The health risks to populations induced by lead (Pb) and high-fat diets (HFD) have become a global public health problem. Pb and HFD often co-exist and are co-occurring risk factors for cognitive impairment. This study investigates effect of combined Pb and HFD on cognitive function, and explores the underlying mechanisms in terms of regulatory components of synaptic plasticity and insulin signaling pathway. We showed that the co-exposure of Pb and HFD further increased blood Pb levels, caused body weight loss and dyslipidemia. The results from Morris water maze (MWM) test and Nissl staining disclosed that Pb and HFD each contributed to cognitive deficits and neuronal damage and combined exposure enhanced this toxic injury. Pb and HFD decreased the levels of synapsin-1, GAP-43 and PSD-95 protein related to synaptic properties and SIRT1, NMDARs, phosphorylated CREB and BDNF related to synaptic plasticity regulatory, and these decreases was greater when combined exposure. Additionally, we revealed that Pb and HFD promoted IRS-1 phosphorylation and subsequently reduced downstream PI3K-Akt kinases phosphorylation in hippocampus and cortex of rats, and this process was aggravated when co-exposure. Collectively, our data suggested that combined exposure of Pb and HFD enhanced cognitive deficits, pointing to additive effects in rats than the individual stress effects related to multiple signaling pathways with CREB-BDNF signaling as the hub. This study emphasizes the need to evaluate the effects of mixed exposures on brain function in realistic environment and to better inform prevention of neurological disorders via modulating central pathway, such as CREB/BDNF signaling.

Exposure to tobacco smoke during pregnancy has been associated with a series of adverse reproductive outcomes; however, the underlying molecular mechanisms are not well-established. We conducted an untargeted metabolome-wide association study to identify the metabolic perturbations and molecular mechanisms underlying the association between cotinine, a widely used biomarker of tobacco exposure, and adverse birth outcomes. We collected early and late pregnancy urine samples for cotinine measurement and serum samples for high-resolution metabolomics (HRM) profiling from 105 pregnant women from the Atlanta African American Maternal-Child cohort (2014–2016). Maternal metabolome perturbations mediating prenatal tobacco smoke exposure and adverse birth outcomes were assessed by an untargeted HRM workflow using generalized linear models, followed by pathway enrichment analysis and chemical annotation, with a meet-in-the-middle approach. The median maternal urinary cotinine concentrations were 5.93 μg/g creatinine and 3.69 μg/g creatinine in early and late pregnancy, respectively. In total, 16,481 and 13,043 metabolic features were identified in serum samples at each visit from positive and negative electrospray ionization modes, respectively. Twelve metabolic pathways were found to be associated with both cotinine concentrations and adverse birth outcomes during early and late pregnancy, including tryptophan, histidine, urea cycle, arginine, and proline metabolism. We confirmed 47 metabolites associated with cotinine levels, preterm birth, and shorter gestational age, including glutamate, serine, choline, and taurine, which are closely involved in endogenous inflammation, vascular reactivity, and lipid peroxidation processes. The metabolic perturbations associated with cotinine levels were related to inflammation, oxidative stress, placental vascularization, and insulin action, which could contribute to shorter gestations. The findings will support the further understanding of potential internal responses in association with tobacco smoke exposures, especially among African American women who are disproportionately exposed to high tobacco smoke and experience higher rates of adverse birth outcomes.

The influence of pollutants on metabolic diseases such as type 2 diabetes mellitus is an emerging field in environmental medicine. Here, we explored the effects of a low-dose endosulfan sulfate (ES), a major metabolite of the pesticide endosulfan and a bio-persistent contaminant detected in environmental and human samples, on the progress of obesity and metabolic disorders. Pregnant CD-1 mice were given ES from gestational day 6 to postnatal day 21 (short-term). After weaning, male pups of exposed dams were provided with a low-fat or a high-fat diet (LFD or HFD) and assessed after an additional 12 weeks. At the same time, one group of male pups continuously received ES (long-term). Treatment with low-dose ES, short or long-term, alleviated the development of obesity and accumulation of hepatic triglycerides induced by HFD. Analysis of gene expression, metabolic profile and gut microbiome indicates that ES treatment inhibits adipogenesis induced by HFD due to enhanced lipid catabolism, fatty acid oxidation and disturbance of gut microbiota composition. However, impaired glucose and insulin homeostasis were still conserved in HFD-fed mice exposed to ES. Furthermore, ES treatment impaired glucose tolerance, affected hepatic gene expression, fatty acids composition and serum metabolic profile, as well as disturbed gut microbiota in LFD-fed mice. In conclusion, ES treatment at levels close to the accepted daily intake during fetal development directly impact glucose homeostasis, hepatic lipid metabolism, and gut microbiome dependent on the type of diet consumed. These findings provide a better understanding of the complex interactions of environmental pollutants and diet at early life stages also in the context of metabolic disease.

Pharmaceuticals and personal care products (PPCPs) have been widely distributed and posed ecotoxicological risks in the aquatic environment. This study aims to evaluate the toxic effects after chronic exposure to PPCPs mixture at the environment relevant concentrations (ERCs). Our results indicated that PPCPs induced serious metabolic effects by disturbing the carbohydrate and lipid metabolism pathways. Chronic exposure caused a significant reduction in the hepatosomatic index (HSI), the gut weight ratios, and histological alterations in liver and gut tissues. Further, exposure to the combined PPCPs disrupted the carbohydrate metabolism via significant upregulation of hk1, gk, pck1, and insr genes. The lipid metabolism was affected with higher ppars expression levels that increased the fatty acid β-oxidation and ultimately decreased the lipidogenesis. Moreover, the altered responses of the insulin growth factor (IGF) pathway more in male gut tissue than that of female revealed sex-dependent disturbance in the gut homeostasis induced by PPCPs mixture. In conclusion, chronic exposure to PPCPs mixtures at ERCs can induce developmental effects and metabolic dysfunction in both male and female fish. The consumption and environmental disposal of these PPCPs should be regulated to ensure ecological health and environmental safety.

Light at night (LAN) negatively impacts the behaviour and physiology; however, very little is known about molecular correlates of LAN-induced effects in diurnal animals. Here, we assessed LAN-induced effects on behaviour and physiology, and examined molecular changes in the liver of diurnal zebra finches (Taeniopygia guttata). Birds were exposed to dim LAN (dLAN: 12L = 150 lux: 12D = 5 lux), with controls on 12L (150 lux): 12D (0 lux). dLAN altered daily activity-rest and eating patterns, induced nocturnal eating and caused body fattening and weight gain, and reduced nocturnal melatonin levels. Concomitant increased nighttime glucose levels, decreased daytime thyroxine and triglycerides levels, and hepatic lipid accumulation suggested the impairment of metabolism under dLAN. Transcriptional assays evidenced dLAN-induced negative effects on metabolism in the liver, the site of metabolic homeostasis. Particularly, increased g6pc and foxo1 mRNA expressions suggested an enhanced gluconeogenesis, while increased egr1 and star expressions suggested enhanced cholesterol biosynthesis and lipid metabolism, respectively. Similarly, overexpressed sirt1 indicated protection from the metabolic damage due to elevated gluconeogenesis and cholesterol biosynthesis under dLAN. However, no effect on genes involved in lipogenesis (fasn) and insulin signalling pathway (socs3 and insig1) might indicate for the post transcriptional/post translational modification effects or the involvement of other genetic pathways in LAN-induced effects. We also found daily rhythm in the hepatic expression of selected clock and clock-controlled genes (per2, bmal1 and reverb-beta), with an elevated mesor and amplitude of per2 oscillation, suggesting a role of per2 in the liver metabolism. These results demonstrate dLAN-induced negative effects on the behaviour and physiology, and provide molecular insights into metabolic risks of the exposure to illuminated nights to diurnal animals including humans in an urban setting.

Environmental obesogens contributed significantly to the obesity prevalence. Recently, antibiotics joined the list of environmental obesogens, while the underlying mechanisms remained to be explored. In the present study, effects of erythromycin (ERY), one widely used macrolide antibiotic, were measured on C. elegans to investigate the obesogenic mechanism. Results showed that ERY at 0.1 μg/L significantly increased the fat content by 17.4% more than the control and also stimulated triacylglycerol (TAG) levels by 25.7% more than the control. Regarding the obesogenic mechanisms, ERY provoked over-eating by stimulation on the pharyngeal pumping and reduction on the satiety quiescence percentage and duration. Such effects were resulted from stimulation on the neurotransmitters including serotonin (5-HT), dopamine (DA) and acetylcholine (ACh). The nervous responses involved the up-regulation of Gsα (e.g., ser-7, gsa-1, acy-1 and kin-2) signaling pathway and the down-regulation of TGFβ (daf-7) but not via cGMP-dependent regulations (e.g., egl-4). Moreover, ERY stimulated the activities of fatty acid synthase (FAS) and glycerol-3-phosphateacyl transferases (GPAT) that catalyze lipogenesis, while ERY inhibited those of acyl-CoA synthetase (ACS), carnitine palmitoyl transferase (CPT) and acyl-CoA oxidase (ACO) that catalyze lipolysis. The unbalance between lipogenesis and lipolysis resulted in the fat accumulation which was consistent with up-regulation on mgl-1 and mgl-3 which are the down-steam of TGFβ regulation. Such consistence supported the close connection between nervous regulation and lipid metabolism. In addition, ERY also disturbed insulin which connects lipid with glucose in metabolism.

Indoor light environment has altered dramatically and exposure to light at night (LAN) potential leads to the progression of cardiometabolic conditions. However, few studies have investigated the effect of bedroom LAN exposure on cardiometabolic risk. To estimate the associations between multi-period bedroom LAN exposure with cardiometabolic risk among Chinese young adults. We objectively measured multi-period bedroom LAN intensity using portable illuminance meter in an ongoing prospective cohort (n = 484). At one-year follow-up, 230 young adults provided fasting blood samples for quantification of cardiometabolic parameters. Cardiometabolic (CM)-risk score was derived as the sum of standardized sex-specific z-scores for waist circumference (WC), mean arterial pressure (MAP), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) and homeostasis model assessment for insulin resistance (HOMA-IR), with HDL-C multiplied by – 1. Multivariate and univariable linear regression models were used to examine associations of multi-period bedroom LAN exposure with cardiometabolic risk. Exposure to higher bedroom LAN intensity is associated with 1.47-unit increase in CM-risk score (95% CI: 0.69–2.25; P < 0.001). Besides, post-bedtime light exposure was associated with elevated fasting insulin (PBL-1h: β = 0.06, 95% CI: 0.01–0.10; PBL-4h: β = 0.33, 95% CI: 0.19–0.47) and HOMA-IR (PBL-1h: β = 0.013, 95% CI: 0–0.03; PBL-4h: β = 0.07, 95% CI: 0.04–0.11) while pre-awake light exposure was associated with elevated total cholesterol (PAL-1h: β = 0.03, 95% CI: 0.02–0.04; PAL-2h: β = 0.02, 95% CI: 0.01–0.03), triglyceride (PAL-1h: β = 0.015, 95% CI: 0.01–0.02; PAL-2h: β = 0.01, 95% CI: 0–0.02) and low-density lipoprotein cholesterol (PAL-1h: β = 0.02, 95% CI: 0.01–0.03; PAL-2h: β = 0.02, 95% CI: 0.01–0.03). Among young adults, bedroom LAN exposure was significantly associated with higher cardiometabolic risk. Furthermore, different periods of bedroom light exposure have time-dependent effect on cardiometabolic risk. Further research is needed to confirm our findings and to elucidate potential mechanisms.

Per- and polyfluoroalkyl substances (PFASs) are environmentally and biologically persistent anthropogenic chemicals linked to adverse health outcomes. Epidemiological data have revealed association between exposure to specific PFAS and disruption of insulin level in bodies. However, the effect of PFASs on insulin secretion and the responsible molecular mechanism are poorly understood. In the present study, we used perfluorooctane sulfonate (PFOS) as a representative PFAS family member to investigate its effect on the insulin secretion in mouse pancreatic β cells (β-TC-6). Our results showed that exposure to PFOS inhibited silent information regulator 1 (SIRT1) activity, and molecular simulation showed PFOS could fit into the pocket overlapped with the nicotinamide adenine dinucleotide (NAD⁺) binding cavity in SIRT1. PFOS exposure upregulated uncoupling protein 2 (UCP2) expression, and this upregulation was blunted in the presence of Ex-527, a SIRT1 specific inhibitor. The mitochondria membrane potential (ΔΨm), as well as the glucose-induced ATP production and Ca²⁺ influx decreased under PFOS treatment. PFOS continual exposure (48 h) impaired glucose stimulated insulin secretion (GSIS), while the gene expression of insulin was not significantly altered. Importantly, the SIRT1 activator and UCP2 inhibitor could partly reverse the PFOS-induced impairment of GSIS. Taken together, the results suggested that PFOS continual exposure could inhibit SIRT1 activity, and the SIRT1-UCP2 pathway mediated, at least partially, the PFOS induced GSIS impairment.

Due to the endocrine disrupting effects of bisphenol A (BPA) several governmental authorities have banned its use and the manufacturers had to find alternative substances with similar chemical properties. This led to the increase in the use of so-called BPA analogues, which however also turn out to possess mild estrogenic and ani-androgenic properties and thus, may cause fertility problems and sex-hormone dependent endocrinopathies. The aim of this study was to evaluate the potential association between the exposure to BPA and its two analogues: BPS and BPF, with the diagnosis of the polycystic ovary syndrome (PCOS), which remains the most common female endocrinopathy. Serum concentrations of BPA, BPS and BPF were measured using high performance liquid chromatography method with tandem mass spectrometry (HPLC-MS/MS) among 199 women with PCOS and 158 control subjects. In women with PCOS serum BPS concentrations were significantly higher compared to the control subjects (geometric mean [95% CI]: 0.14 ng/mL [0.10; 1.17] vs. 0.08 ng/mL [0.06; 0.09], P = 0.023). Serum BPA and BPF concentrations did not differ between the studied groups. There was however a negative correlation between serum BPA and HOMA-IR (r = − 0.233, P = 0.001) and TST (r = − 0.203, P = 0.006) in women with PCOS. No correlations were found between the serum BPs and other metabolic parameters such as serum lipids, insulin, DHEA-S, androstenedione and FAI. When studying the association between serum BPA analogues and PCOS it turned out that women whose serum BPS concentrations were in the first tertile were more likely to be diagnosed with this endocrinopathy (OR [95% CI]: 1.21 [1.04; 3.46], P = 0.017). This association was also statistically significant when adjusted for age, education, BMI, smoking, income, and alcohol consumption (adjusted OR [95% CI]: 1.12 [1.03; 3.71], P = 0.029). These results point to the potential association between the exposure to BPS and the diagnosis of PCOS. The role of BPA is not clear and warrants further studies.

Considerable human data have shown that the exposure to perfluorooctane sulfonate (PFOS) correlates to the risk of metabolic diseases, however the underlying effects are not clearly elucidated. In this study, we investigated the impacts of PFOS treatment, using in-vivo, ex-vivo and in-vitro approaches, on pancreatic β-cell functions. Mice were oral-gavage with 1 and 5 μg PFOS/g body weight/day for 21 days. The animals showed a significant increase in liver triglycerides, accompanied by a reduction of triglycerides in blood sera and glycogen in livers and muscles. Histological examination of pancreases showed no noticeable changes in the size and number of islets from the control and treatment groups. Immunohistochemistry showed a reduction of staining intensities of insulin and the transcriptional factors (Pdx-1, islet-1) in islets of pancreatic sections from PFOS-treated groups, but no changes in the intensity of Glut2 and glucagon were noted. Transcriptomic study of isolated pancreatic islets treated ex vivo with 1 μM and 10 μM PFOS for 24 h, underlined perturbations of the insulin signaling pathways. Western blot analysis of ex-vivo PFOS-treated islets revealed a significant reduction in the expression levels of the insulin receptor, the IGF1 receptor-β, Pdk1-Akt-mTOR pathways, and Pdx-1. Using the mouse β-cells (Min-6) treated with 1 μM and 10 μM PFOS for 24 h, Western blot analysis consistently showed the PFOS-treatment inhibited Akt-pathway and reduced cellular insulin contents. Moreover, functional studies revealed the inhibitory effects of PFOS on glucose-stimulated insulin-secretion (GSIS) and the rate of ATP production. Our data support the perturbing effects of PFOS on animal metabolism and demonstrate the underlying molecular targets to impair β-cell functions.