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Teratology •the study of malformations or serious deviations from the normal type in organisms • the branch of science concerned with the production, development, anatomy, and classification of malformed fetuses. •Teratogens –A teratogen is a substance, organism, or physical agent capable of causing abnormal development. –Teratogens can cause abnormal structure, abnormal function, growth retardation, or death. 6 Principles of Teratology 1. genetic influences-由於遺傳差異,引起個體對致畸作用的 敏感度不同 2. critical periods-不同時期對致畸作用的敏感度不同 3. initiating mechanism-致畸原以特定的機轉對細胞組織作用 引發一連串的不正常發育 4. access to embryo and fetus-致畸原的特性決定其與胚胎接 近的難易 5. abnormal development-不正常的發育的結果→death, malformation, growth retardation, and functional disorder 6. dose-response relationship Critical (Sensitive) Periods Time of exposure is a major determinant of toxicological consequences • range from no effect to death • may affect one organ system at one exposure time and a different organ system at a different time • may affect one part of a structure (or function) at one exposure time and a different part (or function) at a different time • may require continued exposure throughout development • possible that a single acute exposure at the wrong time could affect development Human Development Sensitive Periods During Pregnancy Hamster Development Sensitive Periods Critical periods of susceptibility and endpoints of toxicity Stages of development and toxicity 1. Fertilization 受精 受精後6hr暴露ethylene oxide, ethylmethane sulfonate→malformed fetus mechanism:unclear, may be related to imprinting DNA Methylation Methyl groups may be attached to cytosine (C5 position) • Methyltransferases Methyl groups provide a tag Concentrated in CG-rich domains, often in promoter regions Maintains a gene in inactive state rather than initiating gene repression – Example: •Inactivation of genes of one X chromosome in female mammals occurs prior to a wave of methylation •Implantation – a new wave of methylation occurs •Early Zygote – most methylation tags removed DNA Methylation – Genomic Imprinting Certain genes are active or inactive during early development •Depending on whether they are paternal or maternal genes •Eg – IGF-2 is only active in the gene from the male parent •The gene is imprinted according to parental origin Mammalian genome has > 100 imprinted genes in clusters Imprinted due to selective methylation of one of the alleles 2.Preimplantation著床前期 (blastocyst) 囊胚形成,細胞分裂到1000個細胞,僅3個細胞將 發育成胎兒,餘發育成胎盤等支持組織,在此期暴 露,理論上不影響或稍微影響胎兒生長,不然就導 致死胎。 DDT, nicotine, methylmethane→body and/or brain weight deficits and embryo lethality but not malformation 然而, Methylnitrosourea, cyproterone→malformation Early development: ovulation to implantation Blastocyst The developing embryo becomes a hollow ball of cells and is called a blastocyst. Group of cells within the hollow space forms the inner cell mass (ICM). develops into the embryo. The cells around the ICM become the extraembryonic membranes role in implantation supports embryo’s growth 3. Implantation 著床 第6-13days 4. Gastrulation-三胚層形成, 第3週 在此期暴露有害物質將造成眼、腦及臉部的畸形 5. Organogenesis 器官形成,第3-8週 為最容易受影響的時期,因為本期Cell proliferation, cell migration,cell-cell interactions,morphogenetic tissue remodeling 6. Fetal period胎兒期 第8wk-birth 在此期暴露,影響生長和功能的成熟,需要在出生後仔 細觀察才能察覺。如中樞神經的異常包括行為、智力、 運動的缺失,生殖力降低,以及免疫系統、心臟、肺臟、 腎臟功能受損等。 *若有構造的改變乃是破壞原本正常的構造稱為 deformation,不同於前述malformation Malformation* Timing of Exposure (Days Since Last Menstrual Period) Anotia, facial nerve paralysis Ear malformations 38-46 Absence of arms 38-45 Phocomelia of arms 39-46 35-38 Cardiac malformations 39-45 Absence of legs 41-44 Phocomelia of legs 41-47 The type of malformation could be related, approximately, to the time when the pregnant woman took the drug. This illustrates the concept of critical or sensitive periods during development. Most of the severe malformations could be attributed to thalidomide ingestion during a critical period between 35 and 50 days after the last menses. 6 Principles of Teratology 1. genetic influences-由於遺傳差異,引起個體對致畸作用的 敏感度不同 2. critical periods-不同時期對致畸作用的敏感度不同 3. initiating mechanism-致畸原以特定的機轉對細胞組織作用 引發一連串的不正常發育 4. access to embryo and fetus-致畸原的特性決定其與胚胎接 近的難易 5. abnormal development-不正常的發育的結果→death, malformation, growth retardation, and functional disorder 6. dose-response relationship-however,一般致畸原存在 threshold level Mechanisms and pathologenesis of developmental toxicology 1. mutation 突變 somatic mutation in the early embryo, ex.mutagen 2. chromosomal abnormalities 染色體異常 ex. advanced maternal age, viral infection, irradiation, and chemical agents 3. mitotic interference干擾細胞分裂 slow or arrest DNA synthesis (hydroxyurea or irradiation), interfere with spindle formation (colchicine, vincristine) 4. interference with nucleic acid function干擾核酸的功能 including replication , transcription, translation ex. antibiotics and antineoplastic drugs 5. nutritional deficiencies營養缺乏 ex. vitamins , minerals 6. deficient or alter energy supply 缺少或改變能量的供給 ex. inadequate glucose supply (hypoglycemia), interference with glycolysis (iodoacetate, 6-aminonicotinamide), inhibition of the citric acid cycle (riboflavin deficiency), blockage of the terminal electron transport (hypoxia, cyanide) 7. changes in osmolarity滲透壓的改變 ex. hypoxia, hypertonic solutions, adrenal hormone→edema, hematoma, and blisters 8. changes in cell membranes細胞膜的改變 ex. solvent, vitamin A 9. enzyme inhibition酵素的抑制 抑制代謝酵素,DNA repairing, polymerase Principles of Teratology 4. access to embryo and fetus-致畸原的特性決定其與胚胎接 近的難易 5. abnormal development-不正常的發育的結果→death, malformation, growth retardation, and functional disorder 6. dose-response relationship-however,一般致畸原存在 threshold level Attribution of threshold 1. high restorative growth potential of mammalian embryo 2. cellular homeostatic mechanisms 3. maternal metabolic defenses Lack of threshold-even one molecule exposure→point mutation→abnormal development Dose-response Patterns and the threshold concept Thalidomide Thalidomide was released in 1956 as a mild sedative used to combat nausea in pregnant women. It was later (1961) withdrawn from the market once it was discovered thalidomide was a human teratogen. As little as one dose could cause a significant birth defect. Approximately 5,000-7,000 malformed infants were born to women who ingested thalidomide during pregnancy. Symptoms: malformed intestines, hearing defects, absent ears, and/or ocular and renal anomalies. However, the most striking phenotype is phocomelia: severe limb malformations in which the long bones of the limb are either greatly reduced in length or absent all together. Teratogenic between 20-36 days after fertilization •Proposed mechanisms (more than 30) •Altering cellular redox status Free radical scavenger (alpha -phenyl-butyl-tert-nitrone PBN) Reduce embryonal DNA oxidation and teratogenic effect -Angiogenesis -Integrin regulation -growth factor antagonism Now approved for Oral ulcer for AIDS, erythema nodosum leprosum -new anticancer drug? Anti-angiogenesis Approximately 91 percent of all promoter regions contain the nucleotide sequence TATA, CCAAT, or both. Only 9 per cent have neither TATA nor CCAAT sequences, but have the sequence GGGCGG (called the GC box). The promoter regions for the alpha v beta 3, FGF-2 and IGF-I genes are all TATA-less and contain several GC boxes. Furthermore, the promoter regions of both the FGF-2 and the IGF-I receptor genes contain multiple GC boxes. Diethylstilbesterol DES was prescribed between 1940 and 1970 to prevent miscarriages in high risk pregnancies. This was accomplished by DES increasing estrogen and progesterone synthesis by the placenta. In the mid 1970 cases of vaginal adenocarcinoma in women ages 16-20 were linked to fetal exposure through maternal DES ingestion early in the pregnancy. Approximately 1 in 1000 pregnancies were exposed, 75% of which resulted in female children with vaginal and cervical carcinomas as well as uterine anomalies. Male offspring had abnormal genitalia. Retinoic Acid Retinoic acid Retinoic acid is teratogenic in humans at very low doses. Exposure to retinoic acid during pregnancy between 3-5 weeks of pregnancy may result in malformations of the fetus: craniofacial alterations, cleft palate, neural tube defects, cardiovascular malformations, thymic aplasia, psychological impairments, absent or defective ears, small jaw, kidney alterations. Fifty percent of affected children have an IQ below 85. Mechanism A proposed mechanism is that biologically active retinoic acid binds retinoic acid receptors which in turn bind DNA enhancer elements such as the retinoic acid response elements. Several Hox genes (responsible for early patterning of the embryo) contain this enhancer element in their promotors. Therefore, Hox signaling may be altered due to increased retinoic acid concentrations resulting in multiple birth defects. Molecular biology Target cell RBP–ROH Receptor ROH–CRBP RA–CRABP RA RA Nucleus RA–RXR Regulated gene transcription RA = Retinoic acid RBP = Retinol binding protein CRBP = Cellular retinol binding protein CRABP = Cellular retinoic acid binding protein RXR, RAR = Nuclear retinoic acid receptors Intracellular Extracellular S17 = Retinol RAR–RA DNA ROH ROH Hormonal Targeting of Nuclear Complexes to Chromatin SIGMA-ALDRICH.com/rbi Alcohol (Ethanol) Ethanol is the causative agent of Fetal Alcohol Syndrome (FAS). FAS is seen in approximately 2 in 1000 live births, depending upon culture and socioeconomic status. For instance, there is an occurrences of FAS in 19.5:1000 live births in American Native Indian culture verses a rate of 1.9:1000 in middle class Caucasian families. FAS does seem to be dose dependant in that greater amounts of alcohol consumed increases the chances of having an FAS child. FAS was formally defined in 1970 as containing a combination of the malformations seen below: Growth deficiencies Maxillary hypoplasia Decreased philtrum size Microphthalmia Microcephally Narrow upper lip Cardiovascular disorders Short palpebral fissures Low nose bridge Small brain size Fetal alcohol effects (FAE) Neural crest cells are particularly sensitive to alcohol-induced injury and cell death Alcohol interfere with development of neurotransmitter Systems Tobacco Nicotine restricts uterine blood vessels and restricts blood flow to the fetus resulting in chronic hypoxia and malnutrition leading to birth defects. On average, offspring of smoking women weigh 170-200 g less at birth as compared to a non smoker’s child. There is a dose dependence in that the child weight decreases in proportion to number of cigarettes smoked by the mother. There is also a reduction in overall fetal length, reduced head circumference, intrauterine growth retardation as well as behavioral alterations after birth. Possible outcomes of smoking during preganancy include: spontaneous abortion perinatal deaths increase risk of sudden infant death syndrome increased risk of learning, behavioral, and attention disorders. Perinatal exposure to tobacco smoke can affect branching morphogenesis and maturation of the lung. Smoking during pregnancy increases the risk for premature delivery, abruption placenta, placenta previa and perinatal mortality. Cocaine Cocaine is an anesthetic and vasoconstrictor. An estimated 45% of urban pregnancies and 6% of suburban pregnancies involve cocaine exposure. Exposed fetuses often have intrauterine growth retardation, microcephaly, cerebral infarction, urogenital anomalies, an increased risk of sudden infant death syndrome as well as neuronal and behavioral abnormalities. These pregnancies are at risk for premature labor, spontaneous abortion, increased perinatal mortality and fetal death. Cocaine is thought to induce birth defects by disrupting the vasculature in the placenta thereby inducing intrauterine hypoxia and malnutrition. Valproic Acid Valproic acid was released in 1967 in Europe and in 1978 in the United States to treat epilepsy. Approximately 11,500 epileptic women become pregnant each year, many of which use valproic acid. By 1980, publications began linking malformed children to in utero exposure to valproic acid (greater than 500 mg/day). These children were born with lumbosacral spina bifida with menigomyelocele or menigocele, often accompanied by midfacial hypoplasia, deficient orbital ridge, prominent forehead, congenital heart disease and decreased postnatal growth. The proposed mechanism of action is that valproic acid influences folate metabolism, thereby altering the closure of the spinal column resulting in spina bifida. Congenital Minamata Disease Methylmercury was used in the past as a fungicide on wheat and grains. Cases have been documented in Iraq (19711972), Sweden, Japan and New Mexico of birth defects due to maternal ingestion of bread made with contaminated grain. There have also been documented cases in Canada, New York and Sweden of paper mill contaminants polluting the water with inorganic mercury. Exposure in utero may result in sensory and motor impairments, cerebral palsy, mental retardation and behavioral damage. Children with Congential Minamata Syndrome seem to be normal at birth and begin to present symptoms at approximately six months of age. They have instability of the neck, convulsions, reduced IQ, microcephaly, malformed limbs, restricted growth and an altered cerebellum. In utero exposure to methylmercury induces general brain atrophy and hypoplasia. Mercury Mercury Effects of Higher Dose Prenatal Exposure • • • • • • • • Mental retardation Seizures Cerebral palsy Disturbances of vision, hearing, sensation Abnormal gait Abnormal speech Disturbances of swallowing and sucking Abnormal reflexes Mercury: Declining Threshold of Harm (micrograms/kg/day Hg) DAILY INTAKE 100 Level associated with harmful effect Regulatory standard (maximum safe exposure or high end exposure from allowed fish contamination) 10 1 FDA WHO ATSDR 0.1 EPA 0.01 1970 1980 1990 YEAR 2000 Mercury Mercury Exposures Advised Exposure Limit • EPA Reference Dose (“safe” upper limit) – 0.1 microgram/kilogram/day • Equivalent consumption limit • Women: 1.5 oz. swordfish or 7 oz. tuna/week • Child: 1 oz. tuna per 20 lb. body weight/week Basic Toxicology Toxicity-related Concepts: specific processes disrupted by neurodevelopmental toxicants proliferation radiation, ethanol, mercury, cholinesterase inhibitors migration radiation, mercury, ethanol differentiation ethanol, nicotine, mercury, lead synaptogenesis radiation, ethanol, lead, triethyl tin, parathion, PCBs gliogenesis & myelinization dec. thyroid, ethanol, lead apoptosis signaling ethanol, lead, mercury ethanol, cholinesterase inhibitors, mercury, lead, PCBs Lead Effects of Lead on Cognitive and Behavioral Traits ADHD LD hyperactivity reading, math impulsivity spelling distractibility pattern recognition dif. w. instructs word recognition conduct problems executive function attention/vigilance social skills OTHER fine motor visual motor aggressive antisocial off-task The Significance of Small Effects: EFFECTS OF A SMALL SHIFT IN IQ DISTRIBUTION IN A POPULATION OF 260 MILLION mean 100 6.0 million "gifted" 6.0 million "mentally retarded" 40 80 60 70 100 120 I.Q. 140 160 130 5 Point Decrease in Mean IQ mean 95 57% INCREASE IN "Mentally Retarded” Population 2.4 million "gifted" 9.4 million "mentally retarded" 40 80 60 70 100 I.Q. 120 140 130 160 PCBs PCBs: PERVASIVE DEVELOPMENTAL EFFECTS Infant • • • • Birth weight Head circumference Gestational age Performance on Brazelton Neonatal Behavioral Assessment (BNBA) - motor immaturity, poor lability, startle PCBs: PERVASIVE DEVELOPMENTAL EFFECTS Early Childhood • Memory, attention, verbal ability, information processing • Psychomotor development • Sustained activity, high level play • Withdrawn, depressed behavior • Hyperactivity Preteen • Word and reading comprehension • Full scale and verbal IQ • Memory and attention Full-Scale IQ PCBs Prenatal Exposure to Polychlorinated Biphenyls (PCBs) ug/g of fat PCBs PCB Effects on Thyroid Hormone • Altered thyroid hormone Mothers: Thyroid Hormone, Thyroid Stimulating Hormone (TSH) Infants: Thyroid Hormone, TSH Seals and Rats: Thyroid Hormone • Developmental Implications Elevated maternal TSH during pregnancy, with or without reductions of thyroid hormone, associated with reduced IQ at age 7-9 yrs. PCBs PCB Neurodevelopmental Effects: Possible Mechanisms • Altered neurotransmitter levels • Ah receptor mediated effects (dioxin-like PCBs) Disruption of production of growth factors and hormones including enzyme induction, modulation of growth factors, hormones • Interference with thyroid hormone metabolism through enzyme induction interference with thyroid-hormone-mediated gene transcription displacement of thyroxin from carrier protein Develpmental toxicity of endocrine-disrupting chemicals Definition of endocrine-disrupting chemicals “Exogenous agent that interferes with the production, release, transport, metabolism, binding, action, or elimination of natural hormones responsible for the maintenance of homeostasis and the regulation of developmental processes.” Endocrine-disrupting chemicals Four modes of action 1. Serving as steroid receptors ligands 2. Modifying steroid hormone metabolizing enzymes 3. Perturbing hypothalamic-pituitary release of trophic hormones 4. Uncharacterized proximate modes of action Impact on screening and testing programs 1. Expansion of the periods of dosing from the end of organogenesis to the end of pregnancy in order to include the urogenital differentiation 2. EDSTAC recommended a high through put screening (HTPS) cell-based, receptor-mediated gene transcription assay