Many industrial and environmental chemicals mimic, antagonize or indirectly alter the activity of steroid hormones. Classes of herbicides, fungicides, insecticides, nematocides, and industrial chemicals, such as dioxins, polychlorinated biphenyls (PCBs) and other chlorinated chemicals, such as octylphenol or bisphenol A, may be weakly estrogenic, antiestrogenic, antiandrogenic, or may affect thyroid hormone functioning. These chemicals, known as "endocrine disruptors", may bind to estrogen or other hormone receptors, either imitating the action of the hormone or blocking its activity. By interfering with the normal functioning of receptors, these chemicals can perturb the growth and development in the exposed organism. Other chemicals, i.e. some phthalate esters, glycol ethers and "peroxisome proliferators," appear to be endocrine disruptors by indirectly altering steroid hormone activity at a post receptor site of action.
Many recently published studies indicate that various species of wildlife (birds, reptiles, etc.) have been exposed to endocrine-disrupting chemicals in their habitats and are showing signs of changes in reproductive function and behavior. Taken together, the wildlife data paint a picture of harmful pollution effects on natural habitats that may eventually lead to the decline of various species of animals. Morphological changes in sexual organs, changes in mating behavior and offspring rearing behaviors, smaller litter sizes, and evidence of declines in reproductive capacity all signal alarm for these affected animal populations.
In addition to these natural "sentinel type" studies there are also extensive studies using rodent models showing similar toxicity to the reproductive, immune and nervous systems as a result of prenatal exposures to endocrine disruptors such as tetrachlorodibenzo-p-dioxin (TCDD), Diethylstilbestrol (DES, an estrogenic therapeutic) and various pesticides and industrial chemicals.
In humans there is evidence of adverse reproductive outcomes in the offspring of DES-treated mothers and in offspring of the PCB exposure at Yu-Cheng. Increased concentrations of DDE in breast milk has also been correlated to a decreased period of lactation. There have also been reports of declining sperm quality and increased testicular cancer over the last several decades. The causative agent(s) are unknown but proposed to be environmental estrogens. At this point there is considerable uncertainty regarding the causal relationship between the presence of specific environmental chemicals and subsequent adverse effects in humans. Because of the startling findings in wildlife studies, and suggestions in the scientific literature on cancer and reproductive effects in humans, it is important to move rapidly to understand the impact of exposure to these chemicals on human health.
To answer this important public health question, research supportedy the NIEHS is directed towards defining models and methods for detecting these endocrine disrupting chemicals; determine their efficacy site and mechanism of action in model systems in order to determine cause and effect; the extrapolation of this information to human health and specific studies using humans in free living conditions exposed to low levels of chemicals in the environment.
Polychlorinated biphenyl (PCBs) are synthetic lipid-like compounds once used as insulating materials in transformers and capacitors (banned in US in 1970s) that are persistent in the environment. Indeed, residues of these compounds can be measured in people around the world. Exposure currently is via eating contaminated fish. Jacobson (R01ES05843) has been following a population of children born to mothers who consumed large amounts of fish and thereby had exposure to PCBs during pregnancy. They measured PCB levels in umbilical cord blood and maternal blood and milk samples and correlated these values with behavior, achievement and reading mastery tests (when appropriate). They showed that in utero exposure to PCBs was associated with poorer short term memory during infancy and childhood and deficits in intellectual ability (6.2 deficits in IQ), short and long term memory and focused and sustained attention in school age children (to 11 yrs of age).
Since PCB exposure has been linked to reduced concentrations of thyroid hormones (needed to stimulate neuronal and glial proliferation and differentiation) the NIEHS is funding two epidemiological studies (Jacobson; R01ES08327 and Hertz-Picciotto; R01ES08316) to confirm and determine the role of thyroid hormone alterations in the PCB neurotoxicity. Similarly, Zoeller (R01ESO8333) and Peterson (R01ES06806) are using animal studies to examine the effects of PCB exposure during development. Zoeller has shown that PCBs can exert permanent effects on the thyroid hormones and brain development. Developmental exposure to a commercial mixture of PCBs causes elevation of serum thyroid hormones and a decrease in thyroid hormone receptor levels in the hippocampus, the area responsible for specific kinds of learning. This combination of animal- mechanistic studies with human epidemiologic studies should provide the data needed to protect the public health from this type of endocrine disruptors.
Bisphenol A, one of the top 50 chemicals produced in the U.S. (71.6 billion pounds) is a monomer utilized in the manufacture of epoxy resins that are used to line metal food and drink cans as well as in dental sealants. Studies by Adler (R01ES08301), vom Saal (R01ES08293) and Murray (R01ES08314) have shown that bisphenol A also has weak estrogenic activity in vitro and in animal studies. Vom Saal has shown that Bisphenol A at maternal doses of 2 or 20 g/kg, in the range of human exposures, stimulated enlargement of the prostates (20-30%) of male mice, an effect that persisted into adulthood. The public health significance of these data is that the enlarged prostates may lead to prostate cancer - a form of a cancer that has been increasing in the human population.
The Bisphenol A exposure during development also significantly reduced daily sperm production per gram of adult testis, increased preputial gland weight, all of which could affect fertility. Of additional importance is that these effects occurred at low relevant concentrations, i.e. concentrations that humans could be exposed to, and are concentrations that are orders of magnitude lower than the NOEL (no observed effect level) estimated for bisphenol A from typical high dose toxicity studies. Thus, vom Saal has shown that testing of endocrine disrupting chemicals must be done over a wide range of concentrations down to relevant exposure paradigms and not only high doses with linear extrapolation to low relevant doses.
DES, (diethylstilbestrol, a synthetic estrogen) has been used as a model endocrine disrupting agent concentrating on its toxicity to the reproductive tract including cancers. Offspring of DES-treated mothers have an increased risk for development of vaginal and cervical cancers and also autoimmune disorders. It is now clear that DES (Ahmed; R01ES08043), and by extrapolation presumably other environmental chemicals with estrogenic activity, is profoundly toxic to the developing immune system of mice - toxicity that could result in autoimmune problems. In mice exposed during development to DES at doses lower than human exposure that lead to toxicity, exposure led to profound effects on the immune system in young mice. There was a decreased number of lymphocytes and a small thymus gland. In addition, lymphocytes from DES exposed mice express low levels of important cell markers needed for proper functioning, have defects in early activation pathways and proliferate poorly in response to normal lymphocyte activation pathways. These results not only expand our database of toxicity of endocrine disruptors in animals but also suggest biomarkers that may be useful in human studies to finally delineate if indeed estrogenic chemicals in the environment are detrimental to human health.
Several reports in the scientific literature have demonstrated that binary mixtures of some weakly estrogenic organochlorine pesticides and hydroxy-PCBs gave synergistic responses. Investigators at Texas A&M University, in collaboration with scientists at NIEHS, Duke University and the Chemical Industry Institute of Toxicology, studied binary mixtures of organochlorines (toxaphene, dieldrin, endosulfan and chlordane) (Safe; P42ES04917). Using several in vivo and in vitro estrogen- responsive bioassays, these investigators found that the compounds were weakly estrogenic when tested individually and their binary mixtures gave only additive effects as opposed to the synergistic effects reported by others.
source: http://www.niehs.nih.gov/dert/annrpt.htm
Mindfully.org note: notations such as "vom Saal (R01ES08293)" are the names of the recipients and their NIEHS research grant numbers.
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