Glossary of Key Terms for Teratology

Home , Cephalic disorder, Cranioschisis, Metamorphosis, Prenatal development, Scaphocephaly, Teratology

Maria dos Anjos Pires and Ana M. Calado

Introduction

Teratology (from the Greek, teratos, monster) is the science that studies birth defects, congenital malformations, or developmental disorders and is a complex science to understand. The effort to make it more accessible comprises the construction of a glossary with the most routine used terms, making them more comprehen- sive and accessible. The purpose of this glossary is to make this subject more understandable for all those who want or need to learn this subject.

Glossary

Abiotrophy A group of diseases that are characterized by the premature spontaneous neuron degeneration, and also storage neuron diseases that affected them diffusely. It is limited to a metabolic development and intrinsic error to the neuron that limits its viability and is identified in the inborn. Acardia Absence of the heart. Severe congenital defect conjoint with other anomalies present in one element of a pair of twin. Achondroplasia Anomaly subsequent to a defect of bone grown resulting in an insuffi- cient growth (dwarfism), associated with other skeletal abnormalities (macrocephaly, kyphosis, short limbs). Acromegaly Disproportional enlargement of the face, hands, and feet.

Luís Félix (ed.), Teratogenicity Testing: Methods and Protocols, Methods in Molecular Biology, vol. 1797, https://doi.org/10.1007/978-1-4939-7883-0, © Springer Science+Business Media, LLC, part of Springer Nature 2018 595 596 Maria dos Anjos Pires and Ana M. Calado

Agenesis or aplasia Complete absence of an organ due to nonappearance of its primor- dium in the embryo (examples: anencephaly, cyclopia, amelia, renal agenesis). This is lethal when the affected organ is unique and essential (example: microcephaly) or both bilateral organs (as kidney and lung). Albinism Globally reducing or absence of pigmentation in eye, hair, or skin, related to congenital defects of tyrosinase, a copper-contained enzyme involved in the melanin synthesis. Amelia Refers to the absence of one or more limbs. It is a sporadic anomaly. It can present as an isolated defect or with associated malformations, par- ticularly abdominal wall and renal anomaly. Amniotic band sequence (ABS) Is a group of structural abnormalities that involve mostly the limbs, but may also affect the craniofacial region and trunk. ABS is perhaps the most common example of intrauterine disruption. The specific malformations caused depend upon the time of the disruption. The typical appearance consists of amputations and malformations caused by the encircling constrictions of the limbs or other body structures, but the clinical spectrum is highly variable. Amyoplasia Generalized lack of muscle growth and development, which has, as a consequence, arthrogryposis, a contracture and deformity of the most joints. Anencephaly Is a lethal anomaly with the absence of brain formation or its degeneration as a consequence of cranioschisis (absence of cranial vault formation). Aniridia Absence of the iris. The eye could be complete only without the iris. Ankyloglossia Extension of the tong frenulum to the tip of the tongue, instead it may only be in the base of the tongue where they anchor to the mouth floor. Anophtalmia Absence of the eye. Most times, this is accompanied by severe cranial abnormalities. Anotia Complete absence of external structure of the ear. Aphakia Congenital anomaly with the absence of the eye lens. Aplasia Developmental disturbance in which only a tissue or organ rudiments occur. In some cases, there is no formation of an organ. Development has begun, but this was interrupted early. The organ is composed only by rudiment. Arnold-Chiari malformation Herniation of part of the cerebellum into the foramen magnum obstruct- ing the flow of the cerebrospinal fluid. Glossary of Key Terms for Teratology 597

Arthrogryposis Congenital joint contractures, involving more than one joint, inducing abnormal position of the limbs. This anomaly could be related by amyoplasia. Association Non-random association of two or more anomalies, which are not pathogenically related, and occur together more frequently than expected. Most associations are classified as “Polytopic Field Defects.” As examples, the VATER or VACTERL association includes Vertebral anomalies, Anal atresia, Cardiac defects, TE fistula (tracheoesophageal fistula),R enal defects, and Limb defects. As the anomalies in these associations tend to occur together more frequently, the finding of one of these should prompt the clinician to look for related ones. Atresia A condition in which an orifice, lumen, or passage of the body has incomplete formation, resulting in an abnormality of this aperture, that will be closed or absent. This situation only occurs in tubular organs (examples: Sylvius aqueduct, biliary atresia; oesophageal atresia, anal atresia). Atrichia Congenital absence of hair. This malformation could be associated with other ectodermal anomalies such as teeth and nails anomalies. Atrophy Decrease in size of a normally developed tissue or organ, derived from a decrease in cell size and/or cell number. This process could be physiologic (during the normal embryonic development some structures need to atrophy, as the thyroglossal duct), or pathologic (e.g., after an immobiliz- ing as a consequence of a fracture, the muscle atrophies). In general, this anomaly is associated with apoptosis and autophagy, usually related to a decrease in the number of cytoplasmic organelles, and consequently a reduction in cellular volume and function. Brachycephaly Is a cephalic disorder. The skull has a distinct shape and shorter than characteristic for its species (as in some dog and cat breeds). In man, it is the result of premature closure (craniosynostosis) of the coronal suture resulting in short skull. Brachydactyly The digits are shortened, when compared to the size of other long bones. This anomaly could be associated with other anomalies (as dysmelia) or as part of congenital syndromes. Cachexia Poor body condition related to low weight as a consequence of diverse anomalies (as cardiac congenital anomalies). Cephalopagus The same as janiceps, these joint twins are fused ventrally from the top of the head down including the umbilicus. They share the head, neck, thorax, abdomen. The lowered abdomen, genitalia, vertebral column, and limbs are individualized. The head has a deformed face, in general in opposite sites. 598 Maria dos Anjos Pires and Ana M. Calado

Cheiloschisis Congenital cleft in the middle upper lip. Choristia Presence of normal tissue in an unusual place (heterotopia), due to a local congenital error of development. Examples: pancreatic tissue in the gastric walls, adrenal cortex in the kidneys, lungs in the ovary, and endometrium in the ovary. Cleft Openings resulting from non-fusion of embryonic structures, by delay or stopped in the embryonic development at the stage corresponding to the formation of the structure. This results in an inadequate aperture of the structure or organ (ex. cleft palate). Coloboma Cleft in eye structures. It could be only in the iris (coloboma iris) or be extended to the retina, choroid, ciliary, and optical nerve. This malformation is the result of the closing miscarriage of choroid fissure during the fetal development. Conjoined twin Congenital defects of the twins that are fused by a part of its bodies (head, thorax, abdomen, column, hip, etc.) with different organs fusion and dependency. Some of these situations are severe, implying the death of the twins. The denomination depends on the part that is fused and the extension of its union. Craniopagus Conjoined twins fused by any portion of cranial vault, but never involving neither the foramen magnum nor the basis of the skull, the face nor the vertebrae. Craniopagus Conjoined twins fused by the cranium (united skulls). In this case the twins could be fused by any part of the skull except the foramen magnum or face. The rest of the body is divided. Cranioschisis Failure in the formation of the cranial vault. The encephalic tissue is exposed to the amniotic fluid, resulting in degeneration and loss of this (anencephaly). Craniosysnostosis Premature closure of one or more sutures of the cranium, resulting in an abnormal shape of the skull. Criptorchidia Failure of total or partial (cryptorchidism) fall of the testicles to the scrotum through the inguinal canal (ring). The abnormal position of these organs can be inside the abdomen or in the abdominal wall. Cyclopia Severe congenital disorder with the existence of only one eye in the face, with a non-functional nose (most of times as a trumpet). This anomaly is related to other malformations as encephalon disorders. This malformation is mostly incompatible with the new-born survival. Glossary of Key Terms for Teratology 599

Deformation Are abnormal form, shape, or position of a part of the body due to mechanical forces. Extrinsic forces include multiple gestations, intrauterine mechanical forces that modify a normally formed structure. Intrauterine forces, such as decreased amniotic fluid, uterine tumors, and uterine malformations, can lead to fetal compression. Intrinsic forces include torticollis, arthrogryposis, neuromuscular abnormalities, amyoplasia, or skeletal anomalies. These anomalies have a good prog- nosis and are typically easy to treat with physical therapy or external fixation devices. Developmental field defect One or more developmental defects interrelated in an organ or region (e.g., “Monotopic Field Defect” occurs within a single developmental field. “Polytopic Field Defect” incorporating more than one developmental field but occurs within the same time during development). Dextrocardia Rare anomaly of the heart localization. The apex of the heart is located at the right side of the thorax/body instead of the left side. This anomaly is associated with other, depending on the severity. The “dextrocardia of embryonic arrest” is associated with pulmonary hypoplasia. The “dextrocardia situs inversus” the heart and all visceral organs are located mirrored. Dicephaly Conjoined twins with two heads and a joint body. In general, the organs duplications are limited to the thorax, and its extension differs with the grade of column duplication. Dimelia A condition with duplication of part of or even all a limbs, frequently in a mirror-image pattern. Diplomyelia Rare and severe malformation of the spinal cord in which it is duplicated along a part or all its length. Diprosopus Extremely rare congenital disorder with the craniofacial duplication. This duplication could be complete or only part or all of the face is duplicated on the head. This defect is the result of the abnormal activity of SHH (Sonic Hedgehog) protein. The gene that promotes this protein correlates with the signaling of the craniofacial patterning during the embryonic development. The excess of this signaling leads to duplication of the craniofacial structures in a mirror-image pattern. Diverticulum Saculiform dilation/enlargement or circumscribed pouch created by herniation of the muscular layer of a tubular organ or structure (examples Meckel diverticulum, intestinal diverticulum). Dysgenesis Abnormal development of an organ, especially of the gonads. Dysplasia An abnormal organization of cell into tissues. When dysplasia affects an organ, it encompasses several development and growth disorders, 600 Maria dos Anjos Pires and Ana M. Calado

usually regressive processes, and often is associated with genetic condi- tions (examples: coxo-femoral dysplasia, bone fibrous dysplasia, fetal chondrodysplasia or achondroplasia, osteogenesis imperfect). Dystopia or heterotopy Abnormal positioning of viscera or an organ. The term “paratopia” refers to localization of the viscera on the opposite site (examples: paratopia cordis, situs inversus). Ebstein anomaly Displacement of tricuspid valve toward the apex of the right ventricle, resulting in an expanded right atrium and small right ventricle. Ectopia or heterotopia The presence of a tissue in an organ with normal morphology, outside its habitual location, due to an abnormal development. These are local congenital errors of development in which a seemingly normal tissue develops heterotopically (examples: pancreatic fragments in the gastric walls, adrenal cortex in the kidneys, lungs and ovary, and endometrium in the ovary or heart outside the thorax). This abnormality could have the organ location outside the body walls, as example for the heart location; ectopia cordis—heart externally onto the sternum, ectopia cordis fis- sisternalis heart in the cervical region, ectopia cordis cervicalis, or even outside the integument. Ectrodactyly Absence of a digit in hand and/or foot, with a deep cleft down the center of the hand or foot. This condition is also termed “split hand foot malformation (SHFM).” This abnormality is related to a genital cause linked to X chromosome, chromosome 7, duplication of chromosome 10 or with other gene mutations. Its severity depends on the genetic causes and could present only these defects or include a syndrome associated with abnormalities of other parts of the body. Encephalocele Is a neural tube defect that presents a sac-like protrusion of the brain and its meninges through the skull. These abnormalities are caused by a failure of a complete neural tube closing during fetal development. Encephaloceles could be located in different skull grooves, as the middle of the skull, or between the forehead and nose, or on the back side of the skull. The severity of this defect is dependent on its location. Enterocystoma (or vitelline cyst) Is a cyst (cavity) formed after both ends of vitelline duct have transformed into fibrous cords, remaining in the center as a cavity or cyst. Epispadias Is a congenital defect of males in which the urethra opens on the supe- rior dorsal surface of the upper side of the gland or penis. The corresponding defect in females is a crack or a fissure in the wall of the urethra and out of the body through an opening in the skin above the clitoris. Epispadias is due to a defect in the tissue that folds inward to form the urethra. Exstrophy Absence of closure of the pelvic region. In the bladder exstrophy, this organ did not close during the embryonal development and its mucosa Glossary of Key Terms for Teratology 601 is open to the external surface of the abdomen. It is associated with other abnormal genitourinary defects as cryptorchidic and epispadias. More severe exstrophy involves the bladder and rectum that is exposed forming a cloaca. Fetal ventriculomegaly (VM) Is the term used to describe the enlargement of the ventricles of the brain. When enlargement of the ventricles is caused by an increase in the pressure of the cerebro-spinal fluid, this condition is hydrocephaly. The cause of ventriculomegaly can imply brain damage and loss of neuronal tissue. Fistulas Anomalous communication between a structure and the exterior, or between several structures hollow to each other (example: recto-vaginal, recto-vesical fistulas). Fusion Union of structures that would normally be separated (example: in cyclopia the union of both eyes). When affecting twins (in the cases of “monstrosities”), the suffix "pagus" is used, associated with the designa- tion term of the region in which the fusion occurs (example: pygopagus are twins joined by the pelvic region, side-by- side bodies). Gastroschisis Abnormal closure of the abdominal body wall around the connecting stalk, usually at the right place of the umbilicus, with protrusion of the abdominal visceral contents into the amniotic cavity. Hamartias Are local growth errors in which a tissue develops more than it should. There are mature and normal cells, but with abnormal tissue architec- ture. When results are bulky and tumor-like dimensions these hamartias are called hamartomas (examples: sebaceous gland hamartoma). Hemimelia Absence of the distal part of a limb. This malformation frequently occurs only in one side of the distal half of the member. Hermaphrodites Individuals with the characteristics of both sexes, with different proportions of both male and female gonadal tissues (example the ovotestis). Hydramnios or polyhydramnios Excess of amniotic fluid in the amniotic sac during the pregnancy. This condition results if the fetus produces abundant urine or does not swal- low enough amniotic fluid. This excess of amniotic fluid is related to brain and spinal defects, blockages of the digestive system as atresia of the oesophagus, genetic problems or maternal problems as diabetes. Hydranencephaly Is a rare encephalopathy characterized by the destruction of the cerebral hemispheres which are transformed into a membranous sac (constituted by the leptomeninges) containing cerebrospinal necrotic fluid and the remnants of cortex and white matter. When this malformation is located it is denominated porencephaly. Hydrocephaly Accumulation of cerebrospinal fluid inside the encephalon. 602 Maria dos Anjos Pires and Ana M. Calado

Hyperplasia Is an overdevelopment of an organism, organ, or tissue resulting from an increased number of cells. The increase in volume and weight of an organ may result from increase in functional demand or by increase of trophic stimuli (example: the increase of the uterus by the influence of hormones). The number of cells increases as a consequence of mitoses, so its enlargement is only possible in cells that have this potentiality. Hypertrichosis Excessive number of hair follicles and hair growth, which could be local- ized in a particular body region, or can also be generalized. Hypertrophy Increased synthesis in the cells, increasing the cell volume and as a consequence the increase of organ volume (example: the increase of muscle volume after exercise). Hypochondroplasia Skeletal malformation resulting in shortness of stature, stocky build, dis- proportionately short arms and legs, broad, short hands and feet, mild joint laxity, and macrocephaly. Hypoplasia Underdevelopment of a tissue or organ as a consequence of incomplete development. The organs are smaller and their function is reduced or absent. Physiologically, this situation is less severe than agenesis or aplasia. Organs where this abnormality can occur are the testis, ovary, testis, and kidney. Micrognathia is also an example of hypoplasia. Hypospadias Is a congenital defect in which the urethra of males opens on the inferior surface or underside of the penis. In females with hypospadias, the urethra opens into the cavity of the vagina. During the embryological development of males, a groove of tissue folds inward and then fuses to form a tube that becomes the urethra. Hypospadias occurs when the urethra does not form or does not fuse completely. Hypotelorism A defect that occurs with the decrease in the distance between the pairs organs, as the eyes and its orbits. Ichthyosis Disorder with massive keratinization of all the skin that becomes dry, forming thickened keratin plaques seen as fish scales. Imperforate anus Failure of anal membrane breakdown, resulting in absence of the anus aperture. Iniencephaly Is a rare cephalic disorder that includes: defect of occipital bone, spina bifida in cervical column (rachischisis), and retroflexion of the head. Ischiopagus Rare congenital defects in twins that are fused by the pelvic region, in obtuse angle bodies, along a long axis with heads on opposite sides. Several organs are fused together and the urogenital tract and anus are single or imperforate. Glossary of Key Terms for Teratology 603

Kyfosis Excessive convex curvature of the spine, in the cervical, thoracic, or sacral region. In congenital kyphosis, the column does not develop cor- rectly during the gestation period, having vertebrae fused or malformed. As a consequence, the column progressively reaches severe kyphosis as the child develops. Lissencephaly Is a brain malformation characterized by the absence (agyria) or incomplete development (pachygyria) of the ridges or convolutions (gyri) of the brain cerebral cortex, causing the appearance of brain’s surface unusually smooth. The affected individuals have microcephaly and may manifest sudden episodes of uncontrolled electrical activity in the brain (with seizures), severe or profound intellectual disability, feeding diffi- culties, growth retardation, and impaired motor abilities. Lordosis An increased inward curving of the lumbar spine. Major malformations Are those that have severe medical and/or social implications. These often require surgical or severe medical repair/intervention (example: meningomyelocele, orofacial clefting holoprosencephaly). Malformation Abnormality occurring during the structures’ formation (during the gestation period), resulting in a complete or partial absence or alteration (aberration) of normal structure conformation. Results as a morphological defect of an organ, part of an organ, or a larger region, in severe situations with defects in all the body. Megalocephaly Abnormal enlargement of the head, with large skull and a small midface. Meningocele Relatively small defects in the skull (cranial) through which meninges and/or encephalon tissue herniate forming a cyst filled with cerebrospinal fluid. Meromelia Congenital absence of a part of the limb (arms or legs) having the hand or foot complete or rudiments linked to the residual member. Microcephaly Is the failure of brain growth resulting in cessation to skull expansion. Micrognathia Small size of the mandible, due to incomplete development of its structures. Micromelia Disorder of the limbs characterized by abnormally shortness of one or all extremities, resulting in limb shortness and deformed. Microphthalmia Eye and eyeballs with dimension smaller than normal. It can be a defect in both or only one eye. Microsomia Abnormal smallness of body structures (can be described related to spectrum of skull anomalies as the craniofacial microsomia). 604 Maria dos Anjos Pires and Ana M. Calado

Microtia Congenital anomaly related to the pinna (external ear) underdevelopment (small dimension) or malformation and deformity. Is associated with the narrowed or absence of the ear canal. Multicystic dysplastic kidney (MCDK) Is a group of anomalies that could be non-inherited (caused by a several factors) or inherited disorder correlated with an autosomal recessive or dominant disorder. Both inherited disorders are linked to mutations in genes that encode proteins located on the cilia and related to various abnormalities in other organs. This pathology results in multiple cysts that are formed in utero, in the kidney (most common in the left one). Depending on the cause, the cyst may form from collecting tubes or from all segments of the nephron. The kidney becomes very large and loose function leads to renal failure. Myelomeningocele Cranial defects with the herniation of neural/encephalon tissue from the spinal column forming a sac under the skin. Omphalocele Ventral body wall defect in turn of the umbilical site, that arises from the failure of return to the abdomen of the gut tube (physiologically, the midgut herniates into the umbilical cord in the beginning of the 2nd period of gestation and returns after that to the abdomen cavity). Loops of viscera could herniate into this defect. Omphalopagus twins Conjoined twins fused by the midventral portion of the trunk. The typical is the union extended from the sternum to the umbilicus, where often, an omphalocele is found. Ovotestes The gonad of the individual has both testicular and ovarian tissue in different proportions. Palatoschisis The same as cleft palate, is the fissure or longitudinal opening of the palate, as a result of incomplete closure of the palate’s structures during the embryonic development. In this case, the nasal cavity is open in the mouth. Parapagus Are twins caudolaterally fused, united by the lower abdomen and pelvis. They have various degrees of duplications of cranial and end of the body. Paratopia Localization of a viscera in the opposite at normal site. Misplaced organ. Patent ductus arteriosus (PDA) There is a persistent communication between the descending thoracic aorta and the pulmonary artery that results from failure of physiologic closure of the fetal ductus arteriosus. This hole allows the blood to skip the circulation to the lungs. The persistent hole is called the patent ductus arteriosus, and is one of the more common congenital heart defects. Pectus carinatum Anomaly with protrusion of the anterior chest wall, forming a keel- shaped deformity. Glossary of Key Terms for Teratology 605

Pectus excavatum Congenital deformity producing a concave appearance of the anterior chest wall resultant of several abnormal conformation of ribs and sternum. Phocomelia Disorder of the limbs characterized by the loss of long bones. Hands and feet attach directly to the trunk or hip, respectively. Is a form of meromelia. Piebaldism Rare autosomal dominant disorder of the melanocyte development presenting irregularity of hair and skin depigment. Plagiocephaly Premature closure of coronal sutures (craniosynostosis) only on one side, resulting in an asymmetric distortion with flattening of one side of the skull. Polimelia Congenital anomaly in that the individual presents a higher number of members than usual. Poliotia Is a congenital defect related to the increase of the number of ears. Polydactyly Presence of extra digits in foot and/or hands. Is the same as hyperdactyly. Polyhydramnios Is the same as hydramnios Polymastia Development of a complete supplementary mammary gland (in humans, this is developed as a complete breast) in the remnant mammary line. Polymicrogyria (PMG) Is a malformation in which the surface of the brain has too many and unusual small folds (gyri). This disease can affect only one side of the brain (unilateral) or both sides of the brain (bilateral). Polythelia Condition with accessory nipples that arises in the mammary line. Porencephaly A rare congenital condition that results in cystic degeneration and necrosis (encephalomalacia) of the encephalon, is a less severe form of hydranencephaly. Prosoposchisis Is a congenital facial cleft extending from the mouth to the orbit of the eye. Pygopagus twins Congenital anomaly related to twins, that are fused at hip level, by the caudal portion of the vertebral column and perineum and only rarely affecting the lower limbs. Rachipagus Twin fused dorsally in the trunk, perhaps even the occiput, with fused columns. They could have differentiated faces on opposite sides of the head. 606 Maria dos Anjos Pires and Ana M. Calado

Rachischisis All birth defects involving the neuronal tube. Scaphocephaly Premature fusion of sagittal sutures joint the two parietal bones of the skull (is the most common craniosynostosis). Results in a long narrow head. Schistossomus reflexus Is a rare and fatal congenital defect, common in bovines, involving a complex defect that includes severe torsion of the spine that implies gastroschisis with all abdominal viscera exposed and limb ankyloses inside the inverted skin that could form a bag. Other visceral defects are associated as dextrocardia, lung hypoplasia, and vesical exstrophy. Scoliosis Sideway curve of the spine, in different degrees. Sirenomelia Is a rare severe deformation, characterized by a fusion and an abnormal rotation of the lower limbs, given the appearance of mermaid’s tail. Associated anomalies include anorectal malformations, abnormal or absent genitalia, renal agenesis or cystic kidneys, spine and sacrum defects, preaxial anomalies of the upper limbs, as well as intestinal malformations and cardiopathies. Situs inversus Is defined as the reversal or mirror arrangement related to the normal position of thoracic and abdominal organs, and may be partial or total. Partial situs inversus involves one or two organs, like heart, spleen, or intestines. Total situs inversus is a mirror image of the usual visceral arrangement. Spina bifida Failure of the closure of the blackbone and membranes around the neural tube anywhere from cervical to the caudal region. The most common is absence of closure in the lumbosacral region. Different degrees of incomplete closure have been described as spina bifida occulta the middle form of this disease, where only the outer part of vertebras is not completely closed. The association of spina bifida with the meningocele is the rarest of this condition with the herniation of the meninges through the incomplete vertebra. The most severe is the myelomeningocele where the spina tissues with the meninges herniate. This disease is associated with severe complications as sphincter controls, and others. When the spina bifida is associated with myelocele and infections, men- ingitis can occur. Stenosis or constriction Narrowing of a natural orifice or tubular organ. This is a lighter form of atresia (example: rectal constriction or stenosis). Syndactyly Fusion of two or more digits, being together. It can have different degrees of fusion, from only being joined by the skin between the digits until the bone fusion. Synophthalmia Is a form of cyclopia, with a fusion of some elements of the eyes in the middle region of the forehead. Glossary of Key Terms for Teratology 607

Talipes Developmental disorder of the lower limb (foot), which could be isolated or associated with other congenital anomalies, neurological or neuromuscular defects as spina bifida. It can affect one or both feet, and is observed a rotation inward and downward. This deformity is also named clubfoot. The degree of foot torsion is described as different denomination: talipes varus (inversion of the foot with the outer side touching the ground); talipes calcaneous (the foot present weakness or absence of the calf muscles force that the axis of the calcaneus becomes vertically oriented); talipes calcaneovarus (combination of the talipes varus with talipes calcaneous); talipes equinus (the sole foot is perma- nently flexed implying that walking is done on the toes without touching the heel to the ground); talipes equinovarus (the foot is fixed on adduction, with supination and varus: inclined inward, axially rotated outward and pointing downward); talipes cavus (exaggeration of the foot curvature or its normal arch); talipes valgus (tarsus is rotated inwards and flattening of the plantar arch),talipes calcaneovalgus (excessive dorsiflexion of the foot. Its dorsum come into contact with the anterior portion of lower leg and the toes point upward. The arch is flat) and talipes equinovalgus (is the combination of talipes equinus with the talipes valgus. The foot presents a marked plantar-flexed, and is everted and abducted). Teratogen A product that could promote a birth defect. It could be biological, environmental, toxic, chemical or physics. Teratology or dysmorphology Study of defects that could be congenital malformations or anomalies, present at the birth and can be structural, behavioral, functional, or metabolic disorders. Tetralogy of Fallot Is the most frequent cardiac anomaly of the conotruncal region, due to an unequal division of the conus resulting from anterior displacement of the conotruncal septum, production of four alterations. 1) pulmonary infundibulum stenosis, with narrow right ventricular outflow resulting in some obstruction; 2) a large defect in the interventricular septum; 3) an overriding aorta that arises directly above the septal defect; 4) pressure of the right ventricle gives rise to a hypertrophy of the right ventricle wall. Thoracopagus twins Twins fused by the midsternum until the umbilicus often presenting an omphalocele. This fusion involves internal viscera as the heart, liver, dia- phragm, and usually proximal small intestine. The spine could have some lordosis degree and they have heads, column, genital, and limbs normal. Transposition of the great arteries (TGA) Is a complex congenital heart disease with limited mixing between the systemic and pulmonary circulatory systems patent, as cyanosis in neonates. TGA is the most common cyanotic congenital heart lesion present in neonates. This malformation is part of the tetralogy of Fallot. Index

A Biomarkers...... 49, 148, 423 Birth defects...... 3, 18–20, 23, 24, 97, 165, 205, 217, Abnormal development...... 4, 234, 268, 300, 302, 599 243, 557, 605, 607 Abnormalities...... 6, 7, 9, 11–13, 15–19, 22–24, 35, Bone 51, 52, 205, 233, 246, 253, 264, 272, 277, 279, malformations...... 12, 22, 24, 352–355 301, 310, 345–347, 507, 548, 555, 557, 562, 568, marrow ��556, 560, 562–565, 569, 570, 572 569, 572, 595–598, 600, 602–604 marrow cells ��556, 560, 562–564, 569 Amphibian Bovine serum albumin (BSA)...... 120, 132, 139, 149, embryos...... 47, 50, 300, 309 156, 169, 172, 174, 193, 202, 207, 211, 251, 266, metamorphosis assay...... 47, 49 328, 367, 369, 370, 464, 469, 499, 501, 504, 532, Animal 535, 538–541, 543 live ��62, 64, 166, 422 Brain pregnant �� 18, 52, 177, 191, 591 development...... 10, 22 testing ��37–39, 47, 56, 63, 98, 147 embryonic �� 79, 159, 462 tests ��36, 37, 56, 545–554 segments ��346 welfare �� 36, 48, 63, 70, 422 BSA, see Bovine serum albumin (BSA) Animal models alternative...... 36, 39, 40, 48–50, 62, 63, 71, 87, 234 C non-mammalian �� 39, 47–50, 65, 71, 87 Caenorhabditis elegans...... 65, 66, 72, 74, 217–231, small �� 47, 48, 66, 85, 337, 398, 404, 428 394, 398, 403 Anomalies ...... 4, 6, 7, 9, 11–14, 16, 18–21, Calcium 23, 24, 51, 126, 346, 556, 562, 595–598, 603, assay �� 128, 132, 136, 138–139, 143 605–607 concentration �� 10, 139 Antibodies ��70, 149, 159, 167, 169, 171–174, Cardiac 198–199, 202, 211, 235, 238, 239, 248, 255, 256, development...... 158 266, 270, 328, 330, 331, 365–367, 369, 370, 422, Cardiomyocytes 461–464, 467, 469, 472–474, 498, 502, 503, 505, development...... 99 513, 518, 522, 523, 528–530, 581, 582, 584, 593 embryonic ��147 Antigen retrieval...... 365, 368, 461, 467, 472, 522, 529 Cartilage ��82, 159, 352–356, 361, 375, 515, 526 Apoptosis ��23, 66, 166, 205, 206, 211–212, Catalase ��477, 479, 481–483 321, 531–535, 537, 597 Cell Arduino �� 405, 412–418 animal ��40, 66, 74, 556, 562, 567, 569–571 Assessment apoptotic ��321 developmental toxicity...... 34, 35, 50, 52, 55, 86, blastoderm �� 74, 76, 254 125–144, 147, 246, 338–341, 361, 373, 461–475 concentration �� 109, 110, 135 B count ��100, 110, 111, 121, 134–135, 149 culture �� 40, 46, 84, 99, 100, 105, 112–119, Behavior 129–131, 136–138, 148, 149, 152, 160, 161, 167, alterations...... 23, 403 169–171, 191, 195–196, 235–237, 251–252, avoidance ��284, 293, 294, 409–412, 417, 418 266–268, 398, 428, 557 Behavioral cycle ��66, 245, 309, 556, 570, 571 assays ��278, 284, 404–417 density ��134, 148, 150, 160, 161, 237, 571 teratogen ��277 dead �� 110, 174, 507 Biology ��4, 46, 65, 66, 78, 103, 218, 220, 234, differentiated �� 74, 78, 98, 107, 113, 126, 133, 244, 309, 403, 422, 424, 429, 462, 507 166, 178, 268

Cell (cont.) processes ��3, 50, 178, 325, 422, 427, 437 individual ��107, 133, 462, 493 stages �� v, vi, 4, 68, 69, 181, 186, 188, lineages �� 74, 77, 166, 218, 425 212, 213, 218, 220, 223, 224, 230, 237, 246, 263, living �� 267, 423, 508 278, 303, 325, 348, 350, 396, 425, 431, 591 mesenchymal �� 126, 169, 170, 320, 516 toxicants ��41, 126, 128, 165–174, 246, 421 mesodermal �� 73, 75–77 toxicity �� 34, 35, 37, 38, 47, 48, 50, 52, neural crest ��206 53, 55, 70, 81, 86, 125–144, 166, 177–188, 246, neuronal �� 4, 21, 40 338, 339, 343, 361, 373, 374, 461–475 Cell suspension...... 107–111, 114, 115, 133, 135, Differentiation 137, 142, 156, 160, 171, 174, 560, 561, 564, 565 cardiac ��102, 103, 110, 112–115, 122, 170 Cell viability...... 113, 120, 122, 126, 138, 149, osteogenic ��126, 127, 130, 136 151–155, 159, 160, 167, 171, 173 Dissection �� 68, 178, 181, 184, 186, 187, 208, Central nervous system (CNS)...... 9, 11, 18, 20, 23, 209, 211, 212, 234, 235, 265, 273, 284, 498, 504, 79, 409, 518, 520, 524 509, 520, 526, 528, 534, 538, 560 Chemotaxis...... 283–284, 288–290, 292, 293 DNA ��20, 45, 48, 166, 218, 231, 323, 327, 329, Chorion �� 73, 77, 81, 187, 343, 405 424–426, 431, 434, 462, 474, 518, 555, 557, 559, Chromosome aberration (CA)...... 556–558, 560–562 562, 565–567, 572 CNS, see Central nervous system (CNS) Drosophila Comet assay...... 556, 557, 559, 567, 569, 572 development...... 233–240 Congenital embryos �� 239, 247, 253 anomalies...... 4, 9, 12, 14, 16, 18–21, 597, 606 larvae �� 278, 284 defects �� 4, 24, 557, 595, 598, 600, 602, 605 melanogaster ��v, 65, 66, 72, 74, 233–240, 243–273, malformations ��3, 6, 9, 11, 13, 17, 23, 508, 595, 607 277–296, 403 Craniofacial model ��234, 244, 261, 269 development...... 11 Drugs �� 12, 33, 62, 98, 147, 165, 178, 233, structures ��71, 345, 346, 373, 374, 376, 243, 278, 326, 337, 396, 403, 422, 487, 531, 538, 377, 385, 599 545, 557, 577 Cytotoxicity E endpoints...... 99, 103, 126, 128, 131, 137, 138, 140, 143, 148 Ectoderm ��4, 19, 73–77, 79, 166, 320, 597 D Electrophoresis...... 192, 194, 197–198, 268, 423, 424, 427, 498, 499, 501, 502, 559, 565, 567, 572, Danio rerio, see Zebrafish 593 Dark-light ��416 Embryo Datasets �� 36, 380, 430, 431, 435 culture ��41, 46, 65, 69, 71, 80, 85, 87, 99, Dechorionation...... 68, 252–254, 493, 494 148, 151, 159, 177–188, 191, 205–213, 234–237, Defects 251–252, 266–268, 302, 303, 428 behavioral...... 278, 282, 545 defective �� 254, 256, 345 Development development �� 4, 11, 18, 41, 42, 44, 46–48, anatomy...... 87 51, 62, 65, 71, 77, 85–87, 98, 125, 159, 165–174, phases �� 38, 41, 87 177–188, 205–213, 245, 255, 256, 269, 300, 303, processes �� 243, 462 309, 325, 337, 345, 348, 359, 396, 403, 447, 457, stages ��5, 62, 87, 150, 159, 225, 586 507, 587, 600 toxicology ��65 dissection ��178, 181, 184, 186, 187, 208, Developmental 209, 211, 212 abnormalities...... 17, 246, 345, 507 developing �� 4, 8, 11, 46, 78, 79, 87, 98, alterations ��246, 422, 423, 429–431 166, 206, 226, 396, 447, 487 biology �� 66, 244, 309, 422, 462 early ��22, 71, 337, 348, 428, 430, 578 cardiotoxicity �� 116, 147–161 exposure ��4, 11, 125, 148, 182, 191, 211–212, 243, defects ��v, 12, 249, 259–261, 359, 426, 457 253–254, 256, 300, 303, 304, 321, 343, 359, 360, disorders ��3, 22, 374, 508 396, 400, 430, 444, 447, 480, 487, 488 effects �� 39, 44, 47, 425, 428 frog ��41, 47, 73, 85, 86, 206, 234, 301, 309–323 neurotoxicity �� 53, 55, 86 invertebrate �� 65, 78, 234 parameters �� 36, 181, 586 rodent �� 41, 403 pathways ��50, 338, 427, 430 vertebrate ��41, 47, 65, 67, 78, 79, 85, 234, 337, 487 Teratogenicity Testing: Methods and Protocols 611 Index

whole-mount ��209–211, 365–370, 462, 464, 469, Fish 577–579, 586–591, 593 embryo...... 48, 49, 76, 80, 234, 341, 395, 422, Embryo-fetal 428, 429, 456, 480, 481 abnormality...... 18 embryo test (see Fish embryo test (FET)) development ��18, 51, 62, 65, 86 embryogenesis ��423 Embryogenesis Fish embryo test (FET)...... 49 development...... 9, 11, 166, 218, 252, 254, 337, 422 Flow cytometry (FC)...... 99, 165–174, 433 early ��7, 186, 188, 422, 430, 557 Fetus �� 147, 177 Embryoid bodies...... 102, 112, 113, 116, 119, 121, 122 Frog �� v, 41, 47, 49, 67–69, 73, 76–78, 80, Embryology...... 36, 66, 71–73, 75–84 82–86, 206, 234, 301, 302, 305, 309–323 Embryonic Frog embryo teratogenesis assay xenopus bodies �� 170, 173, 174 (FETAX)...... 41, 47, 86, 299–306, 309 cardiomyocytes ��147–161 Fruit fly �� 66, 72, 75, 78, 82–85, 234, 237–238, cells �� 15, 76, 77, 99, 148, 178, 236–237, 245, 264, 269 251–252, 266–268, 273 G defects ��9, 11, 243, 457 development ��9, 11, 51, 67, 71, 72, Gastrulation...... 9, 71, 73–78, 87 78–82, 85, 86, 150, 159, 185, 218, 234, 267, 301, GD, see Gestational day (GD) 597, 599, 604 Gene expression...... 99, 118, 122, 126, 191, 205, hippocampus �� 531, 534, 535, 537, 543 206, 244, 310, 319, 325–334, 424, 426, 434, 435, period �� 4, 5, 557 578, 586 stages �� 9, 11, 51, 66, 78, 85, 127, 178, Genes ��43, 49, 66, 67, 85, 126, 218, 278, 427, 428 218, 234, 244, 245, 266, 281, 321, 325, 326, 333, stem cell �� 40, 46, 62, 97–123, 148, 165–174, 557 394, 399, 423, 424, 426, 430, 431, 435, 436, 537, Embryotoxic 577, 592, 603 chemicals...... 46, 99, 119, 122 Genotoxicity effects �� 40, 98, 182, 421, 437 tests �� 556–562, 569 Embryotoxicity...... 40, 44, 98, 99, 118, 127, Geometric morphometrics...... 373–389 178, 182, 206, 343, 421, 422, 424, 429, 430, 437, Gestation ��4, 5, 7, 9, 10, 12, 16, 21–24, 52, 497, 505 62, 69–71, 84, 87, 208, 500, 570, 577, 579, Endoderm ��4, 73–75, 77, 78, 166, 320 587–590, 592, 602, 604 Endpoints ��36, 39, 46, 48, 50–52, 54–56, 65, 85, Gestational day (GD)...... 181, 188, 208, 209, 212, 500, 504 98, 99, 102, 103, 113, 119, 126, 128, 131–132, Glutathione reductase (GR)...... 477, 480 136–141, 143, 148, 152, 159, 182, 211, 245, 246, Glutathione-S-transferase (GST)...... 478, 479, 481 254–260, 263, 268, 269, 271, 278, 300, 373, 374, GST, see Glutathione-S-transferase (GST) 443, 447 Guidelines Exposure ��4, 11, 12, 15–20, 22, 34, 39, 44, 45, regulatory...... 34, 51 47–55, 62, 80, 87, 97, 121, 125–127, 147, 148, 150, 152, 153, 165, 170, 177, 191, 200, 208, H 211–213, 217, 218, 220, 223–225, 230, 233, Hatching �� 71, 72, 78, 82–84, 218, 223, 237, 243–273, 282, 303, 305, 343, 348, 350–351, 360, 238, 254, 279, 350, 351, 361, 405, 422, 443 361, 400, 403–418, 443–458, 462–464, 468–470, Heart 474, 475, 480, 487, 497, 531, 545, 546, 557 defects �� 6, 7, 9, 18, 21, 126, 205, 604 F development ��9 malformations �� 11, 352 FC, see Flow cytometry (FC) Hemodynamic...... 487–494 Fetal Hippocampus...... 531, 534, 535, 537, 543, 546 brain development...... 10, 22, 192 Histology ��48, 311, 319, 321, 463, 465, 466, 518, 525 development ��11, 18, 51, 62, 65, 86, 243, 598, 600 Human development...... 5, 245 malformations ��13, 15–16, 24, 86 Human embryonic stem cells (hESC)...... 127–130, 132–133 Fetogenesis...... 40, 41, 44 Human foreskin fibroblasts...... 128, 129, 133–134, 137 Fetus �� 5–12, 14–16, 18, 20–24, 51, 52, 69–71, Hybridization...... 310, 319, 321, 325–334, 400, 78, 81, 86, 191, 233, 237, 278, 424, 501, 507, 509, 431, 433, 434, 508, 577–579, 586–591, 593 514–516, 525, 526, 529, 577, 578 Teratogenicity Testing: Methods and Protocols 612 Index

I Mesoderm ��4, 73, 75–77, 79, 166, 320 Metabolism...... 8, 9, 20, 39, 44, 51, 86, 157, 244, IC50 ��98, 114, 115, 118, 119, 121, 128, 140, 182 279, 306, 340, 393, 394, 399, 424, 428, 538 Immunoblots...... 195 Metabolomics...... 46, 427–430, 443 Immunofluorescence (IF)...... 365, 462–464, 468–470, 473 Mice �� 11, 14–21, 23, 36, 51, 81, 87, 98, 159, 177, Immunohistochemistry...... 158–159, 365–370, 181, 186, 191, 197, 206, 208, 278, 422, 425, 426, 461–463, 465–468, 508, 513, 516, 518, 522, 523, 497, 500–502, 504, 532, 533, 540, 545, 548–551, 529 556, 557, 563, 569, 570, 572 Immunostaining...... 235, 238–239, 247–248, Microinjection...... 206–210, 213 255–256, 365, 497, 505 Micromass Instar larvae...... 237, 238, 282, 283, 285, 287, 288, 296 culture ��46, 99, 148–152, 160 Invertebrates...... 64–67, 71, 74, 78, 82, 84, 85, 87 system ��148, 151, 159, 160 In vitro test �� 46, 99, 148 assays ��37, 39, 43–46, 234–237, 266, 567 MicroRNAs (miRNAs)...... 205–213 methods ��34, 36, 37, 39–46, 98, 178 Microscopy...... 84, 239, 254, 256, 267, 310, techniques ��39, 40, 46, 47, 65 311, 365, 366, 369, 474, 488, 494, 507, 523, 535, teratogen �� 147, 191–202, 206, 208, 235–237 586, 587 L Mitochondria...... 128, 152, 280, 393–395, 398, 399, 537–543 Larvae Mitochondrial membrane...... 394, 538, 539 activity ��238, 278, 408, 416–418 Model organisms...... 234, 246, 277, 309, 373, treated ��287 374, 394, 422, 487 wild type �� 284, 287 Morphological Larval defects �� 237, 603 development...... 47, 66, 71, 78, 218, 256, 257, 259 development ��47, 49, 99, 181, 237–238, 507 locomotion ��278, 288, 417, 418 Morphometrics...... 220, 222, 225, 226, 238, phases �� 256, 257, 270 577–579, 586–591, 593 stages �� 66, 78, 82, 85, 218, 224, 225, 246, Mouse 254, 256, 257, 263, 269, 350, 422, 428 embryo...... 46, 69, 87, 101, 178, 179, 181–182, 185, 188, Lethality ��41, 51, 279, 337–361 205–213, 366, 507, 580 Life cycle �� 51, 66, 82, 85, 218, 220, 234, 244, embryo culture ��69 245, 256, 257, 278, 422, 425 postnatal �� 538, 546 Limb Mus musculus...... 66, 70, 72, 75, 497, 505, 507–530 bud �� 99, 148, 159, 578, 579, 587, 588, 590 N development �� 71, 80, 83 Lipid peroxidation...... 279, 477, 480, 484, 485 Nematode �� 49, 50, 64, 66, 67, 72, 73, 78, M 82–84, 221, 222, 394 Neural Malformation...... 3–7, 9, 11–19, 21, 23, 24, 41, 51, cells ��76 62, 70, 80, 86, 125, 182, 212, 272, 300, 302, plate ��79 304–306, 337–361, 421, 429, 497, 508, 545, 569, tube ��9, 11, 12, 15, 16, 69, 71, 79, 205, 577, 578, 595–603, 605, 607 320, 358, 359, 600, 606 Mammalian Neurons �� 148, 266, 268, 278, 279, 284, 511, cells �� 77, 178 518, 519, 531, 595 development �� 51, 77, 86, 87, 246, 507 Neurotoxicity...... 17, 53, 55, 86 embryos �� 41, 86, 87, 178, 487 O Mammals ��42, 50, 55, 67, 70, 71, 73, 75, 78–81, 83–87, 233, 234, 244, 245, 278, 300, 301, 338, Omics �� 421–437, 443 345, 422, 424, 426, 428, 437, 487 Organisms ��4, 7, 47, 50, 52, 62, 63, 66, 73, Membranes 74, 77, 82–85, 87, 157, 178, 196, 234, 244, 246, embryonic...... 77, 525, 582, 583 277, 278, 309, 337, 373, 374, 394, 399, 403, 404, extra-embryonic ��77, 208–211, 515 421, 422, 424, 425, 427, 477, 478, 480, 485, 487, Mesenchymal stem cell...... 169, 170 557, 601 Teratogenicity Testing: Methods and Protocols 613 Index

Organogenesis �� 4, 41, 47, 50, 51, 62, 71, 78–80, RNA ��20, 67, 74, 104, 116, 117, 120, 210, 218, 86, 87, 188, 218, 246, 321, 338, 343, 422, 578 273, 327–329, 333, 423, 424, 426, 431–435, 518, Oxidative stress...... 20, 80, 157, 477–486 578, 580, 581, 584, 592, 593 P Rodents ��41, 42, 50, 52–54, 65, 66, 69–71, 81, 84, 85, 233, 338, 403, 546, 547, 577 Paraffin �� 310–316, 322, 462–468, 470, 471, 500, ROS, see Reactive oxygen species (ROS) 502, 508–511, 514–516, 520, 522, 523, 526, 529, S 532–534 Pharmaceuticals...... 35, 50, 65, 98, 99, 217, 243, Screening ��33, 40, 41, 43, 44, 47, 48, 50, 52, 53, 299–306, 399, 400, 422, 578 55, 56, 65, 66, 84–86, 98, 126, 220, 234, 244, 246, Phototaxis ��245, 278, 283, 286, 290, 292 251–252, 266–269, 309, 404, 410, 422 Postnatal development...... 51–53, 56, 177, 520 Screening tests...... 52, 53, 55, 85, 86, 177 Pregnancy �� 3–5, 8, 10–12, 14–24, Secondary antibody...... 149, 159, 172–174, 199, 44, 51, 53, 69, 70, 77, 80, 81, 97, 98, 165, 186, 200, 239, 255, 266, 365, 369, 461, 463, 464, 467, 233, 568, 601 469, 472, 502, 523, 528–530 Prenatal development...... 3, 52, 55, 86, 233, 277 Skeleton ��6, 9, 11, 80, 128, 326, 327, 354, 508, Primary antibody...... 149, 171–173, 199, 200, 202, 515, 516, 526, 568 238, 255, 266, 365, 369, 370, 461, 463, 464, 467, Somites �� 69, 71, 76, 79, 182, 183, 209, 211, 469, 472, 513, 523, 528–530 212, 320, 321, 345, 347, 348, 350, 358, 361, 367, Primer ��105, 106, 117, 118, 123, 210, 266, 327, 586, 587 374, 502, 557, 559, 565, 566 Structural abnormalities...... 13, 35, 51, 52, 310, Probes �� 66, 168, 313, 316, 318, 326, 327, 555, 557, 596 329–331, 334, 429, 431, 435, 445, 448, 550, 551, Structures �� 4, 14, 38, 47, 49, 66, 69, 74–81, 553, 578, 580, 581, 584, 592, 593 84, 116, 167, 244, 254, 256, 272, 311, 316, Protein 319–321, 329, 345, 346, 348, 358, 365, 373–375, concentration...... 136, 139, 140, 201, 211, 426, 427, 377, 378, 380, 385, 498, 531, 533, 534, 540, 543, 457, 478, 481–484, 486, 498, 499, 501, 528 555–557, 562, 596–599, 601, 603, 604 expression ��11, 191–202, 207, 210–211, 213, T 238, 424, 497, 577 extraction �� 444–445, 447–449, 451, 457, 498 Teratogens �� 6, 46, 85, 127, 152, 206, 217, 251, lysate ��448, 449, 451, 457 277, 309, 359, 403, 424, 443, 557 quantification �� 201, 445, 457, 458, 481 Teratogenesis �� 4, 11, 14, 15, 17, 18, 41, 47, Proteomics �� 46, 99, 148, 426–430, 443–458 52, 86, 205, 206, 253, 267, 268, 277–296, 301, Pupae ��237, 238, 244, 258–261, 279, 281 309, 421–437, 557 R Teratogenic agents ��4, 6–7, 18, 148, 165, 191–202, 277 Rabbit drugs ��153, 155, 156, 217–231 embryos...... 577–579, 586–591, 593 effects ��9, 14–16, 18–20, 39, 62, 71, 87, 97, Rat embryo 166, 206, 224, 234, 237, 238, 256, 257, 260, 278, culture ��41, 87, 185, 188 310, 343, 358, 373–389, 423, 429, 457, 462, 487, dissection �� 178, 179, 184 489, 491, 494 Rattus norvegicus...... 65, 69, 70, 72, 75 Teratogenicity Reactive oxygen species (ROS)...... 149, 151, 157–158, phenotypes...... 309–323, 429–431 279, 394, 538, 539, 542, 543 risk ��9, 14, 17, 19, 86, 98, 233 Reproduction...... 33, 35, 36, 48–50, 52, 53, 55, testing �� 44, 69, 147, 148, 249, 62, 72, 82, 84, 86, 87, 217, 222, 225, 234, 279, 260–262, 309, 310, 337, 343, 359, 555, 557, 560, 339, 340, 404, 405, 487 568, 569 Reproductive Teratology �� 3–24, 33–56, 206, 233, cycle �� 39, 40, 45, 47, 50, 70, 87, 177, 339 234, 462, 497, 508 toxicity ��40–46, 52–56, 70, 82, 86, 421 Test ��33, 62, 98, 126, 148, 166, 177, 200, 229, Respiration...... 340, 393, 394, 398, 399 234, 243, 281, 300, 338, 381, 394, 427, 451, 472, Risk assessment...... 34, 36, 37, 46, 48, 49, 53, 55, 480, 487, 526, 541, 546, 555, 580 56, 62, 118, 423, 428 Thigmotaxis...... 404, 406–410, 417, 418 Teratogenicity Testing: Methods and Protocols 614 Index

Thiobarbituric acid reactive substances (TBARS)...... 477, X 478, 485 Tissues �� 4, 46, 69, 98, 126, 148, 169, 178, 192, 208, Xenopus 225, 236, 244, 310, 325, 340, 365, 422, 448, 461, embryos...... 304, 306, 309 481, 507, 532, 540, 557, 592 laevis ��65, 72, 74, 300, 301, 303, 309, 311, 325–334 Total glutathione (TG)...... 477, 479–481, 483, 484 Z Toxic effects...... 33, 34, 50–52, 86, 147, 151, 153, 156, 177, 427 Zebrafish Toxicology ��34, 37, 55, 63–65, 67, 70, 71, 78, 84, embryonic...... 423 85, 165, 166, 178, 205–213, 233, 309, 374, 399, embryos ��41, 47, 50, 73, 340, 343–349, 426, 427, 443, 567 352, 355, 359, 360, 366, 393–400, 403, 422, 430, V 431, 435, 436, 447, 448, 451, 457, 462, 480, 485, 487, 489, 491, 494 Vertebrate ��37, 38, 41, 47, 49, 64, 65, 67, 71, 74, larval ��47, 72, 82, 83, 350–351, 373, 385 78, 79, 84–86, 268, 269, 337, 345, 403, 422, 424, Zebrafish embryo...... 47 436, 462, 487, 515 assays �� 41, 403, 422 development �� 41, 47, 423 W Zebrafish embryogenesis...... 337, 422, 430 Zebrafish embryotoxicity test (ZET)...... 343 WEC, see Whole embryo culture (WEC) ZET, see Zebrafish embryotoxicity test (ZET) Western blot...... 191–202, 207, 210–212, 444, 497–505 Zebrafish larvae...... 361, 403–406, 408, 409, 412, Whole embryo culture (WEC)...... 41, 46, 65, 69, 71, 87, 417, 467, 468, 477–486 99, 148, 177–188, 191, 206–209 Whole-mount in situ hybridization...... 325, 577–593