Teratology

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Teratology :

Submitted to: Dr. h.b.patel [dept. of pharmacology and toxicology] Teratology Submitted by: Kuldeep d. chhatpar Roll no. 5 Regn . No. 02-00133-06

INTRODUCTION:

INTRODUCTION Teratology is a specialized area of embryology. It is the study of the etiology of abnormal development (the study of birth defects). Developmental toxicity any morphological or functional alteration caused by chemical or physical insult that interferes with normal growth, homeostasis, development, differentiation, and/or behavior.

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Teratogens therefore are xenobiotics and other factors that cause malformations in the developing conceptus. Examples of teratogens may include pharmaceutic compounds, substances of abuse, hormones found in contraceptive agents, cigarette components, and heavy metals. viral agents, altered metabolic states induced by stress, and nutrient deficiencies (e.g., folic acid deficiency).

PRINCIPLES OF TERATOLOGY:

PRINCIPLES OF TERATOLOGY 1. Susceptibility to teratogenesis depends on the embryo’s genotype that interacts with adverse environmental factors (G × E interaction). 2. The developmental stage of conceptus to the exposure determines the outcome. 3. Teratogenic agents have specific mechanisms through which they exert there pathogenic effects. 4. The nature of the teratogenic compound or factor determines its access to the developing conceptus/tissue. 5. The four major categories of manifestations of altered development are death, malformation, growth retardation, and functional deficits. 6. The manifestations of the altered development increase with increasing dose (i.e., no effect to lethality)[NOAEL->100% lethality]

THREE basic characteristics of teratogens::

THREE basic characteristics of teratogens: A given teratogen can be dose specific . It may be organ specific . It may be species specific .

CRITICAL PERIODS:

CRITICAL PERIODS Major fetal outcomes depend on the stage of pregnancy affected, as there are critical periods for the development of fetal processes and organs. One may divide the developmental stages in to three large categories: pre-implantation, implantation to organogenesis, and the fetal to neonatal stage. The outcomes associated with exposure during these periods vary.

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STAGE OF EXPOSURE OUTCOME(S) Pre-implantation Embryonic lethality Implantation to time of organogenesis Morphological defects Fetal → neonatal stage Functional disorders, growth retardation, carcinogenesis

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The sensitivity of the embryo to the induction of morphological defects is increased during the period of organogenesis. This period is essentially the time of the origination and development of the organs.

Some well known teratogens:

Some well known teratogens

Thalidomide :

Thalidomide Thalidomide is a sedative-hypnotic drug used in Europe from 1957 to 1961. It was marketed for morning sickness, nausea, and insomnia . It went into general use and was widely prescribed in Europe, Australia, Asia, Africa, and the Americas. Women who had taken the drug from gestation days (GD) 35 to 50 gave birth to offspring suffering from a spectrum of different malformations, mainly amelia (absence of limbs) or phocomelia (severe shortening of limbs). Other malformations included: absence of the auricles with deafness, defects of the muscles of the eye and face, and malformations of the heart, bowel, uterus, and the gallbladder. The compound was withdrawn from the market in 1961 after about 10,000 cases had occurred.

Accutane (Isotetrinoin):

Accutane (Isotetrinoin) Accutane is a member of a family of drugs called retinoids , which are related to vitaminA . It is approved to treat serious forms of acne. These painful and disfiguring forms of acne do not respond to other acne treatments. Accutane can cause severe, life-threatening birth defects if the mother takes the medication during pregnancy. Even one dose of Accutane can cause major birth defects of the baby's ears, eyes, face, skull, heart, and brain. Women of child-bearing potential must have regular pregnancy tests before, during, and after taking isotretinoin . Accutane is available only under a special program called iPLEDGE .

Diethylstilbestrol (DES):

Diethylstilbestrol (DES) DES is a synthetic estrogen that inhibits ovulation by affecting release of pituitary gonadotropins . Some of its uses include treatment for hypogonadism , and in some cases of prostate cancer. From 1940 to 1970, DES was used to help maintain pregnancy. In utero exposure to DES has been associated with abnormal development of the uterus. It has also been associated with certain types of tumors. Women who were exposed in utero often developed vaginal neoplasia , vaginal adenosis , and cervical erosion. Effects were not seen in offspring until they reached puberty. Clear cell carcinoma of the vagina is a type of adenocarcinoma found in young women who are exposed to diethylstilbestrol in utero . The reproductive organ of males can also be affected subsequent to in utero exposure. The outcomes include hypotrophic testes, poor semen volume and quality.

Alcohol- “Fetal Alchol Syndrome”:

Alcohol- “Fetal Alchol Syndrome” FAS is a pattern of mental and physical defects that develops in some offspring when exposed to alcohol in utero . The first trimester is the most susceptible period. Some babies with alcohol-related birth defects, such as lower birth weight and body size and neurological impairments, do not have all of the classic FAS symptoms. These outcomes are often referred to as fetal alcohol effects ( FAE). In addition to growth retardation, the most common outcomes of fetal alcohol syndrome include psychomotor dysfunction and craniofacial anomalies. Other infrequent outcomes include skeletal malformations such as deformed ribs and sternum, scoliosis, malformed digits, and microcephaly . Visceral deformities may also be present: heart defects, genital malformations, kidney, and urinary defects. A common concurrent manifestation of FAS include irregular arrangement of neurons and connective tissue.

‘‘Non Chemical’’ Teratogens:

‘‘Non Chemical’’ Teratogens There may be other factors having the ability to cause malformations in the developing conceptus . RESTRAINT STRESS in mice ( 12-hour restraint during early period of organogenesis) elicits axial skeletal defects ( primarily supernumerary ribs). The Rubella virus (first reported in 1941, Austria) is associated with a number of fetal outcomes depending on the stage of development that the exposure occurs. Exposure during the first and second month of pregnancy was associated with heart and eye defects. Exposure during the third month was associated with hearing defects (and mental retardation in some cases).

Testing protocols:

Testing protocols

FDA Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use:

FDA Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use Multigenerational Study. This approach involves the continuous exposure of a rodent species (usually mice). The parental animals are exposed shortly after weaning (30–40 days of age). At reproductive maturity, the animals are mated. The first generation is produced (F1). From these an F2 is produced and then subsequently an F3 generation. The effects of the test is monitored through each generation. The measured parameters include fertility, litter size, and neonatal viability. This is a time-consuming effort that usually takes about two years to complete.

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Single-Generation Studies Segment I : Evaluation of Fertility and Reproductive Performance. Male rodents are treated for 70 days (to expose for one spermatogenic cycle), and nonpregnant females for 14 days (to exposure for several estrous cycles). Treatment is continued in the females during mating, pregnancy, and lactation. Fifty percent of the females are killed and the fetuses are examined for presence of malformations. The other 50% are allowed to give birth. After weaning, these offspring are killed and necropsied.

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Segment II : Assessment of Developmental Toxicity. This involves the treatment of pregnant females only during the period covering implantation through organogenesis (typically from gestational days 6 to 15 in mice with 18-day gestational periods). One day prior to birth, the animals are killed and fetuses examined for viability, body weight, and presence of malformation. Segment II : Postnatal Evaluation. Pregnant animals are treated from the last trimester of pregnancy until weaning. Evaluated are parturition process, late fetal development, neonatal survival, and growth as well as presence of any malformations.

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Alternative Test Methods to reduce the number of whole animals used in studies and/or to obtain more rapid information concerning the potential of a compound to be a reproductive/developmental toxicant. Some of these alternative methods include the use of cell or embryo culture. For example, the micromass culture involves the use of limb bud cells from rat embryos grown in micromass culture for five days. The processes of differetiation and cell proliferation are assessed. In the Chernoff / Kavlock Assay, pregnant rodents are exposed during organogenesis and allowed to deliver. Postnatal growth, viability, and gross morphology of litters are recorded (detailed skeletal evaluations are not performed). Other alternative tests involve the use of nontraditional test species such as Xenopus embryos (FETAX) and Hydra . Xenopus embryos are exposed for 96 hours and then evaluated for morphological defects , viability, and growth. The cells of Hydra aggregate to form artificial embryos . The dose response in these “embryos” is compared to that of the adult Hydra.

CONCLUSIONS:

CONCLUSIONS Understanding the mechanisms of the induction of birth defects is key to determinehow to prevent these effects. Further, increasing the accuracy of experimental animal extrapolation will aid in the interpretation of experimental data in order to more accurately determine the risk of a given compound to elicit birth defects in humans.

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