Lecture 1: Genetic Errors and Teratogens PDF

🐣 Lecture 1: Genetic errors and teratogens LO: Identify types and major causes of developmental disorders Developmetal disorders / congenital anomalies / birth defects = all synonyms of each other...

🐣 Lecture 1: Genetic errors and teratogens LO: Identify types and major causes of developmental disorders Developmetal disorders / congenital anomalies / birth defects = all synonyms of each other Referring to physical abnormalties that occur before a baby is born A lot of them can be observed during scans, ultrasounds, during pregnancy or following birth There are more than 4000 different kinds of borth defects - borth defects can involve any part of any organ in the body Types of developmental disorders Structural - problem with body parts and structures Eg) cleft lip or cleft palate Heart defects, such as missing or misshaped valves Lecture 1: Genetic errors and teratogens 1  Abnormal limbs, such as clubfoot Neural tube defects, such as spina bifida, and problems related to the growth and development of the brain and spinal cord Functional (or developmental) - problem with how a body part or body system works, often leads to an intellectual & developmental disability Nervous system or brain problems Sensory problems Metabolic disorders Degenerative disorders Major causes of developmental disorders 3-5% are teratogen-induced malformations Environmental or iatrogenic exposures during pregnancy Infectious agents Maternal disease states Mechanical problems Irradiation Drug treatment Major causes of birth defects 65-75% are of unknown etiology Multifactorial, polygenic, spontaneous errors of development 20-25% are of genetic origin Genetically inherited diseases New mutations Chromosomal abnormalities Lecture 1: Genetic errors and teratogens 2  LO: Describe the major types of genetic errors that result in developmental disorders Chromosome abnormalties Present in at least 10% of all spermatozoa and 25% of mature oocytes Can arise during first or second meiotic divisions 50% of spontaneous miscarriages have a chromosome abnormality Abnormalities can be: Number (can affect both autosomes & sex chromosomes) Aneuploidies - monosomy or trisomy (extra 1), tetrasomy (extra 2) Structure (can affect both autosomes & sex chromosomes) Maternal age & aneuploidy → increasing age - increasing number of aneuploidy Lecture 1: Genetic errors and teratogens 3  Chromosomal structural abnormalities Balanced abnormalities (no loss of genetic material) can include: Translocation A segment of one chromosome is transferred to another chromosome. In a balanced translocation, no genetic material is lost or gained; it's just rearranged. Inversion A chromosome segment breaks off, flips around, and reattaches in the reverse orientation. Insertion A segment of one chromosome is inserted into another chromosome Unbalanced abnormalities (include loss or gane of genetic material) can include: Deletions A segment of chromosome is deleted Duplications Asegment of chromosome is duplicated within that gene Effect of structural abnormalities/mutations Alterations to a gene – disrupted, deleted Lecture 1: Genetic errors and teratogens 4  Alterations to regulation of gene expression - can lead to too many or not enough of a gene Mutations in DNA Alterations within coding region - exons, introns (may affect splicing) Point mutations affecting exons: Frameshift: Insertion or deletion of nucleotides that changes the reading frame of the gene, leading to a completely altered protein sequence downstream from the mutation. Nonsense: A point mutation that changes a codon into a stop codon, resulting in premature termination of protein synthesis and a truncated, often nonfunctional, protein. Missense: A point mutation that changes one nucleotide, resulting in the substitution of one amino acid for another in the protein. This can alter the protein's function, depending on the amino acid change. Alterations within non-coding regions (may affect gene regulatory region, methylation/epigenetic regulations) LO: Describe the principles of teratology Fetal development is the result of interactions of genetic and environmental factors Teratology: the study of factors that cause congenital malformations/birth defects Teratogen: any plant, food, nutritional state or physical agent, which by acting on the developing embryo or fetus, can cause a congenital malformation PRINCIPLE 1: Genetic Susceptibility “Susceptibility to Teratogenesis Depends on the Genotype of the Embryo and a Manner in which this Interacts with Adverse Environmental Factors" Species differences Lecture 1: Genetic errors and teratogens 5  Humans and other primates are extremely vulnerable to thalidomide, BUT rats and mice, however, are resistant to thalidomide. Strain and Intra-litter differences Even within the same species, different genetic strains or individual embryos in a litter may show different levels of susceptibility to teratogens. Interaction of Genome and Environment The effects of teratogens are influenced by both genetic factors and environmental conditions, leading to multifactorial causation of birth defects. PRINCIPLE 2: Developmental Stage “Susceptibility to Teratogenesis Varies with the Developmental Stage at the Time of Exposure to an Adverse Influence” Different organs of the body are forming at different times and therefore the sensitivity to the teratogen and the affected organ will vary Several important phases in human development are recognised: All or none period Lecture 1: Genetic errors and teratogens 6  Insults to the embryo are likely to result in death of the embryo and miscarriage (or resorption), or in intact survival At this stage, the embryo is undifferentiated and repair and recovery are possible through multiplication of the still totipotential cells to replace those which have been lost Exposure of embryos to teratogens during the preimplantation stage usually does not cause congenital malformations, unless the agent persists in the body beyond this period Embryonic period Critical period of organogenesis, when the basic structures of organs are forming (organogenesis) Period of maximum sensitivity to teratogenicity since not only are tissues differentiating rapidly but damage to them becomes irreparable Exposure to teratogenic agents during this period has the greatest likelihood of causing a structural anomaly. Since teratogens are capable of affecting many organ systems, the pattern of anomalies Lecture 1: Genetic errors and teratogens 7  produced depends upon which systems are differentiating at the time of teratogenic exposure. Fetal period Period when growth and functional maturation of organs and systems already formed Teratogen exposure in this period will affect fetal growth (e.g., intrauterine growth retardation), the size of a specific organ, or the function of the organ, rather than cause gross structural anomalies PRINCIPLE 3: Mechanism "Teratogenic Agents Act in Specific Ways (Mechanisms) on Developing Cells and Tissues to Initiate Sequences of Abnormal Developmental Events (Pathogenesis)” Refers to the early, and often the first, event in a series of intervening events between cause and an effect Proposed mechanisms for teratogenic pathogenesis → these mechanisms lead to abnormal development, depending on the nature of the teratogen and the timing of exposure: Lecture 1: Genetic errors and teratogens 8  Excessive apoptosis Reduced apoptosis Reduced biosynthesis Impeded morphogenetic movements Mechanical disruption of tissues Epigenetic PRINCIPLE 4: Access "The Access of Adverse Influences to Developing Tissues Depends on the Nature of the Influence (Agent)” Physical agents such as x-rays, microwaves, and ultrasound pass unaltered through the mother into the uterus and have direct access to the fetus Agents consumed by the mother, such as drugs, are subject to her metabolism before having access secondarily to the fetus Factors to consider in determining whether a substance will reach the fetus include: Maternal dose Route of entry Physical properties (solid, liquid, or gas) Rate of absorption into the systemic circulation Placental transfer Placenta is not an absolute barrier Molecules with molecular weights less than 600 kd and of low ionic charge cross the placenta by simplediffusion Others cross by facilitated diffusion and active transport PRINCIPLE 5: End Points "The Four Manifestations of Deviant Development are Death, Malformation, Growth Retardation and Functional Deficit” Lecture 1: Genetic errors and teratogens 9  The specific outcome is often related to when the exposure occurs relative to the stage of fetal development, however, the focus is on the possible outcomes or manifestations of abnormal development due to teratogen exposure, regardless of the timing Eg) Pregnancies exposed to Accutane (isotretinoin) Acutane is derived from vitamin A and is a treatment of severe acne Exposure to isotretinoin (Accutane) can result in spontaneous abortion, major malformations, or cognitive impairment, depending on the timing and dosage. PRINCIPLE 6: Dose-response Relationship “Manifestations of Development Increase in Frequency and Degree as Dosage Increases, from No-effect to the Totally Lethal Level” Teratogens may demonstrate a dose-effect relationship No Observable Adverse Effect Level (NOAEL) Intermediate doses the characteristic pattern of malformations will result High dose the embryo will be killed, 100% Lethality (LD100) LO: Apply the principles of teratology to explain the impact of example teratogens + LO: Explain the impact of recognized teratogens on human development and health Teratogenic agents: Infectious agents: Rubella, Toxoplasmosis Physical agents: Hyperthermia Chemicals: Phthalates Maternal health: Obesity Drugs: Ethanol Infectious agents - Rubella Lecture 1: Genetic errors and teratogens 10  Rubella - commonly known as German measles, is a disease caused by the rubella virus. Transmitted by contact with nasal secretions of infected individuals Infected pregnancies are at increased risk for miscarriage Principle 2: Developmental Stage Infection during the first trimester results in a high rate of birth defects in the baby. This risk decreases sharply with infection in the second and third trimesters The birth defects associated with congenital rubella syndrome include: eye defects, hearing loss, heart defects, mental retardation/cognitive deficits, growth retardation Because of routine vaccination, rubella is uncommon Physical agents - Hyperthermia Hyperthermia - elevated body temperature (37–40°C) Causes: Febrile infections Hot/humid environments (hot baths,saunas) Heavy exercise (especially in conditions of high heat and humidity) Study of 24 Australian women revealed they were able to remain in a hot tub set at 40°C until their temperatures reached 39°C, with 54% of the subjects not feeling uncomfortably hot. Suggesting that the subjective feeling of being ‘‘overheated’’ may not be enough to protect all women from teratogenic exposures to heat in saunas and hot tubs Type of defects (hyperthermia) Determined largely by the developmental stage at the time of the exposure Severity and incidence of defects depend largely on the dose Lecture 1: Genetic errors and teratogens 11  The threshold temperature elevation is approx 2.0–2.5°C Duration about 1 hr Can cause a range of impact - different end points: Mental retardation/cognitive deficits Physical abnormalities: club foot, ear anomalies, congenital heart defects, cranofacial structures Functional effects: paralysis of lateral gaze, immobile facial musculature Summary Developmental disorders include structural and functional/developmental anomalies or deficits Genetic errors can be the results of chromosomal abnormalities (aneuploidies or structural changes), or smaller mutations, including point mutations which affect the generation of single proteins. Teratogens are any plant, food, nutritional state, or physical agent that can compromise normal fetal development and result in the production of a developmental disorder In considering the effect of a teratogen on development, use the 6 principles of teratology Lecture 1: Genetic errors and teratogens 12