Biology subjects

Sanchez, S. S.

Publications and source records attributed to Sanchez, S. S..

3 recordsLinked to original sources

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↗