Fry Systems Biology in Toxicology and Environmental Health

1. Auflage 2015
ISBN: 978-0-12-801568-1
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 284 Seiten

Systems Biology in Toxicology and Environmental Health uses a systems biological perspective to detail the most recent findings that link environmental exposures to human disease, providing an overview of molecular pathways that are essential for cellular survival after exposure to environmental toxicants, recent findings on gene-environment interactions influencing environmental agent-induced diseases, and the development of computational methods to predict susceptibility to environmental agents. Introductory chapters on molecular and cellular biology, toxicology and computational biology are included as well as an assessment of systems-based tools used to evaluate environmental health risks. Further topics include research on environmental toxicants relevant to human health and disease, various high-throughput technologies and computational methods, along with descriptions of the biological pathways associated with disease and the developmental origins of disease as they relate to environmental contaminants. Systems Biology in Toxicology and Environmental Health is an essential reference for undergraduate students, graduate students, and researchers looking for an introduction in the use of systems biology approaches to assess environmental exposures and their impacts on human health. - Provides the first reference of its kind, demonstrating the application of systems biology in environmental health and toxicology - Includes introductions to the diverse fields of molecular and cellular biology, toxicology, and computational biology - Presents a foundation that helps users understand the connections between the environment and health effects, and the biological mechanisms that link them

Autoren/Hrsg.

Fry, Rebecca

Fry

Leseproben

Chapter 2 The Cell
The Fundamental Unit in Systems Biology
Paul D. Ray,  and Rebecca C. Fry Abstract
Discerning cellular responses to environmental contaminants requires a basic understanding of the molecular processes of the cell. Metabolomic, transcriptomic, epigenomic, and proteomic responses can be analyzed in tandem to develop a comprehensive working model that predicts how complex biological systems respond to toxicant exposure. These quantitative outputs are the measurable alterations in metabolite levels, gene expression profiles, epigenetic signatures, and the protein expression patterns of the cell. This chapter provides a brief overview of the constituents, organization, and homeostatic processes of the eukaryotic cell, with a focus on the molecular mechanisms that provide quantitative inputs useful for a systems biological perspective. A working knowledge of molecular biology will facilitate an understanding of the molecular processes disrupted by toxicants and an understanding of the biological implications of toxicant exposure. Keywords
Cell; DNA; Environmental exposure; Epigenome; Gene; Protein; Proteome; RNA; Systems toxicology; Transcriptome Contents Introduction 12 The Cell: Structure and Organelles 13 Macromolecules 13 Carbohydrates 14 Lipids 14 Nucleic Acids 15 Proteins 15 Organelles 15 Plasma (Cell) Membrane 15 Cytoplasm 15 Cytoskeleton 15 Nucleus 16 Mitochondrion 16 Endoplasmic Reticulum (ER) and Golgi Apparatus 16 Lysosomes and Peroxisomes 16 Cellular Signaling: Plasma Membrane and Signal Transduction 17 The Plasma Membrane 17 Structure 17 Transport 17 Membrane-Bound Receptors 18 Intracellular Signaling 18 The Phosphatidylinositide 3-Kinase Signaling Pathway 19 Cellular Homeostasis (I): Energy Metabolism 20 Decoding the Genome (I): Transcription 23 DNA Replication 23 The Cell Cycle 26 Regulation of the Cell Cycle 27 DNA Damage Response 29 DNA Damage Detection and Response 30 DNA Damage Repair 30 The Mechanisms of Transcription 30 The Gene Landscape 31 Enhancers, Silencers, and Transcription Factors 32 Preinitiation Complex (PIC) 32 RNA Polymerase 33 Decoding the Genome (II): Translation 35 RNA 36 Processing of mRNA 36 Capping 36 Polyadenylation 36 Splicing 37 Protein Synthesis 37 Amino Acids and Peptide Bonding 37 Codons 37 Transfer RNA (tRNA) 38 Ribosomal RNA (rRNA) and Protein Synthesis 38 Protein Structure and Folding 40 Cellular Homeostasis (II): Cell Differentiation, Death 40 Differentiation 41 Senescence 41 Apoptosis 41 Necrosis 41 References 42 Introduction
The cell is the fundamental unit in the systems biology/toxicology paradigm. Exposure to environmental contaminants may result in tissue, organ, or systemic toxicity in part through altered cellular homeostasis. Specifically, global responses, whether protective or deleterious, originate from the individual responses of cells. This view of the importance of the cell is appropriate in the context of systems biology which seeks to uncover cellular relationships and networks in order to understand the response of the total system. Therefore to predict the systemic effects of contaminant exposure, the molecular mechanisms of cellular homeostasis must be understood, for cellular responses inform the methodologies employed in systems biology. The cell provides a quantifiable response (changes in gene or protein expression) that through systems-level science is incorporated into an integrative framework (adverse cellular or tissue response) to link causative factors such as toxicant exposure with a biological outcome (disease) (Figure 1). A systems biological perspective utilizes cellular responses in the form of alterations in the cellular genetic profiles (genome), global messenger RNA ribonucleic acid (mRNA) expression profiles (transcriptome), global protein expression profiles (proteome), total metabolite levels (metabolome), and the epigenetic alteration signature (epigenome). Therefore, this chapter will focus primarily on the process by which the genome is transcribed into the transcriptome, and subsequently translated into the proteome, with emphasis on intracellular signal transduction and epigenetics, which initiate and regulate transcription and translation, respectively.
Figure 1 Flow of biological response information in a systems biology framework. The Cell: Structure and Organelles
Cells are the primary biological unit of living organisms, with the ability to faithfully pass along to daughter cells the parental genetic information. As this textbook focuses on the effects of environmental contaminants on human health, this chapter focuses on eukaryotic cells. Eukaryotic cells are larger than simple prokaryotic cells, and are more complex, containing membrane-bound subcellular structures called organelles. The genetic code of eukaryotes is enclosed in a membrane-bound organelle called the nucleus; this is a major feature distinguishing eukaryotic cells from prokaryotes. Cellular organelles are surrounded by the cytoplasm, which in turn is contained by an outer cell membrane, or plasma membrane, which separates the inner cell from the environment (Figure 2). Macromolecules
The structural and functional components of the cell are polymeric macromolecules, assembled from carbon-based monomers. Carbon’s unique property of being able to bond with itself and other atoms make it the core element from which a vast number of molecules of diverse structure and function are formed. The increasing complexity of structure and function arises from the addition of oxygen, nitrogen, sulfur, hydrogen, and phosphorous atoms. The cell is mainly composed of four distinct classes of macromolecules: carbohydrates, lipids, nucleic acids, and proteins.
Figure 2 The eukaryotic cell. Carbohydrates Carbohydrates, or sugars, are key sources of energy. They are generally categorized into three classes: monosaccharides, disaccharides, and polysaccharides. Simple sugars, or monosaccharides, are categorized based on the number of carbon atoms they contain. Examples are glucose and ribose. Disaccharides are composed of two linked monosaccharides, such as sucrose, while polysaccharides are made up of large numbers of monosaccharides. Glycogen is an energy storing polysaccharide composed of glucose monomers. Lipids Lipids are a structurally diverse class of biomolecules whose common characteristic is low solubility in water. This class includes oils and fats and is loosely grouped by structure. For example, fatty acids and phospholipids are members of those lipids with an open chain structure, having a hydrophobic nonpolar “tail” and a charged polar “head” component. Many biological membranes are composed of this class of lipids, as will be discussed in the section on the cell membrane. The second major class is ringed lipids, known collectively as steroids, of which cholesterol is a member. Steroids serve important roles in intercellular signaling. Nucleic Acids Nucleic acids carry the genetic “code” of the cell. Nucleic acids are polymers of nucleotides: a sugar (deoxyribose or ribose) ring, phosphate groups, and a purine or pyrimidine base. Deoxyribonucleic acid (DNA) encodes the genetic information of the cell. DNA is composed of a deoxyribose ring and one of four bases: adenine, guanine, cytosine, and thymine. These four bases comprise the genetic code. Ribonucleic acid (RNA) is transcribed from DNA, the “print-out” of the genetic code. It is RNA that directs protein synthesis. Proteins Proteins, or polypeptides, are a chain of amino acids whose sequence is dictated by the RNA transcript. Proteins are the workhorses of the cell, carrying out a vast array of cellular functions from structure to enzymatic reactions. Polypeptides are assembled at ribosomes on the rough endoplasmic reticulum (rER) and are processed and folded into primary, secondary, and tertiary structures. Organelles
Plasma (Cell) Membrane The plasma membrane forms the exterior of the cell, separating the cytosol and nucleus from the environment (Figure 2). The cell membrane serves to protect the cell and regulates transport of molecules in and out of the cell. The plasma membrane is primarily composed of a lipid bilayer and transport proteins. Cytoplasm The cytoplasm is the cytosol and the organelles of the cell. The cytoplasm is bound by the plasma membrane. Cytosol is the aqueous component in which the organelles...