Hormonally Active Agents (Endocrine Disrupters)
So things are tough for polar bears:
More Than One in a Hundred of Svalbard's Polar Bears are Hermaphroditic
And in Holland:
[Go to Blackboard, Course Documents, and read the News Dutch Children Playing story. ]
(Mentioned in the above articles, PCB's, polychlorinated biphenyls, are very persistent environmental chemicals. Their chief use was as a heat transfer fluid in transformers and large electrical equipment, but they were used in many other applications including paint and plastics. PCB use was banned several years ago. We will discuss them more in a few weeks.)
Before we panic, let's go over the general concept of endocrine function and disruption.SEATAC and I don't have to give up TOFU. Here's an article from a vegititarian website, http://www.vegetus.org/other/endocrine.htm which, although the author is not acknowledged, reads quite true to my ideas on the subject.
Before we go further, let me explain a little about where I am coming from. Endocrine disrupters (Hormonally Active Agents is probably a better phrase) were not a hot topic when I went to school, nor is it found in a neat chapter in my textbooks. If it were a topic I am comfortable or familiar with, I would review some of the secondary literature, then find some tertiary literature on the web to send you to. For the topic of endocrine disrupters and human health, it appears there is much bona fide conflict, even in the secondary literature. It is a hot research area, with lots of current research and publications and I don't have the 80 or 100 hours to do a good review. So below I try to point out what I do know and feel comfortable with, point out some of the major issues, then let you think a little about it, by doing a homework assignment in the secondary literature.
First, let's differentiate the sex of humans and mammals from reptiles and amphibians. (Don't do web searches on those key words unless you have a strong stomach and/or strong sense of humor.) Genotypic sex refers to the number of sex-determinative chromosomes. Eggs have one X chromosome. Sperm have either an X or a Y. Hence the zygote will be XX, and be genotypically female, or XY and be genotypically male. (In this case genotype is sometimes called karyotype, because we are talking about a whole chromosome.) There are genetic aberrations that result in an XXY and so on. These start with an non-disjunction during meiosis, which we mentioned in the section on reproductive toxicology. Some of these genetic hermaphrodites are healthy and some not. From here on we'll assume were are talking about an XX, a genetic female, or XY, a genetic male.
Phenotypic (Genital) sex refers to the expression of the genotype, what we see without a microscope, as well as the biochemical and biological function. Amphibians and fishes, at least some species, are capable of changing their sexual phenotype, in response to environmental stimuli. This typically happens in the egg, or in adolescent stages, but a recent article mentioned some fish that can change in mid-life, reproduce, then change back again. The typical environmental stimuli I have read about are environmental heat and nutrition. That's not my specialty, you're welcome to learn more, but its clear mammals are very different than reptiles and amphibians in that department.
In mammals, phenotypic sex develops in utero. Up to the 5th or 6th week (using human gestation time scale), the embryo tissue that will become the sex organs is largely undifferentiated. In a male, by the 6th week, the seminiferous tubules, Sertoli and Leydig cells are developed and by week 9 there are recognizable testis. The production of testosterone by the Leydig cells is required for further differentiation into a male. The opposite is not the case. The female organs will develop simply in the absence of testosterone. There are other chemicals involved as well. In the embryo are two duct systems, the wolffian, that (generally speaking) develops into the male organs, and the mullerian (put two dots over the "u," if you are fussy or German or both) will develop into the female organs. Besides testosterone, the Sertoli cells of the developing testis secrete "anti-mullerian hormone," which causes the developing mullerian ducts to regress. Sometime after this, the Sertoli cells and Leydig cells regress and are not active again until puberty. During this critical week 6 to 9 period, interference with the production of testosterone, or its action at the cellular receptors, can interfere with development of male sex organs. This can vary from minor changes to production of complete female genital organs, including vagina and uterus, that coexist with ectopic male organs or testis. So, lack of testosterone at the critical period leads to greater or lesser derangement - feminization- of male phenotypic development. I have not found any indication that lack of estrogen will cause the opposite, but I have not researched this in great detail.
So how could a chemical that acts like an estrogen affect this process? The answer is that estrogen is chemically similar to testosterone and could competitively bind to the testosterone receptors. Or there could be a more complicated feedback mechanism. Perhaps estrogen can inhibit GnRF at the developing pituitary. Again, I would need to research this more, but it is clear that estrogen in adult males can either inhibit testosterone production and/or inhibit its action. So, a plausible biological hypothesis exists that estrogen in the genotypically male embryo could inhibit phenotypic male development.
Now the mother's of the developing male conceptus always have estrogen, and estrogen is manufactured by the placenta, so it would seem the genotypically male embryo is somehow immune from the mother's (or his own, it's his placenta) estrogen. Perhaps it does not pass the placental barrier. Estrogen is a small lipophilic molecule, but it rides around in a larger carrier, so let us assume it does not pass the barrier. This brings up the plausible hypothesis that a synthetic chemical that mimicked estrogen, but could get through the placental barrier, could inhibit testosterone in the male embryo. But if this happens, its not likely to happen at the testosterone or an estrogen receptor. DES binds to the estrogen receptors about as well as estradiol (estrogen). If estradiol binds with a potency of 1.0, DES binds with a potency of 1/1.57. For comparison, the xenoestrogen, DDT, binds one eight millionths as well as estradiol. Most environmental estrogens bind the estrogen receptor very poorly.
DES
We know that some children of mothers who took DES, which is a synthetic estrogen,
have sex organ problems and there is evidence that the problems are dose dependent.
Only a small percentage of males whose mothers took high doses of DES had reproductive
tract abnormalities. Male children of mothers who took lower doses were apparently
not effected. For this analysis epidemiology is probably very good science,
because there were so many exposed and so much follow-up associated with compensation,
etc.
PCBs.
There were two incidents of mass food poisonings from PCBs in rice oil, one
in Japan (Yusho) in 1968 and one in Taiwan (Yu-Cheng) in 1979. From the Yu-Cheng
incident women still had levels of PCB contaminants 7 to 190 times higher that
typical controls, 14 years after the incident. There were many ill effects from
this incident, both acute in the mothers and in the male offspring.
Dioxin
Look at Chlorinated Dibenzo-p-dioxins and Dibenzofurans (CDDs/CDFs) and PCB's
on ENVE 651 Special Chemicals
These are a bewildering array of compounds with hundreds of related molecules.
It is convenient, and slightly scientific, to consider the equivalence of the
various molecules. From the above site you will find a link to such a table
of Toxicity Equivalence Factors (TEF's) on pages 35 to 37. Look at the various equivalents,
you will see some are 100%, some 3% and some 0% of dioxin potency. Note this
is based on general toxicity, not endocrine disruption potential.
There is little doubt that extremely high levels of estrogenic chemicals can affect males in utero. But such levels are quite rare. How about the smaller amounts found in the environment. Here it gets complicated. There are many chemicals considered estrogenic, including many that are "natural," some are in tofu, even - worse yet, in coffee. And there are many other chemicals that could affect the endocrine system in adults. Visit this site and just glance at the list of chemicals and what they are alleged to affect. Our Endocrine dozen.
In general, one could argue that most of the environmental estrogenic chemicals are much less potent than estradiol and unlikely to have any effect. On the other hand, one could argue that some of these chlorinated compounds stay in the body much, much longer than the natural product and hence their effect could be much greater.
A very important scientific article appeared in the prestigious journal Science
in 1996, "Synergistic activation of
estrogen receptor with combinations of environmental chemicals." You will
often see this article referenced. It's thesis was that certain combinations
of these environmental endocrine disrupters were capable of synergistic effects.
The article was later withdrawn by the author, after many other labs could not
duplicate his results. A publication with the formal withdrawl of the artricle is found in our Course Documents folder. One of the reasons the article was withdrawn was articles such as this that
debunked it. Look at CIIT article, no need to read it all, it's fairly technical,
but look at Table 1, which looks at binding to the estrogen receptor. CIIT
Here is a paper I want you to read for homework. Issue Paper. The lead author, Steven Safe, is a respected expert on toxicology, risk assessment, and health effects. Safe was one of the authors of the NRC book on the subject. You can get the whole book via that site, but only one page at a time. Here is the executive summary, although you don't have to read it, if you read the issue paper. The National Research Council is one of the arms of the National Academy of Sciences. Their publications are of the highest caliber. However, the reason congress appoints them to investigate a topic is because the topic is controversial.
But the issue goes on. Above you read an article in the popular press about Dutch children playing. I have the article in the Course Documents folder, for your classroom use only. The journal where it is published, Environmental Health Perspectives, is a high quality journal, sponsored by the National Institute of Environmental Health Sciences, a branch of the National Institute of Health. I'm sure it only publishes the very best scientific articles, because that is where I published the capstone article of my thesis. Kidding aside the article has too much statistical or statistical-looking stuff to be very readable, although you are welcome, but I'd like you to read the abstract, introduction, then look at Figure 1.
So, should you drink the water? Or breath the air? It appears to me that certain hormonally active chemicals could effect the environment, in a dose dependent way. High doses can probably have an adverse affect on wildlife. There is no real proof that the small amounts of Hormonally Active Agents we ingest are harmful, although it is clear that large doses, from poisonings, are harmful.