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