Teratogens

Topic editor


Sean Foley
Lead author:
Leah Tait

Overview


Teratogens are toxic agents that cause abnormal development resulting in birth defects. Between 3% and 5% of children born in the United States are born with developmental defects. Of these, only 2% to 3% of them are classified as teratogen-induced malformations. However, 60-70% of all defects are of unknown origin--developmental toxicology is an expanding field and some of the unclassified defects may eventually be classified as teratogen-induced. Teratogenic substances do not affect each developing fetus in the same way. The fetus is most at risk during organogenesis (development of organs), which begins at about three weeks post-conception, and continues until the organs' defining characteristics have been achieved. The severity and type of the congenital malformation may vary with the duration of exposure and the specific teratogen. However, exposure to the same substance on different days in development can produce different defects. Many teratogens are fatal at high doses, causing miscarriage.  Defects that present later, such as growth development and functional impairment, are harder to relate to teratogen exposure. In the time between birth and detection of impairment, exposure to other toxicants may have occurred, increasing the difficulty of identifying the responsible toxicant.
Above from #Brent 2004, #Kent 1998, and #Finnel 1999.

Mechanisms of Action


Cell Death
In the developing fetus, communications occur between cells, both through cell-to-cell contact and biochemical signals. This communication is necessary to synchronize cell differentiation, and cell death from toxic exposure can cause abnormal development by its disruption. In addition, substances which interfere with apoptosis, planned cell death that is part of normal development, also can cause fetal malformations.
Exposure to toxic substances causing cell death during early pregnancy, if large numbers of cells are killed, can result in spontaneous abortion. If only few cells die, however, the embryo can replace the dead cells and continue development.
In later development, toxic exposures to such substances usually cause congenital malformations rather than miscarriage.
Impaired Cell Function
Some toxic agents do not cause cell death, instead inhibiting normal cell function. However, the inhibition of cell function has similar effects as cell death.
Genotoxicity
Genotoxic substances cause damage to the DNA in a cell. Such damage frequently leads to cell death and can cause spontaneous abortion, while DNA damage later in development can lead to malformations.

Maternal and Placental Toxicity
Toxins that affect maternal health or the placenta also affect development. A healthy placenta is the mechanism by which the fetus receives nutrition, gas is exchanged, and waste is removed. Impairment of these functions can lead to cell death.

Maternal infections can result in malformation or miscarriage as well. Toxoplamsa gondii infection has been associated with head and eye malfomations.
Above from #Kent 1998.

Teratogenic Agents


  • Radiation - Ionizing radiation breaks both strands of the DNA molecule and causes an alteration in chemical structure of the nitrogenous bases. Cells in a developing embryo are rapidly dividing and are thus more vulnerable to DNA damage.
  • Metals - Metals such as methyl mercury increase the risk of cerebral palsy and other neurological disorders. Other metals, including lead and cadmium, impair the function of enzymes involved in energy production. This leads to cell death or impaired cell reproduction, and causes developmental abnormalities.
  • Thalidomide - A medication administered to pregnant women in Europe in the 1950s and 1960s, thalidomide reduced nausea and vomiting during pregnancy. Thalidomide also caused limb malformations, either a total absence of some or all limbs or a shortening of the long bones in the arms or legs. In addition, those exposed in utero to thalidomide had an increased risk for congenital heart disease, as well as other organ deficiencies.
  • DES - Diethylstilbestrol is a synthetic estrogen. It was another drug administered to pregnant women with the intention to reduce miscarriage risk. However, female children of women who took DES had an increased risk of rare vaginal cancers and frequently malformed uteruses. Male children were likely to have smaller testes and decreased amounts of semen production, and other fertility problems.
  • Ethanol - Ethyl alcohol is associated with Fetal Alcohol Syndrome Disorder (FASD).  Alcohol consumption during pregnancy can lead to behavioral, neurological, and skeletal problems in offspring.
  • Cocaine - Cocaine use during pregnancy is associate with premature labor and low birth weight. Infants may be born addicted and go through withdrawal symptoms included seizures, tremors, and abnormal sleep patterns.

(#Kent 1998)

References


  • Brent RL. 2004. Environmental causes of human congenital malformations: the pediatrician's role in dealing with these complex clinical problems caused by a multiplicity of environmental and genetic factors. Pediatrics. 113:957-968
  • Kent C. 1998. Basics of Toxicology. New York, NY:John Wiley & Sons, Inc.
  • Persaud TVN, Chudley AE, Skalko RG. 1985. Basic Concepts in Teratology. New York, NY:Alan R. Liss, Inc.
  • Finnel RH. 1999. Teratology: general considerations and principles. J Allergy Clin Immunol. 103:S337
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