Extent of the Problem Overall, about half of initial pregnancies do not result in the birth of a...
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Transcript of Extent of the Problem Overall, about half of initial pregnancies do not result in the birth of a...
Extent of the Problem
• Overall, about half of initial pregnancies do not result in the birth of a healthy, normal child
• Developmental abnormalities are common:– One in 33 born with major defect– Minor anomalies in 14-22%– Functional defects in about 5% of children
• Role of environmental agents largely unknown, estimates of 3-50% of all birth defects due to environmental interaction
Suspected Causes of Human Birth Defects
Suspected Cause % of Total
Genetic
Autosomal genetic disease 15-20
Cytogenetic 5
Environmental
Maternal conditions 4
Maternal infections 3
Mechanical Problems 1-2
Chemicals/drugs/radiation/hyperthermia <1
Unknown 65
Historic Events in Modern Teratology1800’s Experimental teratogenesis in chick embryos
(St. Hillaire, Dareste)
1905 1st experimental developmental toxicity in a mammal – Embryolethality in kittens with x-irradiation (Tousey)
1921 1st experimental teratogenesis in a mammal – Limb defects from fatty diet (Zilva et al.)
1929 1st exogenously caused malformations in humans – microcephaly with pelvic x-rays (Goldstein and Murphy)
1935 Teratogenesis by dietary deficiency – Vitamin A deficiency in sows (Hale)
Historic Events in Modern Teratology1937 Masculinization of female mouse fetuses with androgen
(Raynaud)
1941 Virus-caused malformations in humans reported – congenital defects from maternal rubella (Gregg)
1940s Experimental teratogenesis in rats from deficiencies and toxicants (Warkany)
1952 1st reported human malformations by a drug – malformations in abortuses with aminopterin (Thiersch)
1959 1st reported human malformations by environmental chemical – methylmercury (Kitamura et al.)
1961 Thalidomide embryopathy (Lenz And McBride)
1960s Beginnings of regulatory testing for developmental toxicity
Number of Chemicals Tested for Teratogenicity (Schardein, 2000)
Tested Teratogenic Not Terato-genic
4153
Clearly
291
Probably
730
Possibly
372
2760
Human Developmental Toxicants I• Radiation
– Therapeutic– Radionuclide– Atomic fallout
• Infection– Rubella virus– Cytomegalovirus– Toxoplasmosis– Venezuelan equine
encephalitis virus– Syphilis– Parvovirus B-19– Varicella virus
• Maternal Trauma/Metabolic Imbalance– Alcoholism– Amniocentesis (early)– CVS before day 60– Cretinism– Diabetes– Folic acid deficiency– Hyperthermia– Phenylketonuria– Rheumatic disease– Sjogren’s syndrome– Virilizing tumors
Human Developmental Toxicants II• Drugs/Chemicals
– Androgens– ACE inhibitors
• Enalapril, captopril
– Antibiotics• Tetracycline
– Anticancer drugs• Cycloposphamide, busulfan
– Anticonvulsants• Diphenylhydantoin, trimethadione,
valproic acid
– Antithyroid drugs• Methimazole
– Chelators• Penicillamine
– Chlorobiphenyls
– Cigarette smoke– Cocaine– Coumarin (warfarin)– Ethanol– Ethylene oxide– Fluconazole– Diethylstilbesterol– Iodides– Lithium– Metals
• Hg, Pb
– Methylene blue– Misoprostol– Retinoids
• 13-cis retinoic acid, etretinate
– Thalidomide– Toluene abuse
Prenatal Exposures
Critical Periods of Susceptibility (Wilson)
CHD and Birth Weight
Insulin Resistance and Birth Weight
Transgenerational Effects of Vinclozolin (mice)
(Anway et al., 2005)
Transgenerational Effects of Vinclozolin (mice)
(Anway et al., 2006)
Fusion of Pronuclei
15-day embryo
18 Hr Chick Embryo
HoloprosencephalyC57BL/6J mouse gd 18Methanol gd 7
Holoprosencephaly
Cyclopic lamb born to a ewe feeding onVeratrum californicum (contains jervine)
From Gilbert
C D
E F
A B
TAs
1
2
3
4
5
6
7
1
2
3
4
5
6
7
*
*
123
45
4th Week
Control 1000 mg/kg 1250 mg/kg
Day 18 Fetuses
In vivo Antagonist on Day 8
Mandibular Vibrissae
gd 141250 mg/kg L-754,142
Critical Periods for Malformations in Humans Malformation Time of Induction
Cyclopia 23 days
Anencephaly 26 days
Transposition of great vessels 34 days
Cleft lip 36 days
Aplasia of radius 38 days
Ventricular septal defects 6 weeks
Syndactyly 6 weeks
Cleft palate 8-9 weeks
Bicornurate uterus 10 weeks
Hypospadias 12 weeks
Cryptorchidism 7-9 months