Table 3.

General Function and Classifications of the Novel Molecular Targets Identified in ToxCast Assays Prioritized by Their Response Below the CTB

Intended Target gene	Target Name	Description	General Biological Category
RXRB	Retinoid X receptor beta	This nuclear receptor is involved in mediating the effects of retinoic acid. This receptor forms homodimers with the retinoic acid, thyroid hormone, and vitamin D receptors, increasing both DNA binding and transcriptional function on their respective response elements. The gene lies within the major histocompatibility complex class II region on chromosome 6	Nuclear receptor involved in hormonal regulation
RARA, RARB, RARG	Retinoic acid receptor alpha, beta, gamma	The nuclear retinoic acid receptors dimerize with RXR and bind hormone response elements (retinoic acid response elements), repressing transcription of target genes. Upon ligand binding (e.g., retinoic acid) to the RAR, transcription is activated. RARs are involved in various biological processes, including limb bud development, skeletal growth, and matrix homeostasis. RARA has been implicated in regulation of development, differentiation, apoptosis, granulopoeisis, and transcription of clock genes. RARB is thought to limit growth of many cell types
PGR	Progesterone receptor	The progesterone receptor is a member of the steroid receptor superfamily and mediates the physiological effects of progesterone, which plays a central role in reproductive events associated with the establishment and maintenance of pregnancy
NR3C2	Mineralocorticoid receptor	The mineralocorticoid receptor mediates aldosterone actions on salt and water balance within restricted target cells. This ligand-dependent transcription factor binds to the mineralocorticoid response element. Mutations in this gene cause autosomal dominant pseudohypoaldosteronism type I, a disorder characterized by urinary salt wasting. Defects in this gene are also associated with early onset hypertension with severe exacerbation in pregnancy
TSPO	Translocator protein; peripheral benzodiazepine receptor	The translocator protein regulates the transport of cholesterol into mitochondria to permit the initiation of steroid hormone synthesis. It also interacts with some benzodiazepines	Transporter involved in hormone regulation
HTR7	5-Hydroxytryptamine receptor 7	The serotonin receptor 7 is a G protein-coupled receptor, which mediates the effects of the neurotransmitter serotonin (5-hydroxytryptamine) on cognition and behavior. Mutations in this gene are associated with autistic disorder and other neuropsychiatric disorders	Receptor involved in neurotransmission
SIGMAR1	Sigma nonopioid intracellular receptor 1	This receptor interacts with a variety of psychotomimetic drugs, including cocaine and amphetamines, and is believed to play an important role in the cellular functions of various tissues associated with the endocrine, immune, and nervous systems. Mutations in this gene have been associated with juvenile amyotrophic lateral sclerosis 16
CHRM2	Cholinergic receptor muscarinic 2	This receptor is a G protein-coupled receptor which binds acetylcholine. Activated muscarinic receptors are inhibitory regulators of acetylcholine transmission. Muscarinic cholinergic receptor 2 is involved in mediation of bradycardia and a decrease in cardiac contractility
CHRM4	Cholinergic receptor muscarinic 4	This receptor is a G protein-coupled receptor which binds acetylcholine. Activated muscarinic receptors are inhibitory regulators of acetylcholine transmission and have many effects in the central and peripheral nervous system. Muscarinic acetylcholine receptors also influence dopaminergic neurotransmission
SLC6A2	Norepinephrine transporter	This gene encodes a member of the sodium: neurotransmitter symporter family. This protein is responsible for reuptake of norepinephrine into presynaptic nerve terminals and is a regulator of norepinephrine homeostasis. Mutations in this gene cause orthostatic intolerance, a syndrome characterized by lightheadedness, fatigue, altered mentation and syncope	Transporter involved in neurotransmission
SLC6A3	Sodium-dependent dopamine transporter	The sodium-dependent dopamine transporter moves the neurotransmitter dopamine from the synaptic cleft back into the cytosol. Genetic polymorphisms are associated with idiopathic epilepsy, attention-deficit hyperactivity disorder, dependence on alcohol and cocaine, susceptibility to Parkinson disease and protection against nicotine dependence
MAOA	Monoamine oxidase A	Monoamine oxidase A is an enzyme, which catalyzes the oxidative deamination of amines, such as dopamine, norepinephrine, and serotonin. Mutation of this gene results in Brunner syndrome. This gene has also been associated with a variety of other psychiatric disorders, including antisocial behavior	Enzyme involved in neurotransmission
MAOB	Monoamine oxidase B	Monoamine oxidase B is an enzyme located in the mitochondrial outer membrane. It catalyzes the oxidative deamination of biogenic and xenobiotic amines and plays an important role in the metabolism of neuroactive and vasoactive amines in the central nervous sysytem and peripheral tissues. This protein preferentially degrades benzylamine and phenylethylamine
NFE2L2	Nuclear factor, erythroid 2 like 2; NRF2	This transcription factor is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes, which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals	Transcription factor involved in antioxidant and inflammatory response
CSNK2A1	Casein kinase II alpha 1	Casein kinase II is a serine/threonine protein kinase that phosphorylates acidic proteins such as casein. It is involved in various cellular processes, including cell cycle control, apoptosis, and circadian rhythm. The kinase exists as a tetramer and is composed of an alpha, an alpha-prime, and two beta subunits. The alpha subunits contain the catalytic activity whereas the beta subunits undergo autophosphorylation	Kinase involved in cell cycle regulation
CSNK1D	Casein kinase 1 delta	Members of the casein kinase I family have been implicated in the control of cytoplasmic and nuclear processes, including DNA replication and repair. Casein kinase II alpha 1 may also be involved in the regulation of apoptosis, circadian rhythm, microtubule dynamics, chromosome segregation, and p53-mediated effects on growth
TNF	Tumor necrosis factor	Tumor necrosis factor is a multifunctional proinflammatory cytokine mainly secreted by macrophages. It binds the receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation, and has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, and cancer	Cytokine involved in inflammatory response
IL6	Interleukin 6	This cytokine functions in inflammation, the maturation of B cells, and is an endogenous pyrogen capable of inducing fever in people with autoimmune diseases or infections. The protein is primarily produced at sites of acute and chronic inflammation, where it is secreted into the serum and induces a transcriptional inflammatory response through interleukin 6 receptor, alpha. The gene is implicated in a wide variety of inflammation-associated disease states, including susceptibility to diabetes mellitus and systemic juvenile rheumatoid arthritis
CXCL8	C-X-C motif chemokine ligand 8; interleukin 8	This chemokine is in the CXC family and is one of the major mediators of the inflammatory response. Secreted by several cell types, it functions as a chemoattractant, and is also a potent angiogenic factor. It is also believed to play a role in the pathogenesis of bronchiolitis, a common respiratory tract disease caused by viral infection
CXCL10	Chemokine ligand 10	This chemokine belongs to the CXC subfamily and is a ligand for the receptor CXCR3. Binding of this protein to CXCR3 results in pleiotropic effects, including stimulation of monocytes, natural killer and T-cell migration, and modulation of adhesion molecule expression
PDE5A	Phosphodiesterase 5A	Phosphodiesterase 5A is a member of the cyclic nucleotide phosphodiesterase family and specifically hydrolyzes cGMP to 5’-GMP. It is involved in the regulation of intracellular concentrations of cyclic nucleotides and is important for nitric-oxide-mediated smooth muscle relaxation. Important in cardiovascular muscle relaxation and penile erection	Phosphodiesterase involved in signal transduction
SELE	Eselectin; endothelial leukocyte adhesion molecule 1	Eselectin is found in cytokine-stimulated endothelial cells and is thought to be responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. As a member of the selectin family of cell adhesion molecules, it participates in the interaction between leukocytes and the endothelium and appears to be involved in the pathogenesis of atherosclerosis	Protein involved in cell adhesion and inflammatory response
COL3A1	Collagen type III alpha 1 chain	The pro-alpha1 chains of type III collagen contribute to the fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, and frequently in association with type I collagen. Mutations in this gene are associated with Ehlers–Danlos syndrome type IV, and with aortic and arterial aneurysms	Protein involved in connective tissue
SERPINE1	Serpin peptidase inhibitor, clade E	This serine proteinase inhibitor (serpin) is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), and hence is an inhibitor of fibrinolysis. Defects in this gene are the cause ofplasminogen activator inhibitor-1 deficiency (PAI-1 deficiency), and high concentrations of the gene product are associated with thrombophilia	Inhibitor inolved the immune response
POU2F1	POU class 2 homeobox	This transcription factor was among the first identified members of the POU transcription factor family. Members of this family contain the POU domain, a 160-amino acid region necessary for DNA binding to the octameric sequence ATGCAAAT. POU2F1 appears to be involved in lens and nasal sensory development	Transcription factor involved in cell cycle and development
SREBF1	Sterol regulatory element binding transcription factor	This transcription factor binds to the sterol regulatory element-1 (SRE1), which flanks the low-density lipoprotein receptor gene and some genes involved in sterol biosynthesis. The protein is synthesized as a precursor that is attached to the nuclear membrane and endoplasmic reticulum. Following cleavage, the mature protein translocates to the nucleus and activates transcription by binding to the SRE1. Sterols inhibit the cleavage of the precursor, and the mature nuclear form is rapidly catabolized, thereby reducing transcription	Transcription factor involved in sterol/cholesterol regulation
PTPN2	Tyrosine-protein phosphatase nonreceptor type 2	This signaling molecule is a member of the protein tyrosine phosphatase (PTP) family, which regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Epidermal growth factor receptor and the adaptor protein Shc were reported to be substrates of this PTP, which suggested it plays a role in growth factor-mediated cell signaling	Signaling molecule involved in cell cycle regulation
IRAK4	Interleukin-1 receptor-associated kinase 4	This kinase activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. The protein is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease	Kinase involved in inflammatory response
MAPKAP2	Mitogen-activated protein kinase-activated protein kinase 2	This Ser/Thr protein kinase is regulated through direct phosphorylation by p38 MAP kinase. In conjunction with p38 MAP kinase, this kinase is known to be involved in many cellular processes including stress and inflammatory responses, nuclear export, gene expression regulation, and cell proliferation. Heat shock protein HSP27 is one substrate of this kinase.
CASP2	Caspase 2	Caspases (cystein-asparctic acid proteases) mediate cellular apoptosis through the proteolytic cleavage of specific protein substrates. Caspase 2 may function in stress-induced cell death pathways, cell cycle maintenance, and the suppression of tumorigenesis. Increased expression of this gene may play a role in neurodegenerative disorders including Alzheimer’s disease, Huntington’s disease, and temporal lobe epilepsy	Protease involved in cell death