Biomarkers in Toxicology (Biomarkers in Disease: Methods, Discoveries and Applications)

Preface
Series Preface
Contents
About the Editors
Contributors
Part I: Single Components
	1 Soluble Guanylyl Cyclase Alpha1 Subunit as a Biomarker of Toxicity: Applications to Investigate Endocrine-Disrupting Chemica...
		Introduction
		Endocrine-Disruptor Compounds (EDCs)
		Estrogens
		Xenoestrogens
		Current Screening Methods
		Estrogen Receptor Binding Assay Using Rat Uterine Cytosol (ER-RUC)
		Estrogen Receptor Transcriptional Activation
		Steroidogenesis (Human Cell Line: H295R)
		Rat Uterotrophic Assay
		Rat Female Pubertal Assay
		Fish Short-Term Reproduction Assay with Fathead Minnow (Pimephales promelas)
		Soluble Guanylyl Cyclase
		Estrogen and Soluble Guanylyl Cyclase
		sGCα1 Subunit as a Biomarker of Exposure
		Applications to Other Diseases or Conditions
		Mini-dictionary of Terms
		Key Facts of Endocrine-Disrupting Chemicals
		Summary Points
		Cross-References
		References
	2 Serum Paraoxonase 1 as a Biomarker in Toxicology
		Introduction
			Biochemical Properties and Gene Structure of Paraoxonase 1
			Applications to Prognosis, Other Diseases, or Conditions
				Organophosphate Exposure
				Lipid Peroxidation
				Liver Toxicity
		Key Facts of Cirrhosis
		Key Facts of Coronary Heart Disease (CHD)
		Mini-dictionary of Terms
		Summary Points
		References
	3 Erythrocyte Acetylcholinesterase as a Biomarker of Environmental Lead Exposure
		Introduction
		Chemistry, Forms, and Properties of Lead
		Sources and Routes of Environmental Lead Exposure
		Toxicokinetics of Lead
			Absorption, Distribution, and Elimination of Lead
		Toxicodynamics of Lead
			Lead and Hematological Toxicity
			Lead and Renal Toxicity
			Lead and Cardiovascular Disease
			Lead and Reproductive Toxicity
			Lead and Bone Metabolism
			Lead and Neurotoxicity
		Cholinergic System
		Acetylcholinesterase
		Extraction and Purification of Erythrocyte Acetylcholinesterase
		Erythrocyte Acetylcholinesterase in Biological Monitoring of Environmental Lead Exposure
		Blood Lead Level Versus Erythrocyte Acetylcholinesterase in Lead-Induced Neurotoxicity
		The Possible Mechanisms Surrounding the Interference of Lead with Erythrocyte Acetylcholine Activity
		Application of Erythrocyte Acetylcholinesterase to Prognosis
		Application of Erythrocyte Acetylcholinesterase to Other Conditions
		Mini-Dictionary of Terms
		Key Facts of Environmental Lead Exposure
		Key Facts of Erythrocyte Acetylcholinesterase as a Biomarker of Environmental Lead Exposure
		Summary Points
		Cross-References
		References
	4 Fortilin as a Biomarker in Toxicity
		Introduction
		Fortilin Characterization
		Fortilin Functions
		Fortilin Roles in Cell Growth and Organ Development Process
		Regulation of Protein Synthesis and Degradation
		Biological Stress Reactions and Autophagy
		Fortilin-ion Relationship
			Fortilin and Sodium-Potassium ATPase
			Fortilin and Calcium Ion
		Fortilin´s Role in Apoptosis
		Fortilin and p53-Independent Antiapoptosis
		Fortilin and p53-Dependent Antiapoptosis
		Fortilin as a Biomarker of Toxicity
		Fortilin Investigation Methods
		Northern, Southern, and Western Blot
		Immunocytochemistry and Immunohistochemistry
		Yeast Two-Hybrid Assay (Y2H)
		Enzyme-Linked Immunosorbent Assay (ELISA)
		Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) Analysis
		Recommendations
		Applications to Prognosis
		Applications to Other Diseases or Conditions
		Mini-dictionary of Terms
		Key Facts of Fortilin and Fortilin Recombinant
		Summary Points
		References
	5 Antibodies as Biomarkers: Effect of Microcystin Exposure
		Introduction: Cyanobacteria, Their Toxins, and Health Risk
		Microcystins: Structure and Toxicity Mechanisms
			Chemical Structure
			Molecular Mechanisms of Toxicity
				Alterations of Cell Cycle
				Toxicity on Organs
					In Vivo Studies
					In Vitro Studies
		Biomarkers
			Definition and Applications
			Biomarkers of Microcystin Exposure
			Antibodies as Biomarkers
			Isotype Switch of Antibodies
			Antibodies Against Microcystins
		Applications to Prognosis
		Mini-dictionary of Terms
		Key Facts of Antibodies as Biomarkers: Effect of Microcystin Exposure
			Key Facts of Cyanobacterial Blooms
			Key Facts of Microcystins
		Key Facts of Human Intoxications with Microcystins
		Summary Points
		Cross-References
		References
	6 Gamma-H2AX Expression as a Biomarker of Carcinogenesis: Applications to Toxicology
		Introduction
		Histone H2AX
		Phosphorylation of H2AX (γH2AX)
		Functions of γH2AX
		Methods of γH2AX Detection
		The Relationship Between γH2AX Formation and Carcinogens
		Radiation
		Oxidative Stress
		Chemicals
		γH2AX Formation as Genotoxic Biomarker in In Vitro Studies
		γH2AX Formation as Biomarker of Carcinogen in In Vivo Studies
		γH2AX Formation as Biomarker in Clinical Studies
		γH2AX as a Prognostic Marker in Several Cancer Types
		Conclusion
		Mini-dictionary of Terms
		Key Facts of Genotoxicity
		Summary Points
		References
	7 The Carcinogen Glycidol and Use of N-(2,3-Dihydroxypropyl)-valine in Hemoglobin as a Biomarker of Exposure
		Introduction
			Occurrence and Toxicological Relevance of Glycidol
			Human Exposure and Aspects of Hazard Characterization
			Exposure Assessment of Glycidol
		Biomarkers of Glycidol Exposure: Methodological Considerations
			Biomarkers of Short- and Medium-Term Exposure
			Edman Degradation and Mass Spectrometric Quantification of DHP-Val in Hb
		Applications of DHP-Val as Biomarker of Glycidol Exposure
			DHP-Val in Blood Samples from Rats and Humans
			DHP-Val in Cord and Maternal Blood: Prenatal Exposure to Glycidol
			Estimation of External Glycidol Exposure Using DHP-Val (Reverse Dosimetry)
		Important Considerations for the Application of DHP-Val as Biomarker of Glycidol Exposure
			Unknown Exposure Sources of Glycidol
			Biomarker Specificity: Other Xenobiotic Precursors of DHP-Val?
			DHP-Val from Endogenous Exposure to Glycidol or Other Reactants?
		Mini Dictionary
		Key Facts of Valine Adducts in Hb
		Summary
		References
	8 Biomarkers of Antibiotic Toxicity: A Focus on Metronidazole
		Introduction
		Overview of Metronidazole
			Mode of Action
			Pharmacokinetics and Toxicity
		Biomarkers of Antibiotic-Induced Toxicity
			Biomarkers of Nephrotoxicity
			Hepatotoxicity Biomarkers
			Neurotoxicity Biomarkers
			Genotoxicity Biomarkers
		Application to Prognosis
		Mini-Dictionary of Terms
		Key Facts of Antibiotic-Induced Toxicity
		Summary Points
		Conclusion
		Cross-References
		References
Part II: Panels and Arrays
	9 Pro-inflammatory Markers of Environmental Toxicants
		Introduction
		Polycyclic Aromatic Hydrocarbons (PAHs): Toxic Effects and Organ Damage
		Effects of PAHs on Blood Biomarkers
		The Effect of Inflammatory Biomarkers
		Effects of PAH on Oxidative Stress and Mitochondrial Damage
		Natural Antioxidants as Remedy Against PAH Toxicity
		Phellinus torulosus as a Prophylactic Against DMBA Hepatotoxicity
		P. torulosus Effects on TSPO Binding Potential
		Studies About the Hepatoprotective Effects of Phellinus spp.
		Applications to Prognosis, Other Diseases, or Conditions
		Mini-dictionary of Terms
		Key Facts of PAH-Derived Inflammation
		Summary Points
		References
	10 Oxidative Stress Biomarkers and Their Applications to Detect Excessive Fluorine
		Introduction
			Sources of Fluoride Intake and Distribution in the Body
		Influence of Fluorides on Organs and Systems
			Effects on the Skeletal System and Teeth
			Nervous System
			Blood and Cardiovascular System
			Gastrointestinal System
			Urinary System
			Respiratory System
			Reproductive System
			Endocrine System
			Immune System
			Skin
		Oxidative Stress Biomarkers and Applications to Detect Excessive Fluorine
			Biomarkers of Cell Redox Status
			Transcription and Translation Processes
			Biomarkers of Cell Membrane Permeability
			Biomarkers of Intracellular Signaling Pathways
			Biomarkers of Programmed Cell Death (Apoptosis)
			Alterations in Cell Metabolism
			Applications to Prognosis
		Mini-dictionary of Terms
		Key Facts of Fluorosis
		Summary Points
		Cross-References
		References
	11 Biomarkers of Alcohol Toxicity
		Introduction
		Alcohol as a Silent Universal Killer
		Direct and Indirect Markers of Alcohol Use
		Clinical Methods
		Instrumental Methods
		Classification of Biological Markers
		Biochemical Methods
		Immunochemistry Tests
		Alcoholic Cardiomyopathy
		Conclusions
		Prospects for Further Research
		Applications to Prognosis
		Mini-dictionary of Terms
		Key Facts About Alcohol
		Summary Points
		References
	12 Biomarkers of Liver Injury due to Toxic Agents: Progress, Current Applications, and Emerging Directions
		Introduction
		Current Liver Injury Biomarkers
		Limitations of the Current Biomarkers
		Emerging Biomarkers of Etiology and Exposure
		Emerging Predictive Biomarkers
		Emerging Prognostic Biomarkers
		Emerging Biomarkers with Greater Specificity
		Mechanistic Biomarkers
		Summary and Conclusions
		Applications to Prognosis
		Applications to Other Diseases or Conditions
		Mini-dictionary of Terms
		Key Facts of Acetaminophen
		Key Facts of Acute Liver Injury
		Key Facts of Acute Liver Failure
		Key Facts of Drug-Induced Liver Injury
		Key Facts of Pyrrolizidine Alkaloids
		Summary Points
		Cross-References
		References
	13 Biomarkers for Assessing Mycotoxin Exposure and Health Effects
		Introduction
		Regulations for Mycotoxins
		Biomarkers of Exposure to Mycotoxins
			Biomarkers of Aflatoxin Exposure
			Biomarkers of Ochratoxin A Exposure
			Biomarkers of Fumonisin Exposure
			Biomarkers of Deoxynivalenol Exposure
			Biomarkers of Zearalenone Exposure
		Biomarkers of Mycotoxins Health Effects
			Aflatoxins
			Ochratoxin A
			Deoxynivalenol
			Fumonisins
			Zearalenone
		Concluding Remarks
		Applications to Prognosis, Other Diseases, or Conditions
		Mini-Dictionary of Terms
		Key Facts of Mycotoxin Biomarkers
		Summary Points
		Cross-References
		References
	14 Metabolomics Profiling of Di-(2-propylheptyl) Phthalate (DPHP) Biotransformation Products as Exposure Markers: Analytical S...
		Introduction
		DPHP Exposure Marker Discovery
			Workflow of DPHP Exposure Marker Discovery
			Sample Preparation and LC-MS Analysis
			MS Data Processing Approaches
			Dose-Response Verification
			Chemical Structure Identification of DPHP Exposure Markers
		Applications of DPHP Exposure Markers in Biospecimens
			DPHP Exposure Markers in the Human Urine Sample
			DPHP Exposure Markers in Hair Samples
		Mini-dictionary of Terms
		Key Facts of DPHP Exposure Markers
		Summary Points
		References
	15 Biomarkers of Neurotoxicity
		Introduction
		Biomarkers of Oxidative Stress
			Oxidative Stress: Definition, Causes, and Effects
			Biomarkers
			Products of Lipid Peroxidation
				F2-Isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NeuroPs)
				Isofurans (IsoFs) and neurofurans (NeuroFs)
				Malondialdehyde (MDA)
				4-Hydroxy-2-nonenal (4-HNE)
			Products of Nucleic Acid Oxidation
				8-Hydroxydeoxyguanosine (7,8-dihydro-8-oxodeoksyguanosine, 8-OHdG) and 8-hydroxyguanosine (7,8-dihydro-8-oxoguanosine, 8-OHG)
			Other Products of Oxidation
				Protein Carbonyl and Protein Nitration
				Advanced Glycosylated End Products (AGEs)
			Biomarkers of Antioxidant Defense
		Neuroinflammation and Xenobiotics
		The Role of Metabolic Disturbances in the Neurotoxic Effects of Xenobiotics
			The Metabolic Disturbances Induced by Heavy Metals
			Metabolic Disturbances in the Neurotoxic Effects of Pesticides
			Sevoflurane: Disturbances of Glucose Metabolism and Iron Homeostasis
		Excitotoxicity Induced by Xenobiotics
		Types of Xenobiotic-Induced Nerve Cell Death
		Conclusion
		Mini-dictionary of Terms
		Key Facts About Mechanisms of Neurotoxicity and Their Biomarkers
		Summary Points
		Cross-References
		References
Part III: Genetic, Cellular, and Histological Variables
	16 Genetic and Epigenetic Biomarkers Related to 2-Oxoglutarate/Fe(II)-Dependent Oxygenases and Implications for Disease and To...
		Introduction
		DNA Biomarkers
			3-Methylcytosine (m3C) and 1-Methyladenosine (m1A)
			1-Methylguanine (m1G) and 3-Methylthymine (m3T)
			4-Methylcytosine (m4C) and 2-Methylguanine (m2G)
			O6-Methylguanosine (O6mG)
			5-Methylcytosine (m5C), 5-Hydroxymethylcytosine (hm5C), 5-Formylcytosine (f5C), and 5-Carboxylcytosine (ca5C)
			N6-Methyladenine (m6A)
			Thymine and β-D-Glucopyranosyloxymethyluracil (Base J)
			Other Simple Alkylated DNA Biomarkers
			Exocyclic DNA Biomarkers
		RNA Biomarkers
			3-Methylcytosine and 1-Methyladenine
			3-Methyluracil (m3U)
			1-Methylguanine and N2,N2-Dimethylguanine (m22G)
			5-Methylcytosine, 5-Hydroxymethylcytosine, 5-Formylcytosine, 5-Hydroxymethyl-2′-O-Methylcytosine, and 5-Formyl-2′-O-Methylcyto...
			N6-Methyladenine
			5-Carboxymethyluridine (cm5U) and 5-Methoxycarbonylmethyluridine (mcm5U)
		AlkB Family and TET/JBP Family Enzymes
		Brief Summary of Spectroscopic and Computational Studies
		Applications to Prognoses, Other Diseases, or Conditions
		Conclusions and Perspectives
		Mini-Dictionary of Terms
		Key Facts of 2-Oxoglutarate/Fe(II)-Dependent Oxygenases
		Summary Points
		References
	17 DNA Adducts as Biomarkers in Toxicology
		Introduction
		32P Postlabeling
		Antibody-Based Methods
		MS Methods
			Accelerator MS (AMS)
			Gas Chromatography-MS (GC-MS)
			LC-MS/MS
		DNA Adducts as Biomarkers for Alcohol Consumption
			Acetaldehyde DNA Adducts
			Crotonaldehyde DNA Adducts
		Radiation-Induced DNA Adducts
			UV-Induced DNA Adducts
			IR-Induced DNA Adducts
		Heterocyclic Aromatic Amine (HAA) DNA Adducts
			2-Amino-3,8-Dimethylimidazo[4,5-f] Quinoxaline (MeIQx)
			2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine (PhIP)
		Aromatic Amine DNA Adducts
			4-Aminobiphenyl (4-ABP)
		Aflatoxin B (AFB) DNA Adducts
		Aristolochic Acid DNA Adducts
		N-nitroso Compound (NOCs) DNA Adducts
		Aromatic Hydrocarbon DNA Adducts
			Benzene
			Benzo[α]pyrene (BaP)
			Nitrosamines
		Carbonyl Adducts
			Acrolein
			Methylglyoxal (MG)
			Formaldehyde
		Pesticides
		Butadiene
		Chemotherapy-Induced DNA Adducts
			Platinum (Pt)-Based Chemotherapy Drugs
			Temozolomide
			Mitomycin C
			Tamoxifen
		Applications to Prognosis
		Key Facts of DNA Biomarkers in Toxicology
		Mini-Dictionary of Terms
		Summary Points
		Cross-References
		References
	18 DNA Methylation as a Biomarker and Application to Aluminum: ADRB2 5′-Untranslated Region (5′-UTR) Methylation Level
		Introduction
		Bronchial Asthma
		The β-2 Adrenergic Receptor (ADRB2)
		Aluminum
		Aluminum and ADRB2 5′-Untranslated Region (5′-UTR) Methylation Level
		Bronchial Asthma and Epigenetic Events
		Potential Applications to Prognosis
		Mini-dictionary of Terms
		Key Facts
		Summary Points
		References
	19 Autophagy as a Biomarker of Cytotoxicity
		Introduction
		Autophagy and Its Membrane Biogenesis
		Selective Autophagy, LC3-Associated Phagocytosis (LAP), and Amphisomes
		Measurement of Autophagy Flux
		Cytotoxic and Cytoprotective Roles of Autophagy
		Biomarkers in Autophagy-Induced Cytotoxicity
		Conclusions and Implications for Autophagy Biomarkers of Cytotoxicity
		Applications for Prognosis of Other Diseases or Conditions
		Mini-dictionary of Terms
		Key Facts of Autophagy Membrane Biogenesis
		Summary Points
		References
	20 Erythrocyte Glutathione Transferase P1-1 as a Biomarker in Environmental Toxicology: A New Narrative
		Introduction
		GSTs and Toxin Exposure
		The Peculiar Molecular Properties of GSTP1-1
		Activity Detection of GSTP1-1 in Biological Samples: Critical Points
		GSTP1-1 Polymorphism
		GSTP1-1: An Enzyme Dedicated to Biomedical Applications
		Hyper-Expression of GSTP1-1
		Tissue Distribution of GSTP1-1 in Humans
		GSTP1-1 in Human Pathologies
		e-GST as a Long-Term as Well as a Short-Term Biomarker of Blood Toxicity
		Human e-GST as Biomarker in Environmental Toxicology
		Mammalian e-GST as Biomarker in Environmental Toxicology
		e-GST in Fish Erythrocytes
		e-GST as Biomarker in Environmental Toxicology in Other Animal Species
		Future Perspective and Clinical Applications
		Applications to Prognosis and Diseases
		Mini-dictionary
		Key Facts of Glutathione Transferase
		Summary Points
		References
	21 Extracellular MicroRNAs as Putative Biomarkers of Air Pollution Exposure
		Introduction
		Methods of MiRNA Measurement
			Sample Types
			Sample Processing
			Sampling MiRNAs from Different Biological Contexts
			Expression Analysis
		Effects of Air Pollution on MiRNA Expression
			Effects of PM Exposure
			Effects of Diesel Exhaust Exposure
			Effects of Ozone Exposure
			Effects of NOx Exposure
			Effects of SOx Exposure
			Effects of Wildfire Smoke Exposure
			Air-Pollution-Induced Effects Through MiRNA Regulation
		Future Perspectives
			Application
			Limitation
		Conclusions
		Applications to Prognosis
		Applications to Other Diseases or Conditions
		Mini-dictionary of Terms
		Key Facts of MicroRNA
		Summary Points
		Cross-References
		References
	22 Endothelial Extracellular Vesicles as Biomarkers of Toxic Molecules
		Introduction
		EVs´ Classification
		Isolation of Endothelial EVs
			Ultracentrifugation-Based Techniques
			Size Exclusion Chromatography (SEC)
			Ultrafiltration
			Polymer-Based Precipitation
			Immunoaffinity-Based Techniques
		Analysis of Endothelial EVs
			Electron Microscopy
			Atomic Force Microscopy (AFM)
			Nanoparticle Tracking Analysis (NTA)
			Dynamic Light Scattering (DLS)
			Flow Cytometry
			Proteomics
			Transcriptome
				qRT-PCR
				Next-Generation Sequencing (NGS/RNA-seq)
				Microarrays
			Other Techniques
		Endothelial EVs in Cardiovascular Diseases and Kidney Diseases
			EVs and Cardiovascular Diseases
			EVs and Kidney Diseases
		Final Considerations
		Applications to Prognosis
		Mini-Dictionary of Terms
		Key Facts of Cardiovascular Diseases
		Key Facts of Chronic Kidney Disease
		Summary Points
		Cross-References
		References
Part IV: Functional and Physiological Variables and Platforms
	23 Biomarkers of Lead Exposure: Platforms and Analysis
		Introduction
			Biological Matrices and Lead Exposure Biomarkers
			Teeth
			Bone
			Nail
			Blood
			Plasma
			Urine
			Saliva
			Hair
		Elemental Analysis
		Sample Preparation
		Instrumental Analysis
		Applications to Prognosis, Other Diseases, or Conditions
		Dictionary of Terms
		Summary Points
		References
	24 Murine Embryonic Stem Cells as Platform for Toxicity Studies: Use of Human Survivin Promoter with Green Fluorescent Protein...
		Introduction
		Limitations of Animal Models
		In Vitro Assays for Developmental Toxicity Assessment
			MM Test
			WEC Test
			Zebrafish Embryo Assay
			Frog Embryo Teratogenesis Assay
			Embryonic Stem Cell Test (EST)
		mESC-Based Reporter Gene Assays
			EST with Luciferase Reporter Gene
			EST with GFP Reporter Gene
		mESCs for HTS of Embryotoxic Chemicals
			Survivin as a Biomarker for Apoptosis Inhibition and Embryotoxicity Screening
			Other Potential Biomarkers for Embryotoxicity Screening
		Conclusion
		Summary Points
		References
	25 LC-MS-Based Metabolomics in the Identification of Biomarkers Pertaining to Drug Toxicity: A New Narrative
		Introduction
		Metabolomics
			Analytical Platforms in Metabolomics
				NMR-Based Metabolomics
				MS-Based Metabolomics
			Types of Metabolomics
		LC-MS-Based Metabolomics: Workflow and Experimental Design for Drug Toxicity
			Experiment Design
			Sample Collection and Preparation
			Data Acquisition and Analysis
			Data Explanation and Biological Question Addressing
		Applications of LC-MS-Based Metabolomics for the Study of Drug Toxicity
			The Roles of Metabolomics in Drug Toxicity
				Screening Drug Metabolites
				Identifying Biomarker and Mechanisms of Drug Toxicity
			Drug-Induced Hepatotoxicity
			Drug-Induced Toxicity in Other Organs
		Discussion and Future Directions of Biomarker Identification
		Applications to Other Diseases or Conditions
		Mini-dictionary of Terms
		Key Facts of ``LC-MS-Based Metabolomics in the Identification of Biomarkers Pertaining to Drug Toxicity: A New Narrative´´
		Summary Points
		Cross-References
		References
	26 Bovine Whole Blood Cells as a Biomarker Platform for Biological Toxicology: A Focus on Thiacloprid
		Introduction
		Neonicotinoid Insecticides
		Thiacloprid
		Genotoxicity of Thiacloprid
		Genotoxicity of Other Neonicotinoids
		Bovine Cell Cultures
		Applications to Prognosis, Other Diseases, or Conditions
		Mini-dictionary
		Key Facts
		Summary Points
		Cross-References
		References
	27 Blood-Brain Barrier Function as a Biomarker in Toxicology: Impact of Environmental Toxicants
		Introduction
		Overview of the Blood-Brain Barrier
		Blood-Brain Barrier Dysfunction as a Biomarker of Toxicity and Disease
			Polycyclic Aromatic Hydrocarbons
			Dioxins
			Perfluoroalkyl Substances
			Heavy Metals
			Airborne Toxicants and Pollutants
		Approaches to Studying BBB Permeability
			Postmortem and In Situ Assessment
			In Vivo Neuroimaging
			Ex Vivo Resected Blood Vessel Assay
			In Vitro Platforms
				Electrical Cell-Substrate Impedance Sensing (ECIS)
				Transwell Scaffold Model
				Organoids
				Chips/Microfluidics
				Other Platforms
		Conclusion
		Applications to Prognosis and Other Diseases or Conditions
		Mini-Dictionary of Terms
		Key Facts of Blood-Brain Barrier Function as a Biomarker Platform in Toxicology: Impact of Toxicants
		Summary Points
		Cross-References
		References
	28 Anogenital Distance: Features, Measures, and Uses as a Biomarker for Toxicity In Utero
		Introduction
		Sex Determination and the Early Stages of Sexual Development
		Androgen-Dependent Masculinization
		Why Measure AGD
			AGD in Rodent Toxicity Studies
			AGD in Human Epidemiological Studies
		How AGD Is Measured
			AGD Measurements in Rodents
			AGD Measurement in Humans
		Final Remarks
		Application to Other Diseases or Conditions
		Mini-dictionary of Terms
		Key Facts of Androgen-Dependent Sexual Development
		Summary Points
		References
	29 Micronucleus Assay in Lymphocytes for Human Biomonitoring and Clinical Studies
		Introduction
			Occupational and Environmental Monitoring
			Micronuclei in Lymphocytes in the Clinical Settings
			Applications to Prognosis
		Key Facts of Micronucleus Assay in Lymphocytes for Human Biomonitoring and Clinical Studies
		Mini Dictionary of Terms
		Summary Points
		References
	30 Salivary Biomarkers in Toxicology: An Update Narrative
		Introduction
		General Aspects
			Biomarkers and Classes of Biomarkers
			Saliva as a Biological Fluid for the Detection of Markers and Biomarkers for Diagnosis and Toxicology Assessment
			Toxicology and Biomarkers
			Biomarkers of Exposure
			Biomarkers of Response or Toxic Effect
			Biomarkers of Susceptibility
		Analytical Methods
			Separation Methods
			Electrochemical Methods
			Spectral Methods
			Chemometrics
		Toxicity and Sources of Toxicity
			Pollutant-Induced Toxicity
			Toxicity Induced by Local Pathologies
			Toxicity Induced by Drug Screening
			Toxicity Induced by Tobacco and Drugs of Abuse
			Influence of Toxic Factors on Biomarker Levels
		Conclusions
		Mini-Dictionary of Terms
		Key Facts of Salivary Biomarkers in Toxicology
		Summary Points
		References
Part V: Biomarkers in Specific Conditions or Scenarios
	31 Doxorubicin Cardiotoxicity: Preclinical and Clinical Circulating Protein Markers
		Introduction
		Cardiotoxicity as a Serious Adverse Effect of Doxorubicin
			Proposed Mechanisms of Cardiotoxicity
			Potential Risk Factors Associated with Cardiotoxicity
		Technical Barriers for Predicting Early Signs of Cardiac Dysfunction Induced by Doxorubicin
		Circulating Protein Markers of Doxorubicin-Induced Cardiotoxicity
			Preclinical Markers of Cardiotoxicity
				Glycogen Phosphorylase Brain/Heart Isoform
				Neurogenic Locus Notch Homolog Protein 1 and von Willebrand Factor
			Clinical Markers of Cardiotoxicity
				Traditional Cardiac Disease Markers
				Promising Markers of Cardiotoxicity
		Applications to Prognosis
		Mini-dictionary of Terms
		Key Facts of Doxorubicin Cardiotoxicity
		Summary Points
		References
	32 Biomarkers of Sulfur Mustard (Mustard Gas) in Urine
		Introduction
		History
		Toxicokinetics of Sulfur Mustard
		Mechanism of Action
		Clinical Toxicology of SM Poisoning
		Medical Management of SM Poisoning
		Laboratory Diagnosis of SM Poisoning through Urinary Metabolites
		Applications to Prognosis
		Mini-Dictionary of Terms
		Key Facts of Biomarkers of Sulfur Mustard (Mustard Gas) in Urine
		Summary Points
		References
	33 Biomarkers of Cardiopulmonary Injury and Impact of Bromine Toxicity
		Introduction
		Mechanisms, Presentation, and Biomarkers of Respiratory Bromine Toxicity
		Mechanisms, Presentation, and Biomarkers of Cardiac Bromine Toxicity
		Mechanisms, Presentation, and Biomarkers of Bromine Toxicity on External Tissues
		Systemic Mechanisms, Presentation, and Biomarkers of Bromine Toxicity
		Conclusions
		Mini-Dictionary of Terms
		Key Facts on Bromine
		Summary Points
		References
	34 Biomarkers of PM2.5 Exposure: Use of Metabolomics as a Platform
		Introduction
		Untargeted Metabolomics
			Retrieving Relevant Research Studies
			Studies of Human Blood
			Studies of Human Urine
			Studies of Animal Blood
			Studies of Animal Urine
		Applications to Prognosis, Other Diseases, or Conditions
		Mini-dictionary of Terms (5-15 Terms)
		Key Facts of Biomarkers of PM2.5 Exposure: Use of Metabolomics as a Platform
		Summary Points
		References
	35 Sunscreens: Toxic Effects as Determined by Biomarkers
		Introduction
		Sunscreen-Induced Skin Toxicity
			Organic Sunscreen Filter Ingredients and Their Toxicity
			Inorganic Sunscreen Filter Ingredients and Their Toxicity
		Biomarkers in Sunscreen-Induced Skin Toxicity
			Sunscreen Filters Tests as Biomarkers
		Oxidative Stress Biomarkers and Their Role in Sunscreen-Induced Skin Toxicity
			Oxidative Stress Biomarkers and Apoptosis
		Pro-inflammatory Markers and Their Role in Sunscreen-Induced Toxicity
			Inflammation Identifiers as Biomarkers
		Application to Prognosis
		Mini-Dictionary
		Key Facts of Sunscreens: Toxic Effect as Determined by Biomarkers
		Summary Points
		References
	36 Drug-Induced Nephrotoxicity and Use of Biomarkers
		Introduction
		Mechanisms of Drug-Induced Nephrotoxicity
			Changes in Glomerular Hemodynamics
			Tubular Cell Toxicity
			Inflammation
			Crystal Nephropathy
			Rhabdomyolysis
			Thrombotic Microangiopathy
		Nephrotoxicity Biomarkers
			Conventional Biomarkers
				Creatinine
				Glomerular Filtration Rate (GFR)
				Blood Urea Nitrogen (BUN)
				Albuminuria/Proteinuria
				Urine Sediment Microscopy
			Novel Biomarkers
				Neutrophil Gelatinase-Associated Lipocalin (NGAL)
				Interleukins
				Kidney Injury Molecule 1 (KIM 1)
				Liver-Type Fatty Acid-Binding Protein (L-FABP)
				Calprotectin
				Brain Natriuretic Peptide (BNP)
				Soluble ST2
				Galectin-3
				IGFBP7 x TIMP2
				Urinary Angiotensinogen (UAG)
				Urinary MicroRNA
				β2-Microglobulin (β2M)
				Cystatin C (Cys C)
				Clusterin
				Collagen
				Osteopontin
		Symptoms of Nephrotoxicity
		Diagnostic Tests for Nephrotoxicity
		Disorders Related to Nephrotoxicity
			Glomerulonephritis
			Interference in Intra-renal Renin-Angiotensin System
			Renal Tubule Acidosis
			Chronic Kidney Disease (CKD)
		Preventing Drug-Induced Impairment
		Applications to Prognosis, Other Diseases, or Conditions
		Mini-Dictionary of Terms
		Key Facts of Drug-Induced Nephrotoxicity and Use of Biomarkers
		Summary Points
		Cross-References
		References
	37 Biomarkers of Tobacco Use: Relevance to Tobacco Harm Reduction
		Introduction
			Harm Reduction
			Alternative Nicotine-Containing Products
			Cigarette Smoking and Disease
		Biomarkers Related to Tobacco Use
			Biomarkers of Exposure and Tobacco Use
				Changes in Biomarkers of Exposure Accompanying Changes in Tobacco Use
			Biomarkers of Potential Harm
				Changes in Biomarkers of Potential Harm Accompanying Changes in Tobacco Use
		Conclusions
		Applications to Prognosis
		Applications to Other Diseases or Conditions
		Mini-Dictionary of Terms
		Key Facts of Cigarette Smoking and Biomarkers of Exposure and Potential Harm
		Summary Points
		References
	38 Bleaching Agents as Toxic Compounds and Biomarkers of Damage
		Introduction
		Chemical Bleaching Agents
			Hydrogen Peroxide
			Carbamide Peroxide
		Chemical Mechanism of Tooth Bleaching
		Toxicity of Tooth Bleaching
		Natural Alternative Bleaching Agents
			Papain, Bromelain, and Ficin
			Chlorine Dioxide
			Sodium Chloride and Sodium Bicarbonate
		Natural Extract Combined with Hydrogen Peroxide
			Nanoparticle-Added Bleaching Agents
				Polymeric Nanoparticle
				Nitrogen-Doped Titanium Dioxide
				Nano-bioactive Material
				Chitosan
				Ozone
			Low-Intensity Laser
		Applications to Prognosis
		Damage Biomarkers
			Electron Paramagnetic Resonance
			Determination of Oxidative Stress Markers
				Determination of Lipid Peroxidation Products
				Determination of Protein Damage (Hyaluronic Acid and Proteoglycans)
				DNA Damage
			Measurement of the Antioxidant Defense System
				Antioxidant Enzymes
				Determination of Total Antioxidant Activity
				Measurement of Low-Molecular-Weight Antioxidants
			Measurement of Enzyme Cofactors
		Mini-dictionary of Terms
		Key Facts of Bleaching Agents as Toxic Compounds and Biomarkers of Damage
		Summary Points
		References
	39 Endocrine Disruptors and Markers of Anthropogenic Activity: A Risk for Water Supply and Health
		Introduction
		Effects of Endocrine Disruptors on Public Health and the Environment
		Examples of Endocrine Disruptors and Markers of Anthropogenic Activities
		Extraction Methods for Endocrine-Disrupting Micropollutants
		Endocrine Disruptor Analysis
		Applications to Prognosis
		Mini-dictionary of Terms
		Key Facts of Endocrine Disruptors and Markers of Anthropogenic Activity: A Risk for Water Supply and Health
		Summary Points
		Cross-References
		References
	40 Biomarkers in the Biomonitoring of Fluoride Toxicity: An Overview
		Introduction
			A Brief History of Fluoride
		Sources of Fluoride Exposure
		Fluoride and Diseases
		Biomarkers: A New Era for Diagnosis?
		Biomarkers and Fluoride: What´s in the Literature?
		Conclusion
		Mini-Dictionary of Terms
		Key Facts
		Summary Points
		Cross-References
		References
	41 New Approaches to Evaluate the Cytotoxic Potential of Leishmanicidal Drugs Using Human Peripheral Blood
		Leishmaniasis: Neglected Tropical Diseases Are Still Spreading Around the World
		Leishmaniasis Treatment
		Leishmaniasis: The Immune Response for Parasite Control and New Drug Targets
		New Drugs Are Needed!
		Challenges in the Drug Discovery for New Leishmanicidal Drugs
		A Quick Look at In Vitro Assays to Screen New Chemical Entities for Leishmania and Existent Preclinical Assays
		Current Assays to Measure the Cytotoxicity of Chemical Entities
		Proposal of Human Peripheral Leukocytes (HPL) of Whole Blood as a Model to Measure the Cytotoxicity of Leishmanicidal Drugs
		Final Remarks
		Applications to Other Disease
		Mini-Dictionary of Terms
		Key Facts of the Human Whole Blood Model to Measure the Cytotoxicity of Leishmanicidal Drugs
		Summary Points
		References
	42 Contrast-Induced Nephropathy (CIN) and Biomarkers
		Introduction
			Acute Kidney Injury
			Contrast-Induced Nephropathy
		Biomarkers
			Functional Biomarkers
				Creatinine
				Cystatin C (Cys-C)
				Microalbuminuria
				β2-Microglobulin (β2M)
			Structural Biomarkers
				Neutrophil Gelatinase-Associated Lipocalin (NGAL)
				N-Acetyl-b-D-Glucosamine (NAG)
				Kidney Injury Marker 1 (KIM-1)
				Interleukin 18 (IL-18)
				Liver-Type Fatty-Acid-Binding Protein (L-FABP)
				Midkine
				Dickkopf-3 (DKK3)
			Miscellaneous Biomarkers for CIN
				Gamma-Glutamyl Transferase (GGT)
					Homocysteine
				Procalcitonin
				Hepcidin
				G1 Cell-Cycle Arrest Proteins
				Semaphorin 3A
				Fibroblast Growth Factor 23 (FGF23)
				Growth Differentiation Factor 15 (GDF-15)
				Uric Acid (UA)
				Adiponectin
				Glucose
				Copeptin
				Circulating microRNA (miRNA)
				C-Reactive Protein (CRP)
				Asymmetric Dimethylarginine (ADMA)
		Applications to Prognosis
		Applications to Other Diseases or Conditions
		Conclusion
		Mini-Dictionary of Terms
		Key Facts of CIN
		Summary Points for CIN
		References
	43 Lead and Aquatic Ecosystems, Biomarkers, and Implications for Humankind
		Introduction
		Sources of Lead Exposure
		Lead as a Toxic Pollutant
		Lead in Aquatic Environment
		Uptake and Bioaccumulation of Lead
		Absorption of Lead
		Excretion of Lead
		Mechanism of Lead Toxicity
		Effects of Lead Toxicity on Aquatic Organisms
		Impact of Lead Toxicity on Humankind
		Hematopoietic System
		Cardiovascular System
		Renal System
		Skeletal System
		Nervous System
		Respiratory System
		Liver and Gastrointestinal Tract
		Reproductive System
		Applications to Prognosis and Other Diseases or Conditions
		Mini-dictionary of Terms
		Key Facts of Oxidative Stress
		Key Facts of Atherosclerosis
		Key Facts of Na+/K+ ATPase
		Summary Points
		Cross-References
		References
	44 Per- and Polyfluoroalkyl Substances (PFAS) and Their Toxicology as Evidenced Through Disease and Biomarkers
		Key Facts of PFAS
		Introduction
		PFAS Types
		Bioaccumulation
		Environmental Distribution
		Environmental Problems
		Remediation
		Molecular Initiating Events
		Nuclear Receptors
		Peroxisome Proliferator-Activated Receptors (PPARs)
		Molecular Biomarkers
		Health Effects
		Metabolic / Hepatotoxicity
		Immune
		Developmental/Reproductive
		Endocrine
		Cardiovascular
		Neurotoxicity
		Cancer
		Summary
		Mini-Dictionary of Terms
		Summary Points
		References
	45 The Complement System as a Biomarker of Environmental Pollutants as Toxic Agents: A Focus on Polybrominated Diphenyl Ethers...
		Introduction
		Polybrominated Diphenyl Ethers Poisoning Around the World
			Polybrominated Diphenyl Ethers Group: Isomers and Congeners
			Polybrominated Diphenyl Ethers in the Environmental and Human Health
			Polybrominated Diphenyl Ethers in Immune System
		Complement System
		Effects of Polybrominated Diphenyl Ethers on the Complement System
		Applications of Complement Components as Biomarkers of PBDEs Exposure
		Mini-Dictionary of Terms
		Key Facts of Environmental Pollutants
		Summary Points
		Cross-References
		References
	46 Biomarkers of the Toxic Effects of Chemotherapeutic Agents: A Focus on Antimalarials
		Introduction
		Antimalarial Drugs
		Mode of Action and Metabolism of Antimalarial Drugs
		Toxicity of Antimalarial Drug
		Biomarkers of the Toxicity of Antimalarial Drugs
			Cytochrome P450
			Drug Transporter
			P-Glycoprotein
			Organic Anion Transporter 1B1
			Glucose-6-Phosphate Dehydrogenase
		Glutathione S-Transferase
			Potential Applications to Prognosis, Other Diseases, or Conditions
		Summary
		Key Facts of Antimalarial Toxicity
		Mini-Dictionary of Terms
		References
Part VI: Biomarkers in Models and Modeling Toxicity
	47 Linking Arsenic, DNA Methylation Biomarkers, and Transgenerational Neurotoxicity: Modeling in Zebrafish
		Introduction
		Transgenerational Epigenetic Inheritance
		Role of Arsenic-Induced DNA Methylation in Neurotoxicity
		Modeling Transgenerational Arsenic Neurotoxicity in Zebrafish
		Affordable Methodologies for the Study of DNA Methylation in Zebrafish
			Global DNA Methylation
			Gene-Specific Methylation
		Potential DNA Methylation Biomarkers for Transgenerational Neurotoxicity of Arsenic
			Global DNA Methylation
			Differentially Methylated Regions
			Gene-Specific Methylation
			The Brain-Derived Neurotrophic Factor (BDNF) and Tropomyosin-Related Receptor Kinase B (TrkB) Genes
			The Myelin Basic Protein (MBP) Gene
			The Reelin (RELN) Gene
			The Protein Phosphatase 1 Gene
			The Cystine/Glutamate Transporter (SLC7A11) Gene
		Applications to Prognosis, Other Diseases, or Conditions
		Mini-Dictionary of Terms
		Key Facts of DNA Methylation by Arsenic Exposure
		Summary Points (5-15)
		Cross-References
		References
	48 Modeling with Biomarkers: Nitrosamines and Phytochemical Protection
		Introduction
		Nitrosamines
			Chemical Structure
			Sources
			Cytotoxicity
		Phytochemicals
			Definition and Classification of Phytochemicals
				Polyphenols
				Terpenoids
				Thiols
		Medicinal Plants Role in Prevention of DEN-Induced Cytotoxicity
			Capsicum Plant Species
			Garcinia kola
			Protium heptaphyllum
			Cnidoscolus aconitifolius
			Ipomoea batatas
			Zingiber officinale
			Litchi chinensis
			Stephania tetrandra
			Tripterygium wilfordii (Hook F)
			Salvia miltiorrhiza
			Polygonum cuspidatum, Morus alba, Vitis vinifera, and Red Wine
			Rosmarinus officinalis
			Ribes nigrum (Black Currant)
			Pomegranate
			Grapes, Berries, Peanuts, and Red Wine
			Rice Bran
			Garlic and Cinnamon Oils
			Phoenix dactylifera L.
			Curcuma longa
		Conclusion
		Summary Points
		Cross-References
		References
	49 Different Mice Strains in Biomarker Responses to Toxic Agents: The Example of Acetaminophen
		Introduction
		Acetaminophen Epidemiology
		Mechanisms of Acetaminophen Toxicity
		Treatment for Acetaminophen Overdoses: Classic and New Approaches
		Mice Models of Acetaminophen Toxicity
			Routes of Inoculation of APAP
			Different Mice Strains Responses to Acetaminophen
		Applications and Importance of APAP Studies
		Mini-Dictionary of Terms
		Key Facts of Acetaminophen Toxicity
		Abbreviations Such as APAP, AC, Acetaminop, Acetamin, or Acetam, May Be Written on the Label in Place of the Word Acetaminophen
		Summary Points
		References
Part VII: Resources
	50 Recommended Resources for Biomarkers in Disease: Toxicology
		Introduction
		Resources
		Other Resources
		Summary Points
		References
Index