LOS ANGELES -- Scientists from Cedars-Sinai Medical Center in Los Angeles and the University of Calgary in Alberta, Canada will present on Monday, June 14, findings of a study that for the first time has detected and measured contaminants from certain pesticides and industrial chemicals in the amniotic fluid of unborn babies.
This study was not designed to determine whether exposure to these contaminants produces ill effects on fetuses or newborns. Instead, it is seen as a first step in a long-term process of identifying contaminants and later assessing their potential impact.
Of particular interest to the researchers, who will present their findings at the Endocrine Society's meetings in San Diego, are compounds that are known to have the capacity to disrupt natural hormone activity in humans - and which could, theoretically at least, pose a risk to normal development of the fetus.
About 30 percent of the sample had measurable levels of DDE, a waste product of the pesticide DDT that is no longer available in North America but is still in use in some developing countries. The study analyzed the amniotic fluid of 53 women from the Los Angeles area who were between 16 and 20 weeks of gestation.
DDE is known to 'antagonize' the male hormone testosterone. Testosterone is present in the blood of both males and females, although it exists in higher concentrations in males. Circulating in the blood, it 'attaches' to testosterone 'receptors' of cells. While these receptors 'prefer' the natural male hormone, they also can accept DDE as a substitute. Therefore, as concentrations of DDE increase, the ability of testosterone to properly bind and signal target cells to initiate the functions that they are programmed to carry out decreases.
Among the 30 percent of the study population for which DDE levels were measurable, concentrations ranged from 0.1 to 0.63 nanograms per milliliter. This top value of 0.63 nanograms per milliliter is nearly equal to the amount of natural male hormone that should be found in female fetuses. It is about 50 percent of the level of natural hormone that should be found in male fetuses, according to Claude L. Hughes, M.D., Ph.D. A specialist in obstetrics and gynecology, Dr. Hughes directs the Center for Women's Health and holds the Women's Guild Chair in Women's Health at Cedars-Sinai.
"The key factor in assessing the significance of compounds that act like hormones is how their concentrations relate to the naturally occurring hormones," said Dr. Hughes. "The question then is: Does the amount of DDE come anywhere close to the concentration of androgens (male hormones) in the fetus? In the amniotic fluid, the amounts of androgens and DDE are in the same ballpark."
According to Warren Foster, Ph.D., director of research and associate director of the Center for Women's Health, detecting DDE in 30 percent of the population in this study is a finding that deserves attention. A reproductive toxicologist who was the study's first author, Dr. Foster said assessing the possible effects of these amounts of DDE is another challenge. "With these levels of DDE present, the natural hormones will presumably be suppressed or blocked. What impact does that have on the developing fetus? It could have an effect upon the baby's development, such as masculinization; however, it's speculation at this point. We will have to do additional studies to find out."
In fact, this first study marks the beginning of what the researchers anticipate to be a methodical examination of the impact of man-made and naturally occurring compounds that find their way into the amniotic fluid surrounding the developing fetus. The researchers expect to gradually produce scientific evidence that will either support or dispel existing speculation about perceived environmental and even dietary threats to developing fetuses.
"We have to be able to actually measure what is there," said Dr. Foster. "We have to show that we can detect it, we can measure the level, then we can determine whether or not these contaminants are associated with adverse effects."
In this case, the levels of DDE appear sufficient to raise concern but many questions remain unanswered. "How much interference with the normal action of androgens (male sex hormones) in the developing testis do you have to have before a child will have low sperm counts as an adult? How much interference of androgen action in the brain do you have to have before there is a change in the sex-hormone-related development of several structures in the brain? I don't know," said Dr. Hughes.
He noted that in addition to the amount of a 'dose,' timing can play a critical role in determining whether an exposure is likely to have a negative impact on health or development.
Developmentally, "there's a lot going on" during the weeks of gestation when these amniotic fluid samples were taken, making timing a potential factor. "A few weeks before this time is when major organ development is occurring. The organs are really forming from just clumps of cells. Through this time frame, more detailed organization is occurring. And up to three to six months after birth, brain organization is still occurring in important ways and there is evidence to suggest that sex hormones are being produced in some rather dynamic ways before they become quiet during the baby's first year of life. The organs have essentially all formed by the time these samples are taken at 16 to 20 weeks but other detailed events are still unfolding."
In addition to finding and quantifying levels of DDE, the researchers found lesser but still detectable amounts of polychlorinated biphenyls, PCBs, and other compounds associated with man-made industrial and agricultural chemicals. PCBs are a 'family' of chemical compounds with each member possessing its own properties and toxic profile. While certain PCBs appear to be fairly harmless, others have been found to interfere with thyroid hormone metabolism, for example.
In this initial study, which was performed to test the hypothesis that foreign substances are present and quantifiable in amniotic fluid, the researchers searched for a varied but limited group of contaminants.
"We only looked for a selection of contaminants that we had good reason to believe would be there in a large percentage of the population and that were representative of the different methods that we would have to use in order to test for all of the chemicals, natural and synthetic, that we want to study," said Dr. Foster.
Dr. Hughes said that as the studies progress, the researchers will look for several classes of compounds and several different kinds of outcomes. Studying chemicals in amniotic fluid, as well as their possible effects, is complicated by many factors but also offers new opportunities. For example, some compounds that get into a mother's blood tend to persist for days or weeks while others are short-lived, remaining in the system for only hours or days before being excreted. But no one knows what happens if these short-lived compounds are transferred from the mother to the baby who is developing in a closed environment.
"The 'recycling' that occurs within the fetal compartment might provide a good opportunity to look at compounds that in mom's blood would peak and be gone within a few hours or a day or two," said Dr. Hughes. "Instead, the baby will begin excreting and re-ingesting those compounds and there could be a very slow decay. This may make it possible to study short-lived compounds that mom is exposed to because the amniotic fluid may act as a depot. But it also has a different implication: A transient exposure for mom's system may be a lot longer phenomenon in baby."
Looking toward the next phase of their study, the researchers have submitted a grant application to the National Institute of Environmental Health Sciences, which funds research on environment-related disease. They propose to perform analyses of the amniotic fluid of about 1,000 women, mostly from the Los Angeles area but also from Hamilton, Ontario.
"We want two different sites because there is evidence within the literature, both with my own previous studies as well as others, that there are regional differences in exposures," said Dr. Foster. "People on the West Coast typically have higher DDE exposures than people on the East Coast, whereas people on the East Coast may actually have higher PCB exposures."
Prevailing winds carrying pesticides from third-world countries, local industries and even regional dietary factors may play a part in the varying levels of certain chemical exposures. The proposed study will compare results from the Pacific Coast region with those from the manufacturing city of Hamilton in the Great Lakes region.
"One of the things we'll be looking for in addition to man-made chemicals are various naturally occurring dietary chemicals," said Dr. Foster. "Phytoestrogens, for example, are naturally occurring compounds that are present in plants - even plants that are considered nutritious. These compounds interact with the estrogen (female hormone) receptors, and there is a theory that these weak estrogenic compounds could have a negative effect on the development of the male reproductive tract." Again, the first step will be to determine if these compounds reach the amniotic fluid from the mother's diet. If so, do they have any impact?
As part of their ongoing study, the researchers will measure contaminants in maternal blood and umbilical cord samples obtained at birth, and later in breast milk. "In utero exposure is one possible route of contamination. Another is breast feeding, so we will be measuring contaminants in breast milk, as well," said Dr. Foster. "Then we hope to watch the infants for the first year of life to assess neuro-behavioral development."
Theoretically, if contaminants interfere with the normal function of hormones, nervous system development will be impacted, resulting in subtle behavioral deficits that can be measured in babies. Other effects may become apparent later in life but neuro-behavioral changes provide early indications of potential problems resulting from these exposures.
"Short- and long-term follow-up are crucial to testing the hypothesis that man-made chemicals in our environment or even dietary ones have the capacity to interfere with or modulate hormone function and have serious consequences for reproduction, immune function and neuro-behavior," said Dr. Foster. "There's a lot of speculation at present and I think this is the first, thorough, comprehensive study that will try to get at some of the key questions that have not been addressed to date."
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