天美传媒

Cell SIGNALLING; Toxicity; Toxicants; Signal TRANSDUCTION; Oxidative STRESS; Inflammation; Apoptosis; Cancer; Health; Disease

Introduction

Cell signaling plays a pivotal role in regulating cellular functions and maintaining homeostasis. Signal transduction pathways facilitate communication between cells and allow them to respond to various stimuli, including growth factors, hormones, and environmental changes [1]. However, exposure to toxicants, such as heavy metals, pesticides, pharmaceuticals, and pollutants, can interfere with normal cell signaling, leading to pathological conditions. The disruption of these signaling networks may result in altered cellular responses, including uncontrolled cell proliferation, immune dysregulation, and even cell death [2]. This article discusses the key aspects of cell signaling in toxicity, including the types of toxicants involved, the mechanisms through which they interfere with signaling pathways, and the potential health implications of such disruptions [3].

Mechanisms of Cell Signaling and Toxicity

Cell signaling pathways are initiated when molecules (ligands) bind to specific receptors on the cell surface or inside the cell [4]. These receptors activate intracellular signaling cascades, which regulate various cellular functions. The primary components involved in cell signaling include:

Receptors: These are proteins that detect extracellular signals, such as hormones, growth factors, or toxicants. They are typically located on the cell surface (G-protein coupled receptors, receptor tyrosine kinases) or within the cell (intracellular receptors for steroid hormones) [5].

Second messengers: Once receptors are activated, they trigger the production of intracellular signaling molecules known as second messengers (e.g., cyclic AMP, calcium ions). These molecules amplify the signal and activate downstream signaling pathways [6].

Signaling molecules and pathways: The activated second messengers initiate signaling pathways, such as the MAPK/ERK pathway, PI3K/Akt pathway, or JAK/STAT pathway. These pathways regulate gene expression, cell cycle progression, differentiation, and survival.

Effector proteins: These proteins carry out the cellular response to the signal, such as activating enzymes, altering the cytoskeleton, or modifying gene expression [7].

Toxicants can interfere with any of these steps, leading to cellular dysfunction. The key mechanisms through which toxicants disrupt cell signaling include:

Receptor-mediated interference: Many toxicants mimic or antagonize natural ligands, binding to receptors and altering the signaling process. For example, endocrine-disrupting chemicals (EDCs) such as bisphenol A (BPA) can bind to estrogen receptors and either mimic or block estrogen’s effects, leading to reproductive toxicity and developmental abnormalities.

Oxidative stress: Toxicants like heavy metals (e.g., cadmium, lead) and environmental pollutants (e.g., cigarette smoke, air pollution) can generate reactive oxygen species (ROS) or reactive nitrogen species (RNS). ROS and RNS can damage cellular components and activate stress response pathways such as the NF-kB and MAPK pathways. This can lead to inflammation, cell damage, and the initiation of cancerous processes.

Inflammation and immune modulation: Chronic exposure to certain toxicants, including industrial chemicals, pesticides, and pollutants, can trigger persistent inflammation by disrupting immune signaling pathways. Toxicants may activate pro-inflammatory cytokines (e.g., TNF-alpha, IL-6), leading to chronic inflammation, which is associated with various diseases, including atherosclerosis, cancer, and autoimmune conditions.

Apoptosis and necrosis: Toxicants can disrupt cell signaling pathways involved in regulating cell survival and death. Chemicals such as chemotherapeutic agents, heavy metals, and pesticides may activate apoptotic pathways (e.g., intrinsic or extrinsic pathways) or cause necrosis. Dysregulated apoptosis can result in tissue damage, cancer development, or neurodegeneration, while excessive necrosis contributes to inflammation and organ dysfunction.

DNA damage and genomic instability: Certain toxicants can induce DNA damage through the generation of ROS, UV radiation, or direct interaction with DNA. Toxicants such as arsenic and certain chemotherapeutic agents can disrupt DNA repair pathways and activate DNA damage response (DDR) pathways. If left unchecked, this can lead to mutations, chromosomal instability, and carcinogenesis.

Consequences of Disrupted Cell Signaling in Toxicity

When toxicants interfere with cell signaling pathways, the results can be detrimental to cellular function and organismal health. Some of the major consequences include:

Cancer development: Disruptions in signaling pathways that control cell proliferation, apoptosis, and differentiation are closely linked to cancer development. For example, mutations in the PI3K/Akt/mTOR pathway can result in uncontrolled cell growth, while DNA damage due to oxidative stress can lead to the accumulation of mutations in oncogenes or tumor suppressor genes. Chronic exposure to carcinogens such as tobacco smoke, asbestos, and certain industrial chemicals can activate oncogenic signaling pathways, facilitating tumorigenesis.

Neurodegenerative disorders: Toxicants such as pesticides, heavy metals, and air pollutants have been linked to neurodegenerative diseases like Parkinson’s and Alzheimer’s. Disruption of neurotrophic signaling, oxidative stress, and inflammation can accelerate neuronal degeneration. For example, exposure to pesticides like paraquat can inhibit the Akt/PI3K pathway, impairing neuronal survival and function, and contributing to the pathogenesis of neurodegeneration.

Immune system dysfunction: Toxicants can modulate immune signaling pathways, leading to immune suppression or hyperactivation. For instance, exposure to certain heavy metals can impair immune function by disrupting signaling pathways involved in immune cell activation and cytokine production. Chronic exposure to toxicants can result in autoimmune diseases, where the body’s immune system attacks its own tissues, or hypersensitivity reactions such as asthma.

Endocrine disruption: Endocrine disruptors, including BPA, phthalates, and certain pesticides, can interfere with hormonal signaling pathways, leading to reproductive toxicity, developmental disorders, and metabolic diseases. These toxicants can bind to hormone receptors, alter hormone synthesis, or disrupt the feedback mechanisms that regulate endocrine functions. This can lead to developmental abnormalities, fertility issues, and an increased risk of metabolic disorders such as obesity and diabetes.

Chronic inflammation: Toxicants that activate inflammatory pathways can contribute to chronic inflammation, a key driver of several diseases, including cardiovascular disease, diabetes, and chronic respiratory conditions. Persistent inflammation caused by pollutants like particulate matter (PM) or industrial chemicals leads to tissue damage, fibrosis, and impaired organ function.

Conclusion

Cell signaling is a critical process that regulates cellular functions and maintains health. Disruption of signaling pathways by toxicants can lead to a wide range of pathological conditions, including cancer, neurodegenerative diseases, immune dysfunction, and endocrine disruption. Understanding the mechanisms by which toxicants interfere with cell signaling can provide valuable insights into disease development and help identify potential therapeutic targets. By addressing environmental and lifestyle factors that contribute to toxic exposures, it may be possible to mitigate the adverse effects of toxicity and improve public health outcomes. Further research into the molecular mechanisms of toxicity and cell signaling is essential for developing safer chemicals and effective interventions that protect human health from toxic insults.

1. Kovess-Masfety V, Keyes K, Hamilton A, Hanson G, Bitfoi A, et al. (2016) Soc Psychiatry Psychiatr Epidemiol 51: 349-357.

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2. Maselko J, Sikander S, Bangash O, Bhalotra S, Franz L, et al. (2016) . Soc Psychiatry Psychiatr Epidemiol 51: 49-62.

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3. Berg-Nielsen TS, Solheim E, Belsky J, Wichstrom L (2012) . Child Psychiatry Hum Dev 43: 393-413.

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4. Pérez-Bonaventura I, Granero R, Ezpeleta L (2015) . J Pediatr Psychol 40: 455-463.

, ,

5. Sawyer MG, Miller-Lewis L, Guy S, Wake M, Canterford L, et al. (2006 Ambul Pediatr 6: 306-311.

, ,

6. Hestetun I, Svendsen MV, Oellingrath IM (2015) . Eur Child Adolesc Psychiatry 24: 319-326.

, ,

7. Hinkley T, Verbestel V, Ahrens W, Lissner L, Molnár D, et al. (2014) . JAMA Pediatr 168: 485-492.

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