Welcome to PSR's Environmental Health Policy Institute, where we ask questions -- then we ask the experts to answer them. Join us as physicians, health professionals, and environmental health experts share their ideas, inspiration, and analysis about toxic chemicals and environmental health policy.
By Jerome A. Paulson, MD, FAAP
This essay is in response to: How is the developing fetus vulnerable to toxic chemical exposures, and how can our regulatory system more effectively protect our health in the prenatal period?
At the time of conception there is one egg and one sperm. They merge to create a single cell. Approximately nine months later a child is born consisting of several trillion cells and weighing about 7 ½ pounds. While it is obvious that there are many new cells developed in the prenatal period, it is less obvious but extremely important to note that in order for prenatal growth and development to proceed normally, cells must move from one place to another (cellular migration); cells must differentiate and become specialized as liver cells or neurons or skin cells, etc; some cells must die (apoptosis); and in the nervous system, cells must link into a communications network (synaptogenesis). All of these processes are exquisitely timed and if one step is perturbed there is no way to go back and redo the step.
There are any numbers of factors that influence or are associated with birth outcomes. These include race, ethnicity, income, diet, and lifestyle issues such as smoking, exercise, and alcohol consumption. It is very clear that in the US, and globally, members of minority populations and individuals who are poor are more likely to be exposed to and suffer adverse outcomes from environmental health hazards.
Environmental factors which affect birth outcome are not limited to exposures occurring after conception. Exposure of males not only affect sperm quality and quantity, influencing the likelihood of conception; there are exposures that effect the fetus and influence implantation. There is also growing evidence that exposure of the grandmother when she is pregnant with a female fetus, can influence that fetus’ ova (all of which are formed prior to birth) and thus influence the pregnancy, birth outcomes, or adult-onset diseases in the second generation.
Many medications taken during pregnancy are associated with an increased risk of developmental abnormalities. Among the best known is Thalidomide. When taken in the first weeks of pregnancy, when the limb buds are being formed, the risk of delivering a child with phocomelia is high. Taken at the end of pregnancy or when a woman is not pregnant, there is no known risk to the fetus or subsequent pregnancies. The differential outcomes associated with the differential timing of exposure emphasize the importance of specific periods of vulnerability within the overall prenatal time frame. (There are examples of post-neonatal windows of vulnerability as well.)
Other exposures in-utero also result in adverse outcomes in childhood or even adulthood. One example is high doses of methylmercury ingested by mothers eating fish which had been contaminated from the disposal of industrial waste. The result in the offspring was severe brain damage with microcephaly, seizures, severe cognitive delay, and motor deficits (Minamata Disease); whereas the effects on the mothers were minimal. In a review of all data pertaining to lower doses of prenatal exposure to methylmercury, the National Academy of Sciences Committee on Developmental Toxicology concluded that there is a strong association between methylmercury exposure in utero and neurocognitive deficits, including small decreases in IQ and abnormalities in neuropsychological tests of memory, attention, language, and visuospatial perception.
Environmental tobacco smoke is a mixture of over 4,000 chemicals. Prenatal exposure can occur if the mother smokes or if she is exposed to environmental tobacco smoke. In animal studies, prenatal exposure to tobacco smoke via the mother leads to reductions in cortical gray matter and alteration in the development of white matter. Studies of children exposed prenatally to tobacco smoke revealed deficits in speech and language skills, visual/spatial abilities, behavior, and IQ.
Maternal ingestion of alcohol during pregnancy can lead to Fetal Alcohol Spectrum Disorder (FASD), a wide range of physical, behavioral and cognitive problems in the child; damage depends on the amount, timing, and duration of the consumption. Moderating factors include maternal nutrition, stress, and tobacco consumption. There is no known safe level of alcohol consumption during pregnancy.
Polychlorinated biphenyls (PCBs) have been shown to be neurotoxic in animals, and high-dose human intake through food contamination has been associated with cognitive delays, behavior disorders, growth retardation, and other findings. Outcomes associated with low-dose exposure to PCBs in utero and after birth indicate small deficits in neuromotor development and IQ, along with problems with attention and impulse control.
Prenatal exposure to the organophosphate chlorpyrifos has been associated with an increased risk of developmental delay, ADHD, and autism at 3 years of age and deficits in Working Memory Index and Full-Scale IQ at 7 years of age. Based on findings in animal models, these abnormalities may be related to alterations in neurotransmitters, and in axonal growth and development. Chlorpyrifos and diazinon were banned for residential use in the early 2000s, but other organophosphates are still on the market for home use.
The U.S. Environmental Protection Agency (EPA) defines an endocrine disrupting chemical (EDC) as “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental process.” A very diverse group of chemicals have endocrine disrupting properties including phthalates, PCBs, polychlorinated dibenzodioxins, brominated flame retardants, dioxins, DDT, perfluorinated compounds (PFCs), organochlorine pesticides, bisphenol A, and some metals. EDCs can have estrogenic, antiestrogenic, antiandrogenic, antithyroid, or antiprogestin effects. Exposure to phthalates, some of the pesticides, PCBs, and other EDCs has been shown to be associated with decreased IQ and other neurodevelopmental abnormalities.
The picture that is emerging is that exposure to different toxicants in-utero leads to outcomes that clinically look similar. The specifics of the outcome almost certainly relate to the specific timing of exposure and where the fetus/embryo is in the process of development at the time of exposure.
There is a growing body of evidence supporting the Barker Hypothesis, the notion that in-utero nutrition and other factors influence adult-onset diseases such as atherosclerotic cardiovascular disease, hypertension, Type 2 diabetes, stroke, and cancer.
The mechanisms for these in-utero impacts are less clear. Some may be related to programming of intracellular signals, cell-to-cell interactions, and metabolic pathways. There is evidence that there is a reprogramming of the epigenome which occurs after conception. Perhaps toxicants interfere with this reprogramming and that results in disease.
The association between in-utero exposure to certain toxicants and adverse outcomes evident at the time of birth and later is very clear. It is also very clear that the in-utero period is part of a continuum of vulnerability to environmental toxicants that begins before conception and extends at least to the final mylenation of the frontal cortex in individuals in their early 20s. Researchers and policy makers need to be cognizant of this continuum, do more research about the effects of toxicants at various points along the continuum, and take the knowns and unknowns into account when making regulations to protect the health of the population.
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