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Developmental Toxicology

Developmental Toxicology

* Structural malformations
* Growth retardation
* Functional impairment
* Death of the organism
4 manifestations of developmental toxicity

Teratology
1. the study of malformations or serious deviations from the normal type in organisms

2. the branch of science concerned with the production, development, anatomy, and classification of malformed fetuses.

* Teratogen
o Any agent that causes a birth defect
o After Greek “monster creating”
* Environmental conditions (1200)
* Maternal nutritional deficiencies (1930)
* Rubella virus infection (1941)
* Thalidomide (1961)

Adverse Outcomes in Pregnancy
Cause of human birth defects
Chemical teratogenicity
Pregnancy Risk Categories
Therapeutic Drugs Teratogenic to Humans
* Anticonvulsants
o Phenytoin, primidone, trimethadione, valproic acid, carbamazepine
* Anticancer agents
o Alkylating agents –busulfan, cyclophosphamide, chlorambucil, mechlorethamine
o Antimetabolites-aminopterin, methotrexate, cytarabine
* Androgenic hormones-danazol
* Coumarin anticoagulants-warfarin
* Retinoids-accutane, isotretinoin, etretinate, acitretin
* Antihyperlipidemic agents-lovastatin, atorvastatin
* Other drugs-diethystilbestrol, thalidomide, penicillamine, lithium, fluconazole, misoprostol
Thalidomide
Diethylstilbesterol (DES)
Alcohol (Ethanol)
Fetal Alchohol Syndrome (FAS)
Fetal Alchohol Effects (FAE)
* Cranial facial dysmorphism
* Intrauterine and postnatal growth retadation
* Retarded psychomotor and intellectual development
* IQ 68

Tobacco smoke
* Spontaneous abortions
* Perinatal deaths
* Lower birth weight
* Increased risk of
o Sudden infant death syndrome
o Behavioral attention disorders
o Orofacial cleft (particular xenobiotic gene polymorphisms)
o Gastroschisis (with variant alleles N053, ICAM1, NPPA)
o Branching morphogenesis and maturation of the lung
* Nicotine-related adverse nerodevelopmental outcomes
Cocaine
* At risk for premature labor, spontaneous abortion, increased perinatal mortality and fetal death.
* intrauterine growth retardation, microcephaly, altered presencephalic development, decreased birth weight, a neonatal neurologic syndrome of abnormal sleep, tremor, poor feeding, irritability, and occasional seizures.
* Genitaouinary tract malformation
* Impaired uditory process

Retinoic Acid
Retinoic acid is the active ingredient in “Accutane”, a drug used to treat severe acne. Since its introduction in September of 1982, an estimated 160,000 women of child bearing age have ingested the drug. Between 1982 and 1987, approximately 900-1300 malformed children, 700-1000 spontaneous abortions and 5000-7000 elective abortions are due to Accutane exposure. Exposed children may have hydrocephaly, ear malformations, cardiovascular defects and decreased IQ. Accutane carries a pregnancy category X warning, meaning it is a known human teratogen.
c acid
Retinoids
* Malformations of the face, limbs, heart, CNS, and skeleton
* RXR α receptor
* Schizophrenia
Retinoid Therapies
Tretinoin/ATRA (Vesanoid)
Leukemia
Adapalene (Differin),
Tretinoin (Renova),
Isotretinoin (Accutane)
Acne
Tazartene (Zorac),
Etritinate (Tegison)
Psoriasis
Drugs
RAR and RXR (Simple Version)
* Nuclear Receptors (like ER, PPAR, VDR and others)
* RXR/RAR Heterodimer is functional unit
* Bind selectively to REs in genome
* Act as transcription factors
* Up-regulate or Repress the expression of particular genes

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).

Valproic Acid
* spina bifida with menigomyelocele or menigocele
* The proposed mechanism of action is that valproic acid influences folate metabolism

Angiotensin Converting enzyme inhibitors and angiotensin antagonists
* 2-3 trimester
* related reduced amniotic fluid volume and impaired fetal renal function
o Oligohydromnios
o Fetal growth retardation
o Pulmonary hypoplasia
o Renal failure
o Hypotension
o Death
* First trimester
o Congenital malformation

Wilson’s General Principles of Teratology (Table 10-2)
* Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with environmental factors.
* Susceptibility to teratogenic agents varies with the developmental stage at the time of exposure.
* Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate abnormal embryogenesis (pathogenesis).
* The final manifestations of abnormal development are death, malformation, growth retardation, and functional disorder.
* The access of adverse environmental influences to developing tissue depends on the nature of the influences (agent).
* Manifestations of deviant development increase in degree as dosage increases from the no-effect to the totally lethal level.
Critical periods of susceptibility and endpoints of toxicity
* Gametogenesis and Fertilization

Mechanism unclear, may be related to imprinting
Cytosine methylation and change in chromatin conformation ethylene oxide, ethylmethane sulfonate, ethylnitrosourea→malformed fetus

DNA Methylation vs Genomic Imprinting
Mechanisms and pathologenesis of developmental toxicology

* Mutations
* Chromosomal breaks
* Altered mitosis
* Altered nucleic acid integrity or function
* Diminished supplies or precursors of substrates
* Decreased energy supplies
* Altered membrane characteristics
* Osmolar imbalance
* Enzyme inhibition
Example of cyclophosphamide (CP)
Single strand DNA break
A teratogenic chemotherapeutic agent
CP induces DNA damage
Advances in the Molecular basis of dysmorphogenesis
1.Using either singly or double gene knockout Retinoic acid receptor family (syndactyly)
2. Antisense oligonucleotide Wnt-1, Wnt-3a (mid and hindbrain malformation)
3. Reporter transgenes

Pharmacokinetics and metabolism in pregnancy
1.Changes in maternal physiology
hepatic metabolism, GI tract, cardiovascular system, excretory system, respiratory system
2.Overall decrease in hepatic xenobiotic transformation
3.Roles of placenta in influence embryonic exposure help to regulate blood flow
-offer a transport barrier-pH gradient, weak acid rapidly transfer
-metabolize chemicals
2-acetylaminofluorene (proteratogen)
7-hydroxyl metabolites(proximate teratogen)
4.Maternal metabolism of xenobiotics 2-methoxyethanol 2-methoxyacetic acid

Placental toxicity
* Metals, Cd, As, Hg, ethanol, cocaine, cigaratte, sodium salicylate
* Maternal injection vs fetal injection of Cd
* Production of metallothionein
* Interaction with Zn

Maternal toxicity-
* acetazolamide inhibits carbonic anhydrase forelimb ectrodactyly

* diflunsial results in anemia skeleton defects in rabbits
* phenytoin affects folate metabolism and heart rates
* metallothionein synthesis inducer-urathane, mercaptopurine, valproic acid Zn deficiency

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

Fetal Basis and Transgenerational Transmission of Reduced Fertility
Environmental Epigenetics
Decreased spermatogenic capacity and decreased fertility ..as well as increased prevalence of other diseases transferred via MALE germ line

Summary
* A transient embryonic exposure to endocrine disruptors at the time of gonadal sex determination can cause epigenetic transgenerational disease state of subfertility and spermatogenic defects in F1 through F4 generations
* Transgenerational disease phenotype was primarily transmitted through the male germ line
* Exposure appears to have caused an epigenetic reprogramming of the germ cell line that is “permanent” and transferred transgenerationally to subsequent generations

Modern safety assessment
* Regulatory guidelines for in vivo testing
* Multigeneration tests
* Children’s health and the food quality protection act
o Tenfold safety factor for children
* Alternative testing strategies
* Epidemiology
* Concordance of data (among species)
* Elements of risk assessment
use-in pregnancy rating: A, B, C, D, X

In Vivo Regulatory Protocol Guideline
The 17 intercellular signaling pathways by most metazoans
* Early development and later
* 1. Wnt pathway
* 2. Receptor serine/threonine kinase (TGFb) pathway
* 3. Hedgehog pathway
* 4. Receptor tyrosine kinase (small G proteins) pathway
* 5. Notch/Delta pathway
* Mid-development and later
* 6. Cytokine receptor (cytoplasmic tyrosine kinases)
* pathway
* 7. IL1/Toll NFkB pathway
* 8. Nuclear hormone receptor pathway
* 9. Apoptosis pathway
* 10. Receptor phosphotyrosine phosphatase pathway
* Larval/adult physiology
* 11. Receptor guanylate cyclase pathway
* 12. Nitric oxide receptor pathway
* 13. G-protein coupled receptor (large G proteins) pathway
* 14. Integrin pathway
* 15. Cadherin pathway
* 16. Gap junction pathway
* 17. Ligand-gated cation channel pathway

Sonic Hedge-hog signal pathway
cyclopamine
jervine
Holoprosencephaly
Cholesterol synthesis inhibitor
Consequences of Folate Deficiency
* Result of low dietary intake, genetic error of folate metabolism, lifestyle exposures
* DNA Hypomethylation
o Gene overexpression, uncontrolled cell growth, genomic instability
* Hyperhomocysteinemia
o Excessive accumulation of Hcy
* Base Misincorporation
o Decrease in thymine synthesis; replaced by uracil
o DNA strands prone to nicks, breaks and vulnerable to mutagen insertion
Homework

1. Describe the possible mechanisms for teratogenic effects of the following chemicals.
a. aminoglycosides
b. ethylene oxide
c. captopril
d. danazol
e. aminopterin
f. Accutane

Developmental Toxicology.ppt

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