to 0.98) with per 0.1 unit increase in normalized difference in vegetation index (NDVI). These associations have important implications for the assessment and management of urban environment and health in children and adolescents.

Dyslipidemia may be a potential mechanism linking air pollution to adverse cardiovascular outcomes and this may differ among obese and normal-weight populations. However, the joint effect of multiple air pollutants on lipid profiles and the role of each pollutant are still unclear. This panel study aims to investigate and compare the overall associations of major air pollutants with lipid parameters in obese and normal-weight adults, and assess the relative importance of each pollutant for lipid parameters. Forty-four obese and 53 normal-weight young adults were recruited from December 2017 to June 2018 in Beijing, China. Their fasting blood was collected and serum lipid levels were measured in three visits. Six major air pollutants were included in this study, which were PM₂.₅, PM₁₀, NO₂, SO₂, O₃ and CO. Bayesian kernel machine regression (BKMR) was implemented to estimate the joint effect of the six air pollutants on various lipid parameters. We found that decreased high-density lipoprotein cholesterol (HDL-C) in the obese group and increased low-density lipoprotein cholesterol (LDL-C) and non-HDL-C in the normal-weight group were associated with the exposure to the mixture of six air pollutants above. Significant increases in total cholesterol (TC)/HDL-C and non-HDL-C/HDL-C were observed in both groups, and the effect was stronger in obese group. Of the six air pollutants above, O₃ had the largest posterior inclusion probability in above lipid indices, ranging from 0.75 to 1.00. In the obese group, approximately linear exposure-response relationships were observed over the whole range of logarithmic O₃-8 h max concentration, while in the normal-weight group, these relationships existed when the logarithmic concentration exceeded about 2.8. Therefore, lipid profiles of obese adults may be more sensitive to air pollution and this study highlights the importance of strengthening emissions control efforts for O₃ in the future.

Tributyltin (TBT), a bioaccumulative and persistent environmental pollutant, has been proposed as a metabolism disruptor and obesogen through targeting peroxisome proliferator-activated receptor gamma (PPARγ) receptor pathway. However, it remains unknown whether this biological effect occurs in macrophage, a cell type which cooperates closely with hepatocytes and adipocytes to regulate lipid metabolism. This study for the first time investigated the effect of TBT on PPARγ pathway in macrophages. Our results indicated that nanomolar levels of TBT was able to strongly activate PPARγ in human macrophages. TBT treatment also markedly increased the intracellular lipid accumulation, and enhanced the expression of lipid metabolism-related genes in macrophages, while these effects were all significantly down-regulated in PPARγ-deficient macrophages, confirming the involvement of PPARγ in TBT-induced lipogenesis. Next, a mouse model that C57BL/6 mice were orally exposed to TBT with the doses (250 and 500 μg/kg body weight) lower than NOAEL (no observed adverse effect level) was used to further investigate the in vivo mechanisms. And the in vivo results were consistent with cellular assays, confirming the induction of PPARγ and the increased expression of lipogenesis-regulating and lipid metabolism-related genes by TBT in vivo. In conclusion, this study not only provided the first evidence that TBT stimulated lipogenesis, activated PPARγ and related genes in human macrophages, but also provided insight into the mechanism of TBT-induced metabolism disturbance and obesity through targeting PPARγ via both in vitro cellular assays and in vivo animal models.

Numerous pieces of evidence documented the importance of gut microbiota in regulating human health and evaluating the toxicity of environmental pollutants, which are closely related to the host health in various aspects, including nutrition, energy translation, metabolism, pathogen resistance, and immune function. A variety of environmental factors can disrupt gut microbiota and their functions, and inevitably cause immune diseases, obesity and diabetes. However, deciphering the inner mechanisms involved in the functional interaction of gut microbes with host health is still needed extensive investigations. This review focused on the essential roles of intestinal microbes in host-related diseases and highlighted the development and applications of germ-free (GF) animal models, mainly zebrafish. Moreover, the generation, immunity characters, advantages and challenges of GF zebrafish models were also summarized. Importantly, the composition and isolation of zebrafish gut bacteria for further application and toxicity evaluation of aquatic environmental pollutants were also discussed. In conclusion, GF zebrafish play irreplaceable roles in understanding the potential functions and responses of customized microbiota towards human and environmental health implications.

Wild fish living downstream of wastewater treatment plants (WWTPs) often have increased body condition factors or body mass indices compared to upstream fish. This observation has been largely attributed to increased nutrient loading and food availability around wastewater effluent outflows. While a higher condition factor in fish is generally considered a predictor of healthy ecosystems, the metabolic status and capacity of the animals downstream of WWTPs may be a better predictor of fitness and potential population level effects. To address this, we sampled wild longnose dace (Rhinichthys cataractae), a native species in North American waterways, from sites upstream and downstream of WWTPs. Downstream fish had higher body mass indices, which corresponded with higher nutrient (lipid, protein, and glycogen) storage in somatic tissues compared to upstream fish. Liver transcriptome analysis revealed metabolic reprogramming favoring lipid synthesis, including higher hepatic triglyceride levels and transcript abundance of targeted lipogenic genes. This suggests that effluent exposure-mediated obesity in dace is a result of changes at the transcriptional level. To determine potential ecological consequences, we subjected these fish to an acute stressor in situ to determine their stress performance. Downstream fish failed to mobilize metabolites post-stress, and showed a reduction in liver aerobic and anaerobic metabolic capacity. Taken together, fish living downstream of WWTPs exhibit a greater lipid accumulation that results in metabolic disruption and may compromise the ability of these fish to cope with subsequent environmental and/or anthropogenic stressors.

Finding the potential environmental obesogens is crucial to explain the prevalence of obesity and the related pathologies. Increasing evidence has showed that many chemicals with endocrine disrupting effects can disturb lipid metabolism. Whether 4-hexylphenol (4-HP), a widely-used surfactant and a potential endocrine disrupting chemical (EDC), is associated to influence adipogenesis and hepatic lipid accumulation remained to be elucidated. In this study, both the 3T3-L1 differentiation model and oleic acid (OA)-treated HepG2 cells were used to investigate the effects of 4-HP on lipid metabolism, and the underlying estrogen receptor (ER)-involved mechanism was explored using MVLN assay, molecular docking simulation and the antagonist test. The results based on lipid droplet staining and triglyceride accumulation assay showed that 4-HP treatment promoted the adipogenic differentiation of 3T3-L1 cells and increased hepatic cellular OA accumulation in exposure concentration-dependent manners. The study on the elaborated transcription networks indicated that 4-HP activated peroxisome proliferator-activated receptor γ (PPARγ) as well as the subsequent adipogenic gene program in 3T3-L1 cells. This chemical also induced the increase of OA uptake and decreases of de novo lipogenesis and fatty acid oxidation in HepG2 cells. The agonistic activity of 4-HP in triggering ER-mediated pathway was shown to correlate with its perturbation in lipid metabolism, as evidenced by the enhanced development of mature lipid-laden adipocytes and suppression of excessive hepatic lipid accumulation upon its co-treatment with ER antagonist. Altogether, these findings provide new insights into the potential health impacts of 4-HP exposure as it may relate to obesity and nonalcoholic fatty liver disease.

Microbiome community structure is intimately involved in key biological functions in the gastrointestinal (GI) system including nutrient absorption and lipid metabolism. Recent evidence suggests that disruption of the GI microbiome is a contributing factor to metabolic disorders and obesity. Poor diet and chemical exposure have been independently shown to cause disruption of the GI microbiome community structure and function. We hypothesized that the addition a chemical exposure to overfeeding exacerbates adverse effects on the GI microbiome community structure and function. To test this hypothesis, adult zebrafish were fed a normal feeding regime (Control), an overfeeding regime (OF), or an overfeeding regime contaminated with diethylhexyl phthalate (OF + DEHP), a suspected obesogen-inducing chemical. After 60 days, fecal matter was collected for sequencing, identification, and quantification of the GI microbiome using the 16s rRNA hypervariable region. Analysis of beta diversity indicated distinct microbial profiles between treatments with the largest divergence between Control and OF + DEHP groups. Based upon functional predictions, OF + DEHP treatment altered carbohydrate metabolism, while both OF and OF + DEHP affected biosynthesis of fatty acids and lipid metabolism. Co-occurrence network analysis revealed decreases in cluster size and a fracturing of the microbial community network into unconnected components and a loss of keystone species in the OF + DEHP treatment when compared to Control and OF treatments. Data suggest that the addition of DEHP in the diet may exacerbate microbial dysbiosis, a consequence that may explain in part its role as an obesogenic chemical.

The metabolic syndrome (MetS) is a group of diseases that tend to occur together, including diabetes, hypertension, central obesity, cardiovascular disease and hyperlipidemia. Exposure to persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) has been associated with increased risk of development of several of the components of the MetS. The goal of this study is to determine whether the associations with POPs are identical for each of the components and for the MetS. The subject population was 601 Native Americans (Akwesasne Mohawks) ages 18 to 84 who answered a questionnaire, were measured for height and weight and provided blood samples for clinical chemistries (serum lipids and fasting glucose) and analysis of 101 PCB congeners and three OCPs [dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB) and mirex]. Associations between concentrations of total PCBs and pesticides, as well as various PCB congener groups with each of the different components of the MetS were determine so as to ask whether there were similar risk factors for all components of the MetS. After adjustment for other contaminants, diabetes and hypertension were strongly associated with lower chlorinated and mono-ortho PCBs, but not other PCB groups or pesticides. Obesity was most closely associated with highly chlorinated PCBs and was negatively associated with mirex. High serum lipids were most strongly associated with higher chlorinated PCBs and PCBs with multiple ortho-substituted chlorines, as well as total pesticides, DDE and HCB. Cardiovascular disease was not closely associated with levels of any of the measured POPs. While exposure to POPs is associated with increased risk of most of the various diseases comprising the MetS, the specific contaminants associated with risk of the component diseases are not the same.

Previous in vitro studies have implied that triphenyl phosphate (TPHP) may act as an obesogen. However, its specific contributions to the progression of obesity and related metabolic diseases are still unclear in vivo in mice. In this study, we evaluated the effects of in utero and lactational exposure to three doses of TPHP (10, 100, and 1000 μg/kg BW) on obesity and metabolic dysfunctions in adult male mice fed a low-fat diet (LFD) or high-fat diet (HFD), by examining body weight, liver weight, histopathology, blood biochemistry, gene expression, and gut microbiota compositions and metabolic functions. Results showed that TPHP exposure led to increased body weight, liver weight, fat mass, hepatic steatosis, impaired glucose homeostasis, and insulin resistance, and mRNA levels of genes involved in lipid metabolism, especially lipogenesis and lipid accumulation, were significantly altered by TPHP treatment. Gas chromatography-mass spectrometry (GC-MS) analysis further supported the changes in fatty acid composition. Intestinal flora measurements by 16S rRNA gene sequencing and ¹H NMR based fecal metabolomics indicated that TPHP treatment modulated gut microbiome composition and influenced host-gut co-metabolism, especially for bile acids and short chain fatty acids (SCFAs). These results suggest that fetal exposure to TPHP can promote the development of obesity and metabolic dysfunctions in adult mice.