Biology subjects

Lehmler, H.-J.

Publications and source records attributed to Lehmler, H.-J..

8 recordsLinked to original sources

bioRxiv2025

Ramping up the Heat: Induction of Systemic and Pulmonary Immune Responses and Metabolic Adaptations in Mice

Heatwaves pose a growing risk to public health. While most animal studies use sudden, extreme heat exposure, the systemic and pulmonary impacts of gradual heat exposures, reflective of real-world conditions, remain poorly characterized. This study examined the effects of acute, gradual extreme heat exposure to mice. Adult male and female C57Bl/6 mice were randomly assigned to heat-exposed, control, or pair-fed groups. Heat-exposed mice experienced a controlled 8-hour temperature ramp from 20{degrees}C to 38{degrees}C, mimicking the daily transition from nighttime lows to daytime highs. Control and pair-fed mice were maintained in parallel at ambient temperature. Multi-omics profiling was performed to assess cytokine levels in lung and serum, cecal microbiome composition, lung transcriptomics, and serum metabolomics. Heat exposure significantly altered the levels of multiple cytokines in serum and lung, including IL-17, MIP-1, MIP-1{beta}, IL-1, IL-12(p40), and RANTES, indicating shifts in mucosal immunity and immune cell recruitment. Random forest analysis identified 20 taxa that distinguished experimental groups, with a reduction in Lactobacillus observed in males. Lung transcriptomic analysis revealed immune-related gene expression changes involving B cell activation pathways. Serum metabolomics revealed significant decreases in ten metabolites across both sexes, identifying disruptions in amino acid and energy metabolism, with enrichment of the "Glycine, Serine, and Threonine Metabolism" KEGG pathway. Integrative network analyses revealed sex-specific correlations among immune genes, cytokines, and bile acid-related metabolites. These findings show that gradual extreme heat exposure triggers sex-specific systemic and pulmonary immunometabolic responses, offering insight into the biological effects of environmental heat stress and its potential health implications. HighlightsO_LIGradual heat exposure altered lung and serum cytokine profiles in mice C_LIO_LILactobacillus abundance decreased in males, despite stable microbial diversity C_LIO_LILung transcriptomics showed B cell-mediated immune activation after heat exposure C_LIO_LISerum metabolomics revealed heat-induced disruption of amino acid metabolism C_LIO_LIMulti-omics integration revealed sex-specific immunometabolic network responses C_LI

pharmacology and toxicology↗

bioRxiv2025

Spatial transcriptomic profiling uncovers the molecular effects of the neurotoxicant polychlorinated biphenyls (PCBs) in the brains of adult mice

Environmental toxicants, such as polychlorinated biphenyls (PCBs), are highly stable synthetic organic compounds that are present in air, water, and soil. PCBs have been identified in post-mortem human brains of individuals with neurodegenerative diseases, indicating a possible link between environmental factors and disease risk. Research has revealed an association between PCB exposure and cognitive decline. Therefore, it is crucial to evaluate how PCB mixtures relevant to humans affect brain function and cognition. To investigate the effects of PCBs on memory and transcriptomic profiles, we exposed adult male C57BL/6J mice orally to a synthetic PCB mixture daily. After seven weeks of exposure, the mice were assessed in a spatial object recognition task (SOR) to evaluate long-term spatial memory. Our findings showed that mice exposed to PCBs exhibited deficits in long-term spatial memory. To examine the molecular effects of PCB on the brain, we used a spatial transcriptomics technique to analyze gene expression changes in five brain regions: the hippocampus, neocortex, thalamus, caudal putamen, and fiber tracts. Our analysis of spatial gene expression revealed the molecular signatures influenced by PCB in these susceptible brain regions of mice. Network analysis suggests that these changes are associated with higher chlorinated PCBs present in the brain. Additionally, we show that PCB exposure disrupts the expression of tight junction proteins, which are crucial for maintaining the integrity of the blood-brain barrier (BBB). Thus, our results offer mechanistic insights into how PCB exposure affects brain function and cognition.

neuroscience↗

bioRxiv2025

Single-cell transcriptomics showed that maternal PCB exposure dysregulated ER stress-mediated cell type-specific responses in the liver of female offspring

Polychlorinated biphenyls (PCBs) are persistent environmental toxicants that bioaccumulate in the food chain and readily cross the placenta, raising concerns for developmental toxicity. While PCB exposure has been associated with metabolic and neurodevelopmental disorders, its cell type-specific effects on liver development remain poorly understood. This study aimed to investigate how maternal exposure to an environmentally relevant Fox River PCB mixture affects liver development in female offspring at single-cell resolution. We hypothesized that early-life PCB exposure disrupts hepatic metabolic and immune function in a cell type-specific manner. Using single-cell RNA sequencing (scRNA-seq) on liver tissue from postnatal day 28 female mice perinatally exposed to PCBs, we identified major hepatic and immune cell populations and assessed cell-specific transcriptional responses. PCB exposure significantly altered the proportions of endothelial cells and Kupffer cells and reduced neutrophil abundance. Transcriptomic analysis revealed that PCBs dysregulated key pathways in hepatocytes and non-parenchymal cells, including ER stress responses, drug metabolism, and glucose/insulin signaling. Notably, hepatocytes exhibited upregulation of phase-I drug-metabolizing enzymes and uptake transporters, but downregulation of phase-II enzymes and efflux transporters. Kupffer cells and endothelial cells had altered immune and metabolic gene expression, and intercellular communication analysis predicted disrupted fibronectin, collagen, and chemokine signaling due to PCB exposure. RT-qPCR validation confirmed increased hepatic ER stress marker expression. Together these findings demonstrate that perinatal PCB exposure induces persistent, cell type-specific transcriptomic reprogramming in the liver, impairing metabolic and immune functions. This study highlights the utility of single-cell transcriptomics for revealing toxicant effects with cellular precision during critical windows of development.

systems biology↗

bioRxiv2023

Predicted Versus Observed Activity of PCB Mixtures Toward the Ryanodine Receptor

Non-dioxin-like polychlorinated biphenyls (NDL PCBs) alter the activity of the ryanodine receptor (RyR), and this activity is linked to developmental neurotoxicity. Most work to date has focused on the activity of single congeners rather than relevant mixtures. The current study assessed the RyR activity of single congeners or binary, tertiary, and complex PCB mixtures. Observed mixture activity was then compared to the expected activity calculated using the concentration addition (CA) model or a RyR-specific neurotoxic equivalency scheme (rNEQ). The predictions of the CA model were consistent with the observed activity of binary mixtures at the lower portion of the concentration-response curve, supporting the additivity of RyR1 active PCBs. Findings also show that minimally active congeners can compete for the RyR1 binding site, and congeners that do not activate the RyR1 do not interfere with the activity of a full agonist. Complex PCB mixtures that mimic PCB profiles detected in indoor air, fish tissue, and the serum of mothers and children activated the RyR1 and displayed similar efficacy and potency regardless of varying congener profiles. Neither the CA model nor the rNEQ perfectly predicted the observed activity of complex mixtures, but predictions were often within one magnitude of change from the observed response. Importantly, PCB mixtures approximating profiles found in environmental samples or human serum displayed RyR1 activity at concentrations reported in published research. The work presented will aid in the development of risk assessment platforms for NDL PCBs, and similar compounds, towards RyR1 activation and related neurotoxicity.

pharmacology and toxicology↗

bioRxiv2023

Disposition and Toxicity of 2,2',5,5'-Tetrachlorobiphenyl in Female Rats Following Intraperitoneal Exposure

The disposition and toxicity of lower chlorinated PCBs (LC-PCBs) with less than five chlorine substituents have received little attention. This study characterizes the distribution and metabolomic effects of PCB 52, an LC-PCB found in indoor and outdoor air, three weeks after intraperitoneal exposure of female Sprague Dawley rats to 0, 1, 10, or 100 mg/kg BW. PCB 52 exposure did not affect overall body weight. Gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis identified PCB 52 in all tissues investigated. Hydroxylated, sulfated, and methylated PCB metabolites, identified using GC-MS/MS and nontarget liquid chromatography-high resolution mass spectrometry (Nt-LCMS), were primarily found in the serum and liver of rats exposed to 100 mg/kg BW. Metabolomic analysis revealed minor effects on L-cysteine, glycine, cytosine, sphingosine, thymine, linoleic acid, orotic acid, L-histidine, and erythrose serum levels. Thus, the metabolism of PCB 52 and its effects on the metabolome must be considered in toxicity studies. HighlightsO_LIPCB 52 was present in adipose, brain, liver, and serum 3 weeks after PCB exposure C_LIO_LILiver and serum contained hydroxylated, sulfated, and methylated PCB 52 metabolites C_LIO_LIMetabolomics analysis revealed minor changes in endogenous serum metabolites C_LIO_LILevels of dopamine and its metabolites in the brain were not affected by PCB 52 C_LI

pharmacology and toxicology↗

bioRxiv2022

Toxicity impacts on human adipose MSCs acutely exposed to Aroclor and non-Aroclor mixtures of PCBs.

PCBs accumulate in adipose where they may impact the growth and function of cells within the tissue. This is particularly concerning during adolescence when adipocytes expand rapidly. Herein we sought to understand how exposure to PCB mixtures found in U.S. schools affects human adipose mesenchymal stem/stromal cell (MSC) health and function. We investigated how exposure to Aroclor 1016 and Aroclor 1254, as well as a newly characterized non-Aroclor mixture that resembles the PCB profile found in cabinets, Cabinet Mixture, affects adipose MSC growth, viability, and function in vitro. We found that exposure to all three mixtures resulted in two distinct types of toxicity. At PCB concentrations >20 M, the majority of MSCs die, while at 1-10 M MSCs remained viable but display numerous alterations to their phenotype. At these sublethal concentrations, MSC rate of expansion slowed, and morphology changed. Further assessment revealed PCB-exposed MSCs had impaired adipogenesis and a modest decrease in immunosuppressive capabilities. Thus, exposure to PCB mixtures found in schools negatively impacts the health and function of adipose MSCs. This work has implications for human health due to MSCs role in supporting the growth and maintenance of adipose tissue. SYNOPSISPCB mixtures found in schools are toxic to human adipose mesenchymal stem/stromal cells, stunting their growth and altering their function in ways that could contribute to metabolic diseases.

pharmacology and toxicology↗

bioRxiv2018

Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes: Involvement of Arene Oxide Intermediates

PCBs and their hydroxylated metabolites have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB developmental neurotoxicity; however, only limited information is available regarding the metabolism of these congeners in humans. We hypothesize that the oxidation of 2,2',3,3',4,6'-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) is atropselective and displays inter-individual variability. To test this hypothesis, PCB 132 (50 M) was incubated with pooled or single donor HLMs for 10, 30 or 120 min at 37 {degrees}C, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite formed by different HLM preparations was either 2,2',3,4,4',6'-hexachlorobiphenyl-3'-ol (3'-140) or 2,2',3,3',4,6'-hexachlorobiphenyl-5'-ol (5'-132). 2,2',3,3',4,6'-Hexachlorobiphenyl-4'-ol (4'-132) and 2,2',3,3',4,6'-hexachlorobiphenyl-4',5'-diol (4',5'-132) were minor metabolites. The second eluting atropisomer of PCB 132 was slightly enriched in some HLM incubations. The formation of the first eluting atropisomer of 3'-140 was nearly enantiospecific (EF > 0.8). The second eluting atropisomer of 5'-132 was enriched in all microsomal preparations investigated. EF values differed slightly between single donor HLM preparations (EF = 0.84 to 0.96 for 3'-140; EF = 0.12 to 0.19 for 5'-132). These findings suggest that there are inter-individual differences in the atropselective biotransformation of PCB 132 to OH-PCBs in humans that may affect neurotoxic outcomes.

pharmacology and toxicology↗

bioRxiv2017

Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect susceptibility to developmental polychlorinated biphenyl exposure in mice: Relevance to studies of human neurological disorders

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with the discovery of new sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but there is some evidence that high PCB exposure in adults increases the risk of Parkinsons disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect susceptibility to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity AhrbCyp1a2(-/-) mice were most susceptible compared with poor-affinity AhrdCyp1a2(-/-) and wild type AhrbCyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in multiple tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated immune suppression with reduced thymus and spleen weights and significantly reduced thyroxine at P14. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immuno-staining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity AhrdCyp1a2(-/-) while AhrbCyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinsons disease.

pharmacology and toxicology↗