Multi-omics and gut microbiome: Unveiling the pathogenic mechanisms of early-life pesticide exposure.

The extensive application of pesticides in agricultural production has raised significant concerns about its impact on human health. Different pesticides, including fungicides, insecticides, and herbicides, cause environmental pollution and health problems for non-target organisms. Infants and young children are so vulnerable to the harmful effects of pesticide exposure that early-life exposure to pesticides deserves focused attention. Recent research lays emphasis on understanding the mechanism between negative health impacts and early-life exposure to various pesticides. Studies have explored the impacts of exposure to these pesticides on model organisms (zebrafish, rats, and mice), as well as the mechanism of negative health effects, based on advanced methodologies like gut microbiota and multi-omics. These methodologies help comprehend the pathogenic mechanisms associated with early-life pesticide exposure. In addition to presenting health problems stemming from early-life exposure to pesticides and their pathogenic mechanisms, this review proposes expectations for future research. These proposals include focusing on identifying biomarkers that indicate early-life pesticide exposure, investigating transgenerational effects, and seeking effective treatments for diseases arising from such exposure. This review emphasizes how to understand the pathogenic mechanisms of early-life pesticide exposure through gut microbiota and multi-omics, as well as the adverse health effects of such exposure.

Bifidobacterium mediate gut microbiota-remedied intestinal barrier damage caused by cyproconazole in zebrafish (Danio rerio).

The widespread use of cyproconazole (CPZ) enhances food security but may pose potential risks to non-target organisms. Therefore, we applied Multi-omics techniques to reveal the response of the intestinal barrier to CPZ exposure and explore whether the Bifidobacterium intervention experiment can repair the damage. First, we found that exposure to CPZ at environmentally relevant concentrations led to intestinal injury phenotype, significantly down-regulated intestinal protein gene expression, and up-regulated pro-inflammatory gene expression, further causing intestinal dysbacteriosis and metabolic disorders. In particular, by combining analysis of gut microbiota and metabolites, we noticed acetate, a key metabolite, which decreased sharply after exposure to high concentration of CPZ. Expectedly, after supplementing with Bifidobacterium (a core bacterium that produces acetate), we noticed that the acetate content was quickly restored. Further, we also verified that the increase in acetate content after Bifidobacterium supplementation at least partially promoted IL-22 secretion, which in turn stimulated the secretion of ß-defensins (zfbd-1, zfbd-2, zfbd-3), thereby repairing the intestinal damage. In conclusion, our work confirms the potential of Bifidobacterium to improve intestinal damage and metabolic dysbiosis caused by CPZ exposure. It provides directional recommendations for the application of probiotics to repair the toxicological risk of pesticide exposure.

Toxicity effects of pesticides based on zebrafish (Danio rerio) models: Advances and perspectives.

Pesticides inevitably enter aquatic environments, posing potential risks to organisms. The common aquatic model organism, zebrafish (Danio rerio), are widely used to evaluate the toxicity of pesticides. In this review, we searched the Web of Science database for articles published between 2012 and 2022, using the keywords "pesticide", "zebrafish", and "toxicity", retrieving 618 publications. Furthermore, we described the main pathways by which pesticides enter aquatic environments and the fate of their residues in these environments. We systematically reviewed the toxicity effects of pesticides on zebrafish, including developmental toxicity, endocrine-disrupting effects, reproductive toxicity, neurotoxicity, immunotoxicity, and genotoxicity. Importantly, we summarized the latest research progress on the toxicity mechanism of pesticides to zebrafish based on omics technologies, including transcriptomics, metabolomics, and microbiomics. Finally, we discussed future research prospects, focusing on the combined exposure of multiple pollutants including pesticides, the risk of multigenerational exposure to pesticides, and the chronic toxicity of aquatic nanopesticides. This review provides essential data support for ecological risk assessments of pesticides in aquatic environments, and has implications for water management in the context of pesticide pollution.

A powerful helper of azoxystrobin degradation-the unique mechanism of UGT72E2 promoting environmental degradation of azoxystrobin.

In recent years, environmental pollutants such as pesticide residues have become one of the severe public problems that endanger the ecological environment and affect human health. The development of biotechnology to rapidly and efficiently degrade pesticides is essential to reduce their environmental risks. Azoxystrobin (AZ) is representative of the most widely used agricultural fungicide in the world. A large number of studies have shown that AZ has toxic effects on non-target organisms such as fish, algae, earthworms, etc., which may pose a potential threat to the environmental ecosystem. Therefore, it is particularly important to develop new AZ phytoremediation methods. Based on the constructed Arabidopsis UGT72E2 knockout (KO) and overexpression (OE) lines, this study found that overexpression of UGT72E2 in Arabidopsis can enhance resistance to exogenous AZ stress and maintain a relatively stable physiological state while enhancing the metabolic degradation of AZ. Correspondingly, knockout mutants showed the opposite results. The results showed that the AZ glycosylation and malonyl glycosylation products produced by UGT72E2 overexpression lines increased by 10%~20% compared with normal lines, and increased by 7%~47% compared with gene knockout plants, and exhibited lower phytotoxicity. In summary, our findings highlight the critical role of UGT72E2 overexpression in constructing new varieties of phytoremediation and may provide new ideas for reducing the indirect or direct risks of pesticides or other environmental pollutants to non-target organisms and improving biological and environmental resilience.

Chlorothalonil induces obesity in mice by regulating host gut microbiota and bile acids metabolism via FXR pathways.

As the most commonly used organochlorine pesticide nowadays, chlorothalonil (CHI), is ubiquitous in a natural environment and poses many adverse effects to organisms. Unfortunately, the toxicity mechanisms of CHI have not been clarified yet. This study found that the CHI based on ADI level could induce obesity in mice. In addition, CHI could induce an imbalance in the gut microbiota of mice. Furthermore, the results of the antibiotic treatment and gut microbiota transplantation experiments showed that the CHI could induce obesity in mice in a gut microbiota-dependent manner. Based on the results of targeted metabolomics and gene expression analysis, CHI could disturb the bile acids (BAs) metabolism of mice, causing the inhibition of the signal response of BAs receptor FXR and leading to glycolipid metabolism disorders in liver and epiWAT of mice. The administration of FXR agonist GW4064 and CDCA could significantly improve the CHI-induced obesity in mice. In conclusion, CHI was found to induce obesity in mice by regulating the gut microbiota and BAs metabolism via the FXR signaling pathway. This study provides evidence linking the gut microbiota and pesticides exposure with the progression of obesity, demonstrating the key role of gut microbiota in the toxic effects of pesticides.

A new strategy to alleviate the obesity induced by endocrine disruptors-A unique lysine metabolic pathway of nanoselenium Siraitia grosvenorii to repair gut microbiota and resist obesity.

Obesity caused by endocrine disruptors (EDCs) has become a hot topic threatening human health. Recently, Nanoselenium Siraitia grosvenorii (NSG) has been shown to have potential health-modulating uses. Based on the results of 16S rRNA sequencing and metabolomics analysis, NSG has the unique function of improving gut microbiota and inhibiting obesity. Specifically, NSG can enhance gut microbiota diversity and change their composition. A significant positive correlation exists between the liver change in lysine and the high-importance dominant species ([Ruminococcus]_gnavus, Alistipes_finegoldii, etc.). NSG metabolites analysis showed that the lysine level increased by 44.45% and showed a significantly negatively correlated with (TG, TC, Leptin, etc.). Significantly, NSG reduces the degradation of lysine metabolism in the liver and inhibits fatty acid ß-oxidation. In addition, NSG decreased Acetyl-CoA levels by 24% and regulated the downregulation of TCA genes (CS, Ogdh, Fh1, and Mdh2) and the upregulation of ketone body production genes (BDH1). NSG may have a positive effect on obesity by reducing the participation of Acetyl-CoA in the TCA cycle pathway and enhancing the ketogenic conversion of Acetyl-CoA. In conclusion, the results of this study may provide a new dietary intervention strategy for preventing endocrine disruptor-induced obesity.

Intergenerational reproductive toxicity of parental exposure to prothioconazole and its metabolite on offspring and epigenetic regulation associated with DNA methylation in zebrafish.

Prothioconazole (PTC) is a widely used agricultural fungicide, and its parent and metabolite prothioconazole-desthio (dPTC) have been detected in diverse environmental media. This study was aimed at investigating the gender-dependent effects on adult zebrafish reproduction and intergenerational effects on offspring development following parental exposure to PTC and dPTC. The results showed that after the adult zebrafish (F0) was exposed to 0.5 and 10 µg/L PTC and dPTC for 21 days, the fertility and gametogenesis of female zebrafish were decreased more significantly than that of male zebrafish. After that, three fecundity tests were conducted in the exposure period to explore the development endpoints of F1 embryos/larvae without further treatment with PTC and dPTC exposure. However, PTC and dPTC exposure did lead to abnormal development of F1 embryos, including delayed hatching, shortened body length, abnormal development and significant changes in locomotor behavior. These changes were related to the abnormal expression of sex hormones and the regulation of DNA methylation in F0 fish. In a word, the results of this study showed that parental PTC and dPTC interference have sex-dependent reproductive toxicity on F0 zebrafish, which may be passed on to the next generation through epigenetic modification involving DNA methylation, resulting in alternations in growth phenotype of offspring.

Azoxystrobin Disrupts Colonic Barrier Function in Mice via Metabolic Disorders Mediated by Gut Microbiota.

The widespread use of azoxystrobin (AZO) over the past few decades has drawn great attention to its environmental health effects. The objective of the present study was to explore the effects of AZO on intestinal barrier function in mice from the perspective of gut microbiota. Specifically, exposure to AZO could cause colonic barrier dysfunction in mice. Meanwhile, AZO could also cause dysbiosis of gut microbiota. Further studies revealed that the metabolic profile of the microbiota was significantly disturbed with AZO exposure. Last but not least, we confirmed that the gut microbiota played a central role in AZO-induced colonic barrier dysfunction through the gut microbiota transplantation experiment. Gut microbiota mediated colonic barrier dysfunction induced by AZO via inducing dysbiosis of the microbiota metabolic profile. The findings of this study strongly support a new insight that the gut microbiota can be a key target of health risks of pesticides.

Widening the Lens on Prothioconazole and Its Metabolite Prothioconazole-Desthio: Aryl Hydrocarbon Receptor-Mediated Reproductive Disorders through in Vivo, in Vitro, and in Silico Studies.

Reproductive disorders are a serious public health problem worldwide. Epidemiological data suggest that exposure to environmental pollutants is associated with the onset of reproductive disorders. However, the effects in reproductive health and exact mechanism of action of representative agricultural compounds prothioconazole (PTC) and its metabolite prothioconazole-desthio (dPTC) on mammals remain unclear. Here, we studied the physiological effects of the exposure to environmentally relevant doses of PTC and dPTC in mice reproductive systems. Combining in vivo, in vitro, and in silico studies, we observed that PTC and dPTC disrupt reproductive health by inducing metabolic perturbation, induction of apoptosis, and inflammation in gonadal tissue, which are achieved via activation of the aryl hydrocarbon receptor (AhR). Convincingly, the addition of alternate-day injections of CH223191 (an AhR inhibitor) to the 30-day exposure regimen ameliorated ovarian tissue damage, as evidenced by decreased TUNEL-positive cells and partially restored the inflammation and apoptotic factor levels. This study comprehensively reports the toxic effects of low-dose PTC and dPTC in the reproductive system in vivo and identifies AhR as a potential therapeutic target for the amelioration of reproductive disorders caused by similar endocrine-disrupting chemicals.

Feeding foliar nano-selenium biofortified panax notoginseng could reduce the occurrence of glycolipid metabolism disorder in mice caused by high-fat diets.

Nano-selenium (nano-Se) has been extensively explored as a biostimulant for improving the quality of grain crops. However, there are few reports about the effect on the medicinal components of Chinese herbal medicine cultured with nano-Se. Here, we sprayed nano-Se during the cultivation of Panax notoginseng (SePN), and measured the changes of medicinal components compared with conventional Panax notoginseng (PN). Furthermore, we identified a more pronounced effect of SePN on reducing obesity in animals compared with PN. By measuring antioxidant capacity, histopathology, gene expression related to glycolipid metabolism, and gut microbiota composition, we propose a potential mechanism for SePN to improve animal health. Compared with the control groups, foliar spraying of nano-Se increased saponins contents (Rb2, Rb3, Rc, F2, Rb2, and Rf) in the roots of Panax notoginseng, the content of Rb2 increased by 3.9 times particularly. Interestingly, animal studies indicated that taking selenium-rich Panax notoginseng (SePN) can further ameliorate liver antioxidation (SOD, MDA, and GSH) and enzyme activities involved in glycolipid metabolism (ATGL and PFK). It also relieved inflammation and regulated the expression of genes (MCAD, PPAR-α, and PCSK9) related to fatty acid oxidation. The abundance ratio of Firmicutes/Bacteroides and beneficial bacteria abundance (Bifidobacterium, Butyricimonas, and Parasutterella) in gut microbiota were improved relative to the control. In summary, the application of nano-Se on PN may effectively raise the content of Panax notoginseng saponins (PNS) and immensely lower the risk of metabolic disorders of glycolipids.

In utero exposure to decabromodiphenyl ethane causes rapid growth in mice cubs by activating glycogenolysis and lipid synthesis.

Decabromodiphenyl ethane (DBDPE) as a novel brominated flame retardant is frequently detected in environmental media due to its widespread use. Studies have shown that exposure to environmental pollutants in utero could lead to weight loss in newborns and obesity in adulthood. However, the mechanisms of how the cubs grow rapidly from low birth weight to obesity remain unclear. Although it has been reported that perinatal DBDPE exposure caused obesity in the offspring of mice in adulthood, its metabolic changes in offspring juvenile are unknown. Here, we monitored changes of body weight in cubs following exposure to DBDPE in utero. Furthermore, 1H NMR-based metabolomics was used to investigate the effects of in utero DBDPE exposure on the metabolic profile of neonates included days 1 and 25. Additionally, the expression levels of key genes in the relevant pathways were quantified. The results showed that exposure to high levels of DBDPE in utero caused cubs to be smaller at birth and grow rapidly during lactation. Metabolomics analysis showed that cubs in the exposed group consistently accelerated glycogenolysis and lipid synthesis to promote appetite and energy absorption, and achieved rapid growth in the subsequent lactation, which was further evidenced by the expression levels of genes related to glycolipid metabolism. These results reveal the mechanism for the first time how the weight loss of newborns in utero environmental pollutant exposure transformed into obesity in adulthood, although the exposures here were much higher than would be anticipated from the environment.

Combined ingestion of polystyrene microplastics and epoxiconazole increases health risk to mice: Based on their synergistic bioaccumulation in vivo.

Microplastic and pesticide are two common environmental pollutants whose adverse effects have been widely reported, but it is unclear whether they cause combined toxicity in mammals. In this study, polystyrene microplastics (5 µm, 0.012 or 0.120 mg/kg) or/and epoxiconazole (0.080 mg/kg) were administered orally to mice for 6 weeks, their toxicity to liver and kidney was assessed from changes in histopathology, tissue function, oxidative defense system and metabolic profile. In addition, mechanism of combined toxicity was explored in terms of bioaccumulation levels, intestinal barrier, gut microbiota. Results showed that combined ingestion of polystyrene (0.120 mg/kg) and epoxiconazole caused more severe tissue damage, dysfunction, oxidative stress, and metabolic disorders compared to single exposure sources. Interestingly, occurrence of combined toxicity was associated with their increased accumulation in tissues. In-depth exploration found that epoxiconazole caused intestinal barrier damage by targeting the gut microbiota, leading to massive invasion and accumulation of polystyrene, which in turn interfered with the metabolic clearance of epoxiconazole in liver. In all, findings highlighted that polystyrene and epoxiconazole could cause combined toxicity in mice through the synergistic effect of their bioaccumulation in vivo, which provided new reference for understanding the health risks of microplastics and pesticides and sheds light on the potential risk to humans of their combined ingestion.

Imazalil and its metabolite imazalil-M caused developmental toxicity in zebrafish (Danio rerio) embryos via cell apoptosis mediated by metabolic disorders.

Imazalil (IMZ) is a highly effective fungicide employed in crop production. It has been consistently detected in aquatic environments. The main environmental metabolite of IMZ is imazalil-M (IMZ-M). Limited studies have focused on the toxicity of IMZ and IMZ-M in aquatic organisms. This study systematically evaluated the developmental toxicity of IMZ and IMZ-M on zebrafish (Danio rerio) embryos and explored the potential mechanisms involved. The results showed that IMZ and IMZ-M caused developmental toxicity, characterized by decreased heart rate, hatching inhibition, and pericardial cyst in zebrafish embryos. Subsequently, acridine orange (AO) staining revealed cell apoptosis in the area around the heart regions of zebrafish larvae. Besides, the expression levels of apoptosis-related genes also varied significantly. Furthermore, 1H NMR-based metabolomics analysis showed that IMZ and IMZ-M exposure could induce metabolic profiles disorder in zebrafish larvae. Importantly, zebrafish exposure to IMZ and IMZ-M significantly affected the metabolism of branched - chain amino acids, energy, and ketone bodies, which are related to cell apoptosis. Overall, the toxicity of IMZ and IMZ-M in zebrafish embryos and larvae was characterized, suggesting a theoretical basis for the potential environmental risks of IMZ and its metabolite IMZ-M on non-target organisms.

Charge-specific adverse effects of polystyrene nanoplastics on zebrafish (Danio rerio) development and behavior.

Nanoplastics are being detected with increasing frequency in aquatic environments. Although evidence suggests that nanoplastics can cause overt toxicity to biota across different trophic levels, but there is little understanding of how materials such as differently charged polystyrene nanoplastics (PS-NP) impact fish development and behavior. Following exposure to amino-modified (positive charge) PS-NP, fluorescence accumulation was observed in the zebrafish brain and gastrointestinal tract. Positively charged PS-NP induced stronger developmental toxicity (decreased spontaneous movement, heartbeat, hatching rate, and length) and cell apoptosis in the brain and induced greater neurobehavioral impairment as compared to carboxyl-modified (negative charge) PS-NP. These findings correlated well with fluorescence differences indicating PS-NP presence. Targeted neuro-metabolite analysis by UHPLC-MS/MS reveals that positively charged PS-NP decreased levels of glycine, cysteine, glutathione, and glutamic acid, while the increased levels of spermine, spermidine, and tyramine were induced by negatively charged PS-NP. Positively charged PS-NP interacted with the neurotransmitter receptor N-methyl-D-aspartate receptor 2B (NMDA2B), whereas negatively charged PS-NP impacted the G-protein-coupled receptor 1 (GPR1), each with different binding energies that led to behavioral differences. These findings reveal the charge-specific toxicity of nanoplastics to fish and provide new perspective for understanding PS-NP neurotoxicity that is needed to accurately assess potential environmental and health risks of these emerging contaminants.

Synergistic effect of ZnO NPs and imidacloprid on liver injury in male ICR mice: Increase the bioavailability of IMI by targeting the gut microbiota.

Although many toxicological studies on pesticides and nanoparticles have been conducted, it is not clear whether nanoparticles will increase the toxicity of pesticides. In this study, we chose imidacloprid (IMI) as a representative pesticide, and explored the influence of ZnO NPs on the toxic effect of IMI. In addition, we studied the bioaccumulation of IMI in mice. Using biochemical index analysis, liver histopathological analysis, non-targeted metabolomics, and LC/MS analysis, we found that ZnO NPs increased the toxicity of IMI, which may be related to the increase in IMI bioaccumulation in mice. In addition, we used intestinal histopathological analysis, RT-qPCR, and 16sRNA sequencing to find that the disturbance of the gut microbiota and the impaired intestinal barrier caused by ZnO NPs may be the reason for the increase in IMI bioaccumulation. In summary, our results indicate that ZnO NPs disrupted the intestinal barrier and enhanced the bioaccumulation of IMI, and therefore increased the toxicity of IMI in mice. Our research has deepened the toxicological insights between nanomaterials and pesticides.

Prothioconazole and prothioconazole-desthio induced different hepatotoxicities via interfering with glycolipid metabolism in mice.

Prothioconazole (PTA), a new triazole fungicide, has been widely used worldwide. A recent study has confirmed that PTA and its main metabolite prothioconazole-desthio (dPTA) interfere with the liver metabolism in reptiles. However, little is known about liver toxicity of these two pollutants in mammals. Here, female mice were orally exposed to PTA (1.5 mg/kg body weight/day) and dPTA (1.5 mg/kg body weight/day) for 30 days. Additionally, growth phenotype and indexes related to serum and liver function were examined. Using metabolomics and gene expression analysis, PTA- and dPTA-induced hepatotoxicity was studied to clarify its potential underlying mechanism of action. Together, the results indicated that PTA and dPTA exposure caused changes in growth phenotypes, including elevated blood glucose levels, triglyceride accumulation, and damage of liver function. Additionally, exposure to PTA and dPTA caused changes in genes and metabolites related to glycolipid metabolism in female mice, thereby interfering with the pyruvate metabolism and glycolysis/gluconeogenesis pathways, ultimately leading to hepatic metabolism disorders. In particular, the effect of dPTA on hepatotoxicity has been proven to be more significant than that of PTA. Thus, these findings help us understand the underlying mechanism of action of PTA and dPTA exposure-induced hepatotoxicity in mammals and possibly humans.

A common fungicide tebuconazole promotes colitis in mice via regulating gut microbiota.

As a common fungicide, tebuconazole are ubiquitous in the natural environment and poses many potential risks. In this study, we examined the effects of exposure to tebuconazole on colitis in mice and explored its underlying mechanism. Specifically, exposure to tebuconazole could cause structural damage and inflammatory cell infiltration in colon tissue, activate the expression of inflammation-related genes, disrupt the expression of barrier function-related genes, and induce the colonic inflammation in mice. Similarly, exposure to tebuconazole could also exacerbate DSS-induced colitis in mice. In addition, we found that tebuconazole also could change the composition of the gut microbiota. In particular, tebuconazole significantly increases the relative abundance of Akkermansia of mice. Moreover, tebuconazole resulted in metabolic profiles disorders of the serum, leading to significant changes in the relative contents of metabolites involving glycolipid metabolism and amino acid metabolism. Particularly, the results of the gut microbiota transplantation experiment showed that exposure to tebuconazole could induced colonic inflammation in mice in a gut microbiota-dependent manner. Taken together, these results indicated that tebuconazole could induce colitis in mice via regulating gut microbiota. Our findings strongly support the concept that the gut microbiota is a key trigger of inflammatory bowel disease caused by pesticide intake.

New insights into bisphenols induced obesity in zebrafish (Danio rerio): Activation of cannabinoid receptor CB1.

Bisphenols (BPs), as widely used plastic additives, penetrate into our daily lives. BPs are considered endocrine disruptors and could potentially induce obesity. In this study, the effects of bisphenol A (BPA) and tetrabromobisphenol A (TBBPA) on food intake and lipid metabolism in zebrafish were determined. Moreover, the impact of BPA and TBBPA on the endocannabinoid system (ECS) of zebrafish was further explored by metabolomics, transcriptomics, and molecular docking analysis. Here we show that exposure to BPA and TBBPA at concentrations commonly found in the environment (20, 100, and 500 µg/L) led to hyperphagia and obesity in adult male zebrafish. Metabolomics and histopathological analysis revealed significant lipid accumulation in the liver of zebrafish exposed to BPA and TBBPA. The expression of ECS-related genes, in conjunction with RNA-Seq results, further indicated that BPA and TBBPA increased appetite and induced obesity by activating cannabinoid receptor type 1(CB1). Furthermore, molecular docking revealed that six representative BPs including BPA and TBBPA could bind to the CB1 receptor. Collectively, these findings indicate that CB1 may be a potential target for BPs to induce obesity.

Effects of penconazole enantiomers exposure on hormonal disruption in zebrafish Danio rerio (Hamilton, 1822).

PEN is a widely used triazole fungicide, usually used to control grape white rot. In the process of agricultural use, PEN will be scattered to the soil and water environment, which brings certain environmental safety risks. In this study, we used a 200-µg/L solution of Rac-PEN, (+)-PEN, and (-)-PEN to perform a 28-day exposure test on zebrafish. The results showed that long-term low-dose PEN exposure did not significantly change the growth factor K and the number of spawning of zebrafish. However, the content of four important hormones vitellogenin, 17ß-estradiol, testosterone, and 11-ketotestosterone in zebrafish has changed significantly. Furthermore, we measured the expression of hypothalamus-pituitary-gonads-liver (HPGL) axis-related genes, and the results showed that the expressions of related genes in the brain, gonads, and liver all changed significantly. Combining the above results, we can conclude that PEN has obvious endocrine disrupting effect on zebrafish, and has gender-specific endocrine effects. Meanwhile, Rac-PEN and (+)-PEN had stronger effects on the endocrine system of zebrafish than (-)-PEN.

Effects of incremental endosulfan sulfate exposure and high fat diet on lipid metabolism, glucose homeostasis and gut microbiota in mice.

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.