Environmental toxins and fetal development

It has long been known that the fetus can be sensitive to impacts from adverse environmental exposures. Fetal development can be affected by exposures that occur to either parent prior to conception and to the mother post conception.

Fetal development

Historically, it was recognized that certain infections or poisons that were harmful to the pregnant woman often were as harmful, or more harmful, to the fetus. Infectious syndromes such as congenital rubella syndrome and congenital syphilis were examples. In the last century evidence emerged that certain environmental exposures that were not obviously harmful to the mother could cause serious harm to the fetus. Substances that caused birth defects and other adverse effects to the fetus, in the absence of recognized toxicity to mothers, were: genital abnormalities and vaginal cancer occurring among girls born to mothers given the estrogenic hormone diethylstilbestrol during pregnancy; phocomelia (failure of growth of limb buds) to babies born to mothers who took thalidomide to control nausea during pregnancy; and Minamata disease, an epidemic of babies born with severe mental retardation and deformities due to mercury poisoning caused by mothers eating methylmercury contaminated fish from Minimata Bay in Japan. More recently, maternal tobacco smoking and even environmental tobacco smoke, modest consumption of ethanol during pregnancy, and low levels of exposure to lead and mercury have been found to be have adverse impacts on fetal growth and development. The healthy placenta does form a barrier for most pathogens and for certain xenobiotic substances. However, it is by design an imperfect barrier since it must transport substances required for growth and development, such as nutrients and immunoglobulins. Placental transport can be by passive diffusion for smaller molecules that are lipid soluble or by active transport for substances that are larger and/or electrically charged. Some toxic chemicals may be actively transported. For example, it is believed that lead is transported using mechanisms designed for transport of iron, calcium and possibly other essential elements such as zinc. The dose of a substance received by the fetus is determined by the amount of the substance transported across the placenta as well as the rate of metabolism and elimination of the substance. The fetus has immature metabolism and is not able to detoxify substances very efficiently; the only routes of excretion is via diffusion or active transport back to the maternal circulation or elimination into the amniotic fluid.

The timing and duration of exposure are critical. The level of response to a given dose may change dramatically depending on the stage of development at which a fetus is exposed. To identify potential hazards for fetal development requires a basis of scientific information. In 2004, Brent proposed a set of criteria for identifying causes of congenital malformations that also are applicable to developmental toxicity generally. Those criteria are:
* There are well conducted epidemiology studies consistently show a relationship between particular effects and exposure to the substance to humans.
* Trends in data over time support a relationship between changing levels of exposure to a substance and the specific effect.
* Animal studies give evidence that the fetus is susceptible and provide biological information that is supportive of the human studies and specifically:
** (1) evidence for a dose response;
** (2) the embryonic stage of exposure is critical to whether the developmental effect will be produced;
** (3) specificity between the substance and the effect to be produced; and
** (4) lack of effects other than those produced by a specific substance (that are suggestive of a different mechanism).ref|Brent2004

Environmental toxins

Bioaccumulation and persistence are important aspects to consider since such substances are more likely to be present over several developmental stages than substances that are quickly eliminated. Such substances, known as persistent organic pollutants (POPs), include a number of chemicals that are known to have adverse effects on fetal development given the level and timing of exposure: polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans and organochlorine insecticides such as DDT are examples of such compounds that can be toxic to the fetus at high enough doses. Others, such as lead and methylmercury are persistent but not bioaccumulative. (Later, such chemicals continue to be passed from mother to baby via breast milk.ref|bsk1994

A number of environmental toxins known to have adverse effects on fetal development are endocrine disruptors. Processes involved with differentiation and growth of embryonic and fetal cells are under the tight control of a myriad of messaging systems, some of which involve hormones. In particular, chemicals that mimic or otherwise disrupt the normal response to estrogen, androgen, or thyroid hormone have been particularly of concern during fetal development.

Environmental carcinogens also are of concern during this time. Research has indicated that in utero exposure to carcinogens may confer much higher risks than later in life. This may be due to the rapid growth and differentiation of cells during this time, with, perhaps, less ability to repair the damage caused by carcinogens or to mount an effective immune response.

References

Footnotes

# Brent, R.L., 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, 2004. 113(4 Suppl): p. 957-68.
# "Children's Health". Chemical & Engineering News, April 7, 2003, pp. 23-26.

General

# Buelke-Sam, Judy and Kimmel, Carol A., eds. Developmental Toxicology. (1994). 2nd ed. New York: Raven Press.
# Chudley, Persaud & Skalko. Basic Concepts in Teratology. (1985) New York: Alan R. Liss, Inc.
# Schardein, James L., ed. Chemically Induced Birth Defects. (2000). 3rd ed.
# Steingraber, Sandra. (2001). Having Faith. Cambridge, MA: Perseus Publishing.