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88 Cards in this Set
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1) Definition: Following chemical exposure potentially leading to abnormal development, Dev. Tox. is study of :
2) Outcomes include |
1) Pharmacokinetics
Mechanisms Pathogenesis Outcomes 2) Structural malformations Growth retardation Functional impairment Death |
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1) 1930s - 1st _____ _____ __ mammalian species
(Developmental Toxicology History) |
1) - (Blanks) Induced birth defects in
- Experimental maternal nutrient deficiences (sows) - Anophthalmia and cleft palate (Hale 1935) |
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1940s
(Developmental Toxicology History)) |
– maternal dietary deficiencies and other environmental factors affects intrauterine development (rats)
(Warkany et al. 1940) |
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1940s – 1960s
(Developmental Toxicology History) |
– Chemical, physical agent exposure in mammals malformations
- Nitrogen mustard, trypan blue, hormones, antimetabolites, alkylating agents, hypoxia, x-rays, and others |
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1941 –– what was the1st human epidemic of malformations induced by environmental agent
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(rubella epidemic) (Gregg reported)
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what is the effects of Rubella
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- Eye, heart – 1st or 2nd month exposure
- Hearing , speech, retardation – 3rd month infection |
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Rubella 1966
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(Cooper & Krugman) 20,000 children impaired due to prenatal rubella in U.S.
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Rubella 1967
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1967 (Sever) Rubella: 61% risk w/ 1st 4 mo exposure; 26% in wk 5-8; 8% in wk 9-12
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What was discovered to be toxic in 1961
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Thalidomide
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Teratology - definition
(4 parts) |
1. Study of abnormal formations in plants or Animals
2. Search for teratogens Teratology – study of structural birth defects 3. Substance capable of causing harm to a fetus in the form of a birth defect or death 4. Greek word for monster, teras teratology |
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(Teratogens) 150,000 per year born w/ birth defects.- Triggers?
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- 25% of birth defects from mutagens
- Other 75% likely triggered by environmental factors |
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leading cause of U.S. infant mortality
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Birth defects
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Annual U.S. births
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2 million
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# of human conceptions that result in birth of completely normal, health infant
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< 1/2
- Reasons largely unknown |
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Estimates (Schardein 2000)
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- 31% - Postimplantation pregnancy loss
- 2-3% - major birth defects at birth; 6-7% at 1 yr - 14% - minor birth defects - 7% - low birth weight - 1.4% - infant mortality (< 1 yr) - 16-17% - abnormal neurological function |
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Estimates (Brent & Beckman 1990):
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- 15-25% - genetic
- 4% - maternal conditions - 3% - maternal infections - 1-2% - deformations (mechanical problems) - 1% - chemicals, environmental influences - 65% - unknown etiologies |
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Of the 4100 chemicals tested for teratogenicity there percentages are: 66%, 7%, 18%, 9%
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- nonteratogenic
- teratogenic in > 1 species - teratogenic in most tested species - equivocal experimental results |
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__-__ (numbers) chemical, chemical classes, conditions documented to alter prenatal development in humans
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50 - 60
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(Known Human Teratogens)
Ionizing radiation |
- X-rays
- Nuclear fallout |
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(Known Human Teratogens)
Drugs & Chemicals |
- Dioxin
- Anesthesia - Cigarette smoke - Dilantin - Valproic acid - Accutane - Tegison |
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(Known Human Teratogens)
Pathogenic infections |
- German measles (rubella)
- Syphilis, herpes 2 - Cytomegalovirus - Toxoplasmosis |
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(Teratogen Tragedies)
Ongoing |
- Fetal Alcohol Syndrome (FAS)
- Cigarette smoke - Cocaine - Retinoids - Valproic Acid |
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(Teratogen Tragedies)
1940, 1941, 1960s, 1970s |
- nutritional deficiencies study
- 1941, German measles (Rubella) - 1960s, Thalidomide (Cantergen) - 1970s, Diethylstilbestrol (DES) |
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(Thalidomide)
1960 – 30 West German newborns – rare limb malformations |
- Amelia – limb absence
- Phocomelia – reduction of long bones of limbs |
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(Thalidomide)
Other anomalies and malformations |
Congenital heart disease, ocular, intestinal, renal, external and inner ears
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(Thalidomide)
1961 – 1963 |
McBride (1961) and Lenz (1961, 1963) – ID’d cause as thalidomide
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(Thalidomide)
Introduced in 1956 as a |
Sedative/hypnotic, to ameliorate nausea and vomiting during pregnancy
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(Thalidomide)
Nov. 1961 |
– withdrawn from market
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(Thalidomide)
Mid 1962 |
– case reports ended
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(Thalidomide)
Total cases world-wide |
5850
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Thalidomide Testing
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- In rabits it was seen to affect between the ranges 1 to 100 mg/kg
- Humans happened to be at the extreme lower end of the range at 1 mg/kg - Teratogenic between 20 and 36 days after fertilization |
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Thalidomide Mechanism of Action
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- Alteration of cellular redox status
- Pretreatment of pregnant with free radical scavenger, alpha-[phenyl-N-t-butlnitrone (PBN) - Reduced DNA oxidation by 73% - Abolished adverse developmental effects - Thalidomide activated to free-radical intermediate - Initiates reactive oxygen species formation - Limb defects due to misregulation of gene expression critical for outgrowth of limb in embryo |
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Teratogenesis
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- Dose-Response dependant on stage of fetal development at exposure time
- Most sensitive time: organogenesis - 18th to 60th day after conception - 30th day peak sensitivity - Gross structural defects during this time - Exposure in 1st week lethal - > 8th week, major structural damage passed |
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Diethylstilbestrol (DES)
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- Synthetic nonsteroidal estrogen
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Diethylstilbestrol (DES)
1940s to 1970s Use |
in U.S. for prevention of threatened miscarriage
- Stimulation of estrogen and progesterone synthesis in placenta |
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Diethylstilbestrol (DES)
1966 –1969 |
- 7 females aged 15 to 22 yr w/ clear cell adenocarcinoma of vagina
- Never seen in females < 30 yr |
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Diethylstilbestrol (DES)
Case-control epi study: 1st trimester DES exposure |
- Maternal use < 18th week of gestation necessary to induce
- 1971 - Registry of CCA of Genital Tract of Young Females |
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Diethylstilbestrol (DES)
Risk of noncancerous alteration of vagina, cervix |
75%
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Diethylstilbestrol (DES)
Risk of CA of vagina, cervix |
est. 0.14-1.4/1000 exposed
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(DES – Effect on Females)
Mechanism of action in females |
Alterations in genetic pathways governing uterine differentiation
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(DES – Effect on Females)
Daughters: |
- Cancer
- Tubal pregnancies - Miscarriages - Premature deliveries; |
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(DES – Effect on Females)
Granddaughters: |
Genetic changes in embryo’s egg cells from grandmother may pass risk of cancer to granddaughters.
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(DES – Effects on Males)
Male effects in exposed pregnancies |
- High incidence of epididymal cysts
- Hypotrophic testes - Capsular induration - Low ejaculated semen volume - Poor semen quality |
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DES (cont’d)
2006 – mice study of DES |
- Increased susceptibility to tumors and reproductive tract abnormalities
- May be passed on to future generations (males and females) of exposed mothers |
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Ethanol – Fetal Alcohol Syndrome
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- A totally preventable tragedy
- 1-3 of every 1000 babies affected - An “extreme form of maternal child abuse” - “and it lasts for life” - “most toxic of any abused drug” |
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Ethanol – Fetal Alcohol Syndrome
CNS damage |
- neurobehavioral traits
- mental retardation |
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Ethanol – Fetal Alcohol Syndrome
Other defects include |
- cleft lip and palate
- heart defects - skeletal defects |
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(Ethanol)
1973 - Jones & Smith described Fetal Alcohol Syndrome (FAS) |
- Recognition of developmental toxicity of alcohol
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(Ethanol)
Effects |
- Craniofacial dysmorphism
I- ntrauterine and postnatal growth retardation - Retarded psychomotor and intellectual development - Nonspecific major and minor abnormalities - FAS has spectrum of effects |
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(Ethanol)
Average IQ of FAS children reported |
68
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(Ethanol – Mechanisms of Action)
Craniofacial malformations and similar structural effects possibly involve: |
- Interference with retinol metabolism in early embryo
- Oxidation of retinol crucial to normal development - Probably involve complex combination of maternal factors and biochemical/cellular effects in embryo - Excess cell death in sensitive cell populations common |
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(Ethanol – Mechanisms of Action)
Dose-response |
- Full-blown FAS – born to alcoholic mothers
- Incidence 25 per 1000 - Other FAS – 3-4 oz of alcohol per day required |
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(Ethanol – Mechanisms of Action)
Timing |
when anterior part of embryo (including brain) just beginning to form
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(Ethanol)
Fetal Alcohol spectrum Disorder (FASD) |
- Effects of lower exposure
- Isolated components of FAS - Milder neurological and behavioral disorders - Short-term memory deficits -Lower performance on standardized tests |
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(Ethanol)
Birth weight – dose-related even if nonalcoholic mother |
For each oz of absolute ethanol per day during late pregnancy 160-g decrease in weight
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(Ethanol)
Prenatal alcohol exposure significantly associated with _____________________ |
drinking problems at age twenty-one, regardless of family history or other environmental factors
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(Ethanol)
Prenatal exposure of high dosages of ethanol during 2nd half of pregnancy in rats shortens life span of offspring by how much? (Males, Females) |
- 20 weeks in females ( ~ 86 yr vs 69 yr in human)
- 2.5-7 weeks in males ( ~ 83 yr vs 77 yr in human) |
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Leading cause of environmentally induced developmental disease and morbidity today
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Tobacco Smoke
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% of pregnant women in U.S. continue to smoke
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25%
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Epi studies provide clear picture of what effects?
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- Spontaneous abortions
- Perinatal deaths - Increased risk of SIDS (1/3 deaths prevented if no smoke exposure) - Increased risk of learning, behavioral, and attention disorders, lower birth weight - Orofacial clefts - Increased risk xenobiotic metabolizing gene polymorphisms - Elevated risk of gastroschisis if mom has certain alleles |
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Nicotine is a ______ _________ __ ______
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Known neuroteratogen in animals
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Cotinine is a ______ and yeilds ________
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- nicotine metabolite
- hypertonia |
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Perinatal exposure to tobacco smoke yeilds
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Affects branching morphogenesis and maturation of lung altered physiologic function
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Environmental tobacco smoke (ETS): associated with ...
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many of effects caused by active maternal smoking
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Hypertonia is
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Increased tightness of muscle tone. Untreated hypertonia can lead to loss of function and deformity. Treatment is by physical and/or occupational therapy, and in some cases muscle relaxant medication. Injections of botulism toxin (botox) are a recent treatment for chronic hypertonia in cerebral palsy and other disorders. Also known as spasticity
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Cocaine is derived from _______ and is a ______ ______
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- coca
- Plant alkaloid |
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(Cocaine)
1980s |
– more potent forms available which lead to cocaine abuse
- ~ 45% of pregnancies at urban teaching hospital and 6% in suburban hospital had recent cocaine exposure |
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(Cocaine)
Fetal effects are |
- complicated and controversial
- Difficult to monitor human population for adverse reproductive outcomes - Confounding factors: -Concurrent use of tobacco, alcohol, other drugs of abuse - Neurological and behavioral changes difficult to identify and quantify |
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Cocaine Effects
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- Abruptio placentae
- Premature labor and delivery - Microcephaly - Altered prosencephalic development - Decreased birth weight - Neonatal neurologic syndrom of abnormal sleep - Tremor - Poor feeding - Irritability - Occasional seizure - SIDs |
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(Abruptio placentae)
Risk factors include |
- Advanced maternal age
- Cigarette smoking - Cocaine use - Diabetes - Drinking > 14 alcoholic drinks /wk during pregnancy - High blood pressure - History of placenta abruptio - Increased uterine distention - Large number of prior deliveries |
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(Wilson’s General Principles of Teratology)
I. Susceptibility depends on |
- genotype of conceptus
- interaction with adverse environmental factors |
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(Wilson’s General Principles of Teratology)
II. |
Varies with developmental stage at time of exposure to adverse factor
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(Wilson’s General Principles of Teratology)
III. |
Agents’ specific mechanisms initiate pathogenesis
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(Wilson’s General Principles of Teratology)
IV. |
Access of adverse factors to developing tissues depends on nature of agent
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(Wilson’s General Principles of Teratology)
V. |
Four expressions of abnormal development are death, malformation, growth retardation, and function deficit
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(Wilson’s General Principles of Teratology)
VI. |
Abnormal development expressions increase in frequency and degree as dosage increases from no effect to totally lethal
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(Developmental Principles)
Critical periods of sensitivity |
- Based on developmental stage of conceptus
- Primary and unique consideration |
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Developmental Principles
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Development is a continuum
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