Biology subjects

Koshko, L.

Publications and source records attributed to Koshko, L..

7 recordsLinked to original sources

bioRxiv2024

Integrative multiomics analysis of metabolic dysregulation induced by occupational benzene exposure in mice

Background: Type 2 Diabetes Mellitus (T2DM) is a significant public health burden. Emerging evidence links volatile organic compounds (VOCs), such as benzene to endocrine disruption and metabolic dysfunction. However, the effects of chronic environmentally relevant VOC exposures on metabolic health are still emerging. Objective: Building on our previous findings that benzene exposure at smoking levels (50 ppm) induces metabolic impairments in male mice, we investigated the effects of occupationally relevant, below OSHA approved, benzene exposure on metabolic health. Methods: Adult male C57BL/6 mice were exposed to 0.9ppm benzene 8 hours a day for 9 weeks. We assessed measures of metabolic homeostasis and conducted RNA and proteome sequencing on insulin-sensitive organs (liver, skeletal muscle, adipose tissue). Results: This low-dose exposure caused significant metabolic disruptions, including hyperglycemia, hyperinsulinemia, and insulin resistance. Transcriptomic analysis of liver, skeletal muscle, and adipose tissue identified key changes in metabolic and immune pathways especially in liver. Proteomic analysis of the liver revealed mitochondrial dysfunction as a shared feature, with disruptions in oxidative phosphorylation, mitophagy, and immune activation. Comparative analysis with high-dose (50 ppm) exposure showed both conserved and dose-specific transcriptomic changes in liver, particularly in metabolic and immune responses. Conclusions: Our study is the first to comprehensively assess the impacts of occupational benzene exposure on metabolic health, highlighting mitochondrial dysfunction as a central mechanism and the dose-dependent molecular pathways in insulin-sensitive organs driving benzene-induced metabolic imbalance. Our data indicate that current OSHA occupational exposure limits for benzene are insufficient, as they could result in adverse metabolic health in exposed workers, particularly men, following chronic exposure.

pharmacology and toxicology↗

bioRxiv2024

Hypothalamic Sex-Specific Metabolic Shift by Canagliflozin during Aging

The hypothalamus undergoes significant changes with aging and plays crucial roles in age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-diabetic agents that promote glucose excretion, and promote metabolic homeostasis. Recent studies have shown that SGLT2i, Canagliflozin (Cana), can extend the median survival of genetically heterogeneous UM-HET3 male mice and improve central metabolic control via increases in hypothalamic insulin responsiveness in aged males, as well as reduced age-associated hypothalamic inflammation. We studied the long- and short-term effects of Cana on hypothalamic metabolic control in UM-HET3 mice. We show that Cana treatment reduced body weight and fat mass in male mice that was associated with enhanced glucose tolerance and insulin sensitivity observed by 12 months. Indirect calorimetry showed that short-term Cana treatment (5 months) increased energy expenditure in male, but not female mice, at 12 months of age. Long-term Cana treatment (18 months) increased metabolic rates in both sexes, and markedly increasing formation of both orexigenic and anorexigenic projections to the paraventricular nucleus of the hypothalamus (PVH) mostly in females by 25 months. Hypothalamic RNA-sequencing analysis revealed sex-specific genes and signaling pathways related to insulin signaling, glycogen catabolic pathway, neuropeptide signaling, and mitochondrial function upregulated by Cana, with males showing a more pronounced and sustained effect on metabolic pathways at both age groups. Overall, our data provide critical evidence for sex-specific mechanisms that are impacted by Cana during aging suggesting key targets of hypothalamic Cana-induced neuroprotection for metabolic control.

neuroscience↗

bioRxiv2023

Microglial NF-κB Signaling Deficiency Protects Against Metabolic Disruptions Caused by Volatile Organic Compound via Modulating the Hypothalamic Transcriptome

Prolonged exposure to benzene, a prevalent volatile organic compound (VOC), at concentrations found in smoke, triggers hyperglycemia, and inflammation in mice. Corroborating this with existing epidemiological data, we show a strong correlation between environmental benzene exposure and metabolic impairments in humans. To uncover the underlying mechanisms, we employed a controlled exposure system and continuous glucose monitoring (CGM), revealing rapid blood glucose surges and disturbances in energy homeostasis in mice. These effects were attributed to alterations in the hypothalamic transcriptome, specifically impacting insulin and immune response genes, leading to hypothalamic insulin resistance and neuroinflammation. Moreover, benzene exposure activated microglial transcription characterized by heightened expression of IKK{beta}/NF-{kappa}B-related genes. Remarkably, selective removal of IKK{beta} in immune cells or adult microglia in mice alleviated benzene-induced hypothalamic gliosis, and protected against hyperglycemia. In summary, our study uncovers a crucial pathophysiological mechanism, establishing a clear link between airborne toxicant exposure and the onset of metabolic diseases.

neuroscience↗

bioRxiv2023

Prenatal benzene exposure alters offspring hypothalamic development predisposing to metabolic disease in later life

The hypothalamus is essential in the regulation of metabolism, notably during critical windows of development. An abnormal hormonal and inflammatory milieu during development can trigger persistent changes in the function of hypothalamic circuits, leading to long-lasting effects on the bodys energy homeostasis and metabolism. We recently demonstrated that gestational exposure to benzene at smoking levels induces severe metabolic dysregulation in the offspring. Given the central role of the hypothalamus in metabolic control, we hypothesized that prenatal exposure to benzene impacts hypothalamic development, contributing to the adverse metabolic effects in the offspring. C57BL/6JB dams were exposed to benzene in the inhalation chambers exclusively during pregnancy (from E0.5 to E19). The transcriptome analysis of the offspring hypothalamus at postnatal day 21 (P21) revealed changes in genes related to metabolic regulation, inflammation, and neurodevelopment exclusively in benzene-exposed male offspring. Moreover, the hypothalamus of prenatally benzene-exposed male offspring displayed alterations in orexigenic and anorexigenic projections, impairments in leptin signaling, and increased microgliosis. Additional exposure to benzene during lactation did not promote further microgliosis or astrogliosis in the offspring, while the high-fat diet (HFD) challenge in adulthood exacerbated glucose metabolism and hypothalamic inflammation in benzene-exposed offspring of both sexes. These findings reveal the persistent impact of prenatal benzene exposure on hypothalamic circuits and neuroinflammation, predisposing the offspring to long-lasting metabolic health conditions.

neuroscience↗

bioRxiv2022

Growth hormone receptor (GHR) in AgRP neurons regulatesthermogenesis in aged mice in a sex-specific manner

Evidence for hypothalamic regulation of energy homeostasis and thermoregulation in brown adipose tissue (BAT) during aging has been well recognized, yet the central molecular mediators involved in this process are poorly understood. The arcuate hypothalamus (ARC), orexigenic agouti-related peptide (AgRP) neurons control nutrient intake, energy homeostasis, and BAT thermogenesis. To determine the roles of growth hormone receptor (GHR) signaling in the AgRP neurons we used mice with the AgRP-specific GHR deletion (AgRP{Delta}GHR). We found that female AgRP{Delta}GHR mice were resistant to temperature adaptation, and their body core temperature remained significantly lower when held at 10{degrees}C, 22{degrees}C, or 30{degrees}C, compared to control mice. Low body core temperature in female AgRP{Delta}GHR mice has been associated with significant reductions in Ucp1 and Pgc1 expression in the BAT. Further, neuronal activity in AgRP in response to cold exposure was blunted in AgRP{Delta}GHR females, while the number of Fos+ AgRP neurons was increased in control females exposed to cold. Global transcriptome from BAT identified increased expression of genes related to immune responses and chemokine activity and decreased expression of genes involved in triglycerides synthesis and metabolic pathways in AgRP{Delta}GHR females. Importantly, these were the same genes that are downregulated by thermoneutrality in control mice but not in the AgRP{Delta}GHR animals. Collectively, these data demonstrate a novel circuit of thermal regulation between the hypothalamic AgRP-GHR and BAT and provide insight into the brain systems that are critical for the thermogenic vitality of the elderly.

neuroscience↗

bioRxiv2020

Metabolic Reprogramming by In Utero Maternal Benzene Exposure

Environmental chemicals play a significant role in the development of metabolic disorders, especially when exposure occurs early in life. We have recently demonstrated that benzene exposure, at concentrations relevant to a cigarette smoke, induces a severe metabolic imbalance in a sex-specific manner affecting male but not female mice. However, the roles of benzene in the development of aberrant metabolic outcomes following gestational exposure, remain largely unexplored. In this study, we exposed pregnant C57BL/6JB dams to benzene at 50 ppm or filtered air for 5 days/week (6h/day from gestational day 1 to birth) and studied male and female offspring metabolic phenotypes in their adult life. While no changes in body weight or body composition were observed between groups, 4-month-old male and female offspring exhibited reduced parameters of energy homeostasis (VO2, VCO2, and heat production). However, only male offspring from benzene-exposed dams were glucose intolerant and insulin resistant at this age. By six months of age, both male and female offspring displayed glucose and insulin intolerance, associated with elevated expression of hepatic gluconeogenesis and inflammatory genes. Additionally, this effect was accompanied by elevated insulin secretion and increased beta-cell mass only in male offspring. Thus, gestational benzene exposure can reprogram offspring for increased susceptibility to the metabolic imbalance in adulthood with differential sensitivity between sexes.

pharmacology and toxicology↗

bioRxiv2020

Acarbose Protects From Central and Peripheral Metabolic Imbalance Induced by Benzene Exposure

Benzene is a well-known human carcinogen that is one of the major components of air pollution. Sources of benzene in ambient air include cigarette smoke, e-cigarettes vaping and evaporation of benzene containing petrol processes. While carcinogenic effects of benzene exposure have been well studied, less is known about metabolic effects of benzene exposure. We show that chronic exposure to benzene at low levels induces severe metabolic imbalance in a sex-specific manner, which is associated with hypothalamic inflammation and endoplasmic reticulum (ER) stress. Benzene exposure rapidly activates hypothalamic ER stress and neuroinflammatory responses in male mice, while pharmacological inhibition of ER stress response by inhibiting IRE1-XBP1 pathway significantly alleviates benzene-induced glial inflammatory responses. Additionally, feeding mice with Acarbose, a clinically available anti-diabetes drug, protected against benzene induced central and peripheral metabolic imbalance. Acarbose imitates the slowing of dietary carbohydrate digestion, suggesting that choosing a diet with a low glycemic index might be a potential strategy for reducing the negative metabolic effect of chronic exposure to benzene for smokers or for people living/working in urban environments with high concentrations of exposure to automobile exhausts.

physiology↗