Biology subjects

Sille, F. C. M.

Publications and source records attributed to Sille, F. C. M..

6 recordsLinked to original sources

bioRxiv2026

Perinatal exposure to individual and a metal mixture induces persistent and sex-specific alterations to the cardiac transcriptome of offspring

Exposure to heavy metals, such as lead, arsenic, cadmium, and chromium, has been individually linked to cardiac dysfunction during development and into adulthood. Although these metals are commonly encountered as a mixture, few studies have investigated the mixture effects of gestational exposure to these metals on the developing postnatal heart. To this end, we investigated the transcriptomic effects of individual heavy metals (arsenic, cadmium, chromium, and lead) and the combined mixture on female C57BI/6 mice prior to gestation through lactation. RNA was extracted from whole offspring hearts, and total RNA was sent for bulk RNA-sequencing. We found heavy metal exposure altered genes associated with circadian rhythm, cell division and DNA damage repair, and immune signaling. Moreover, we detected changes to the cellular composition of these hearts and an increase in Il2ra expression, indicating an increase in activated natural killer cells. When targeting postnatal heart development and maturation pathways, we found the mixture induced a general upregulation of almost all targeted pathways, which seemed to be driven by co-exposure to all metals instead of one metal driving the mixture phenotype, and revealed a potential functional-energetic mismatch. This study is one of the first to show that perinatal exposure to heavy metals altered circadian rhythm and immune signaling gene expression in a metal- and sex-specific manner, disrupted normal cardiac cellular composition, and upregulated genes associated with postnatal heart maturation.

pharmacology and toxicology↗

bioRxiv2025

Perinatal Exposure to Metal Mixtures Disrupts Neuronal Function and Behavior

BackgroundEnvironmental exposure to heavy metals such as lead (Pb), arsenic (As), hexavalent chromium [Cr(VI)], and cadmium (Cd), (PACC), is linked to neurodevelopmental disorders. These metals often co-occur in contaminated environments, but their combined effects on brain development remain poorly understood. ObjectiveTo test the hypothesis that perinatal exposure to a mixture of environmentally relevant levels of Pb, As, Cd, and Cr(VI), causes developmental defects in cognition, behavior, and neuronal function. MethodsFemale C57BL/6J mice were exposed to either a single metal or the PACC mixture in drinking water. Exposure began two weeks preconception and continued until weaning at postnatal day 21. Juvenile mice were tested at 4-5 weeks of age in open field (locomotion), novel object recognition (short-term memory), Y-maze (working memory), and elevated plus maze (anxiety-like behavior). A subset of animals underwent Whole-cell patch-clamp recordings in the medial prefrontal cortex (mPFC) and hippocampal CA1 neurons. ResultsPerinatal exposure to PACC metal mixture increased anxiety-like behavior and impaired short-term memory but not locomotion or working memory. Pyramidal neurons in mPFC and hippocampal CA1 displayed increased intrinsic excitability, mPFC neurons also showed elevated amplitude in spontaneous excitatory postsynaptic currents. DiscussionOur findings suggest that perinatal exposure to the PACC metal mixture impairs cognition, increases anxiety-like behavior, and alters neuronal function in specific brain regions of juvenile mice, leading to disruption in neuronal function and behavior later in life. Further studies are needed to provide mechanistic insight into how perinatal heavy metal exposure affects neuronal development. HighlightsO_LIPerinatal exposure to a metal mixture including lead (Pb), arsenic (As), hexavalent chromium (Cr(VI)), and cadmium (Cd), collectively termed PACC metal mixture--impairs cognition and increases anxiety in mice. C_LIO_LINeuronal excitability and synaptic transmission are altered in medial prefrontal cortex after PACC metal mixture exposure. C_LIO_LIPACC mixture exposure decreases short-term memory in both males and females, and increases anxiety in males C_LIO_LIPrincipal component and clustering analyses reveal that PACC mixture exposure and control mice form distinct, nonoverlapping populations in physiological-behavioral space. C_LIO_LIEnvironmentally relevant PACC metal mixtures exert stronger effects than individual metals alone. C_LI

pharmacology and toxicology↗

bioRxiv2025

Developmental Immunotoxicity of Low-dose Inorganic Arsenic Reprograms Macrophages Inducing Tumor-promoting Phenotypes

In many regions around the world, including the United States, inorganic arsenic (iAs) contaminates groundwater used for drinking, food production, and irrigation. Although the World Health Organization has set a safety limit of 10 {micro}g/L for arsenic in drinking water, an estimated 200 million people worldwide are still exposed to arsenic concentrations above this threshold. Eliciting a broad range of adverse health effects, arsenic is a known carcinogen classified by the International Agency for Research on Cancer (IARC) and causes increased susceptibility to infectious diseases, highlighting its role as an immunotoxicant. The purpose of this study is to elucidate the effects of arsenic on the innate immune system, namely macrophages, using in vitro exposure models. Bone marrow-derived macrophages (BMDMs) were cultured from adult male and female C57/BL6 mice. These naive macrophages ("M0" BMDMs) were exposed in vitro to a non-cytotoxic dose of iAs (0.1 {micro}M sodium (meta)arsenite) during the 7 day period of macrophage differentiation and stimulated for 24 hrs with LPS and IFN{gamma} (to induce "M1" pro-inflammatory activation) or IL-4 and IL-13 (to induce "M2" anti-inflammatory activation). In a parallel chronic exposure model, RAW 264.7 (RAW) macrophages were cultured in vitro with iAs for 70 days. Culture supernatant analysis for nitric oxide and cytokine secretion revealed sex-dependent differences in immune response between exposure models, as well as between iAs-exposed and nonexposed macrophages, with and without stimulation. Additionally, iAs-exposed macrophages exhibited increased lipid droplet formation and altered lipidomic and metabolomic profiles, as determined by LC/MS. Flow cytometric analysis further revealed changes in macrophage polarization markers in a sex- and stimulation-dependent manner, with M2-related markers being upregulated in iAs-exposed conditions. Finally, to assess the effects of iAs on macrophages in the context of cancer, we demonstrated that iAs-exposed macrophages displayed increased migration toward cancer cell-conditioned media, and promoted cancer cell proliferation. These results suggest that dysregulated macrophage polarization due to iAs exposure could impact susceptibility to diseases. This research contributes to our understanding of the full spectrum of adverse health effects of iAs exposure and may aid in the development of therapeutics for iAs-induced diseases, including cancer.

immunology↗

bioRxiv2024

Prenatal Arsenic Exposure and Gene Expression in Fetal Liver, Heart, Lung, and Placenta

Prenatal arsenic exposure has been linked to a myriad of negative health effects. There is relatively little insight into the mechanisms and signaling alterations across different fetal organs that drive long-term immune-related issues following prenatal arsenic exposure. Therefore, the effects of this exposure window on gene expression in the liver, placenta, heart, and lung of gestation day (GD) 18 C57BL/6 mouse fetuses were investigated. From two weeks prior to mating until tissue collection at GD18, mice were exposed to 0 or 100 ppb sodium (meta) arsenite in drinking water. Genes of interest were analyzed by RT-qPCR, complemented with untargeted Agilent 44K microarray analysis. Data cleanup and analysis was performed in RStudio. Differentially expressed mRNAs were queried in the String Database and using Cytoscape to create interaction networks and identify significantly enriched biological pathways. A total of 251, 165, 158, and 41 genes were significantly altered in the liver, placenta, heart, and lung, respectively, when treated samples were compared to controls. Many altered pathways were immune-related, supporting prior research. Most notably, gene expression of Gbp3, a key player in the cellular response to interferon gamma, was found to be reduced in placentas of female fetuses exposed to arsenic compared to controls (p=0.0762). ImpactThis is the first study comparing alterations in gene expression across multiple organs following prenatal exposure to environmentally relevant levels of arsenic. These findings, elucidating the multi-organ impact of prenatal arsenic exposure on predominantly immune-related pathways, further our mechanistic understanding of the long-term health effects observed in early-life arsenic-exposed populations.

pharmacology and toxicology↗

bioRxiv2023

Subchronic exposure to ambient PM2.5 impairs novelty recognition and spatial memory

Air pollution remains a great challenge for public health, with the detrimental effects of air pollution on cardiovascular, rhinosinusitis, and pulmonary health increasingly well understood. Recent epidemiological associations point to the adverse effects of air pollution on cognitive decline and neurodegenerative diseases. Mouse models of subchronic exposure to PM2.5 (ambient air particulate matter < 2.5 {micro}m) provide an opportunity to demonstrate the causality of target diseases. Here, we subchronically exposed mice to concentrated ambient PM2.5 for 7 weeks (5 days/week; 8h/day) and assessed its effect on behavior using standard tests measuring cognition or anxiety-like behaviors. Average daily PM2.5 concentration was 200 {micro}g/m3 in the PM2.5 group and 10 {micro}g/m3 in the filtered air group. The novel object recognition (NOR) test was used to assess the effect of PM2.5 exposure on recognition memory. The increase in exploration time for a novel object versus a familiarized object was lower for PM2.5-exposed mice (42% increase) compared to the filtered air (FA) control group (110% increase). In addition, the calculated discrimination index for novel object recognition was significantly higher in FA mice (67 %) compared to PM2.5 exposed mice (57.3%). The object location test (OLT) was used to examine the effect of PM2.5 exposure on spatial memory. In contrast to the FA-exposed control mice, the PM2.5 exposed mice exhibited no significant increase in their exploration time between novel location versus familiarized location indicating their deficit in spatial memory. Furthermore, the discrimination index for novel location was significantly higher in FA mice (62.6%) compared to PM2.5 exposed mice (51%). Overall, our results demonstrate that subchronic exposure to higher levels of PM2.5 in mice causes impairment of novelty recognition and spatial memory.

pharmacology and toxicology↗

bioRxiv2023

Transcriptomic Effects of Low-Dose Inorganic Arsenic Exposure on Murine Bone Marrow-Derived Macrophages.

Both tissue-resident macrophages and monocytes recruited from the bone marrow that transform into tissue-resident cells play critical roles in mediating homeostasis as well as in the pathology of inflammatory diseases. Inorganic arsenic (iAs) is the most common drinking water contaminant worldwide and represents a major public health concern. Several diseases that macrophages have implicated involvement in are caused by iAs exposure, including cardiovascular disease, cancer, and increased risk of infectious disease. Therefore, understanding the effects of iAs exposure on macrophages can help us better grasp the full range of arsenic immunotoxicity and better design therapeutic targets for iAs-induced diseases particularly in exposed populations. In this study, we analyzed the transcriptome of low dose iAs-exposed male and female murine bone marrow-derived macrophages (BMDMs) with either M0, M1, or M2 stimulation. We identified differentially expressed genes by iAs in a sex- and stimulation-dependent manner and used bioinformatics tools to predict protein-protein interactions, transcriptional regulatory networks, and associated biological processes. Overall, our data suggest that M1-stimulated, especially female-derived, BMDMs are most susceptible to iAs exposure. Most notably, we observed significant downregulation of major proinflammatory transcription factors, like IRF8, and its downstream targets, as well as genes encoding proteins involved in pattern recognition and antigen presentation, such as TLR7, TLR8, and H2-D1, potentially providing causal insight regarding arsenics role in perturbing immune responses to infectious diseases. We also observed significant downregulation of genes involved in processes crucial to coordinating a proinflammatory response including leukocyte migration, differentiation, and cytokine and chemokine production and response. Finally, we discovered that 24 X-linked genes were dysregulated in iAs-exposed female stimulation groups compared to only 3 across the iAs-exposed male stimulation groups. These findings elucidate the potential mechanisms underlying the sex-differential iAs-associated immune-related disease risk.

pharmacology and toxicology↗