Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology caused by teratogens. Teratogens are substances that may cause non-heritable birth defects via a toxic effect on an embryo or fetus. Defects include malformations, disruptions, deformations, and dysplasia that may cause stunted growth, delayed mental development, or other congenital disorders that lack structural malformations. The related term developmental toxicity includes all manifestations of abnormal development that are caused by environmental insult. The extend to which teratogens will impact an embryo is dependent on several factors, such as how long the embryo has been exposed, the stage of development the embryo was in when exposed, the genetic makeup of the embryo, and the transfer rate of the teratogen.
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth defects are divided into two main types: structural disorders in which problems are seen with the shape of a body part and functional disorders in which problems exist with how a body part works. Functional disorders include metabolic and degenerative disorders. Some birth defects include both structural and functional disorders.
Sonic hedgehog protein(SHH) is encoded for by the SHH gene. The protein is named after the character Sonic the Hedgehog.
Cyclopia is the most extreme form of holoprosencephaly and is a congenital disorder characterized by the failure of the embryonic prosencephalon to properly divide the orbits of the eye into two cavities. Its incidence is 1 in 16,000 in born animals and 1 in 200 in miscarried fetuses.
Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.
A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.
Smith–Lemli–Opitz syndrome is an inborn error of cholesterol synthesis. It is an autosomal recessive, multiple malformation syndrome caused by a mutation in the enzyme 7-Dehydrocholesterol reductase encoded by the DHCR7 gene. It causes a broad spectrum of effects, ranging from mild intellectual disability and behavioural problems to lethal malformations.
Neural crest cells are a temporary group of cells that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia.
Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs in the family of steroidal alkaloids. It is a teratogen isolated from the corn lily that causes fatal birth defects. It prevents the embryonic brain from separating into two lobes, which in turn causes the development of a single eye (cyclopia). The chemical was named after this effect, as it was originally noted by Idaho lamb farmers who contacted the US Department of Agriculture after their herds gave birth to cycloptic lambs in 1957. It then took more than a decade to identify the corn lily as the culprit. Later work suggested that different rain patterns caused the sheep to graze differently, impacting the amount of corn lily ingested by pregnant sheep. The poison interrupts the sonic hedgehog signaling pathway during development, thus causing birth defects.
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include cancer.
Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecular target of the natural teratogen cyclopamine. It also is the target of vismodegib, the first hedgehog pathway inhibitor to be approved by the U.S. Food and Drug Administration (FDA).
Veratrum nigrum, the black false hellebore, is a widespread Eurasian species of perennial flowering plant in the family Melanthiaceae. Despite its common name, V. nigrum is not closely related to the true hellebores, nor does it resemble them.
Veratrum californicum is an extremely poisonous plant native to western North America, including the Sierra Nevada and Rocky Mountains, as far north as Washington and as far south as Durango; depending on latitude, it grows from near sea level to as high as 11,000 feet. It grows 1 to 2 meters tall, with an erect, unbranched, heavily leafy stem resembling a cornstalk. It prefers quite moist soil, and can cover large areas in dense stands near streams or in wet meadows. Many inch-wide flowers cluster along the often-branched top of the stout stem; they have 6 white tepals, a green center, 6 stamens, and a 3-branched pistil. The buds are tight green spheres. The heavily veined, bright green leaves can be more than a foot long.
Acrania is a rare congenital disorder that occurs in the human fetus in which the flat bones in the cranial vault are either completely or partially absent. The cerebral hemispheres develop completely but abnormally. The condition is frequently, though not always, associated with anencephaly. The fetus is said to have acrania if it meets the following criteria: the fetus should have a perfectly normal facial bone, a normal cervical column but without the fetal skull and a volume of brain tissue equivalent to at least one-third of the normal brain size.
Protein patched homolog 1 is a protein that is the member of the patched family and in humans is encoded by the PTCH1 gene.
Forkhead box C1, also known as FOXC1, is a protein which in humans is encoded by the FOXC1 gene.
Patched (Ptc) is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. Patched is an essential gene in embryogenesis for proper segmentation in the fly embryo, mutations in which may be embryonic lethal. Patched functions as the receptor for the Hedgehog protein and controls its spatial distribution, in part via endocytosis of bound Hedgehog protein, which is then targeted for lysosomal degradation.
Vismodegib, sold under the brand name Erivedge, is a medication used for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval. The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma as of June 2011. The drug was developed by the biotechnology/pharmaceutical company Genentech.
Saridegib, also known as IPI-926, is an experimental drug candidate undergoing clinical trials for the treatment of various types of cancer, including hard-to-treat hematologic malignancies such as myelofibrosis and ligand-dependent tumors such as chondrosarcoma. IPI-926 exhibits its pharmacological effect by inhibition of the G protein-coupled receptor smoothened, a component of the hedgehog signaling pathway. Chemically, it is a semi-synthetic derivative of the alkaloid cyclopamine. The process begins with cyclopamine extracted from harvested Veratrum californicum which is taken through a series of alterations resulting in an analogue of the natural product cyclopamine, making IPI-926 the only compound in development/testing that is not fully synthetic.
Hedgehog pathway inhibitors, also sometimes called hedgehog inhibitors, are small molecules that inhibit the activity of a component of the Hedgehog signaling pathway. Due to the role of aberrant Hedgehog signaling in tumor progression and cancer stem cell maintenance across cancer types, inhibition of the Hedgehog signaling pathway can be a useful strategy for restricting tumor growth and for preventing the recurrence of the disease post-surgery, post-radiotherapy, or post-chemotherapy. Thus, Hedgehog pathway inhibitors are an important class of anti-cancer drugs. At least three Hedgehog pathway inhibitors have been approved by the Food and Drug Administration (FDA) for cancer treatment. These include vismodegib and sonidegib, both inhibitors of Smoothened (SMO), which are being used for the treatment of basal cell carcinoma. Arsenic trioxide, an inhibitor of GLI transcription factors, is being used for the treatment of acute promyelocytic leukemia. In addition, multiple other Hedgehog pathway inhibitors are in different phases of clinical trials.
