Endocrine Disruptors: A Hot Topic for Neuroendocrinology & Toxicology

[Moonbear]

Now that we have a toxicologist on board (DocToxyn) whose interests complement my own interests in neuroendocrinology, I think it's high time we delve into a true "hot topic," that of endocrine disruptors.

I would love to set this up in a bit of a journal club format, beginning with a general review article that raises some interesting questions, but I can't find one that's freely available online, and I'm not sure if I can attach the PDF file of one without violating copyright policies on the board here.

In the meantime, for those of you who have access to the the journal Toxicology, I've gotten my initial idea for a topic from this article:
Fisher JS 2004 Are all EDC effects mediated via steroid hormone receptors? Toxicology, 205:33-41.

EDC in the title refers to endocrine disrupting chemicals; those compounds that in some way interact with the endocrine system to alter normal functioning. (DocToxyn, feel free to add to this definition if it should be more precise).

The article raises three general mechanisms through which endocrine disruptors may act:
1) interaction with a hormone receptor, either as an agonist or antagonist
2) alteration of hormone biosynthesis
3) alteration of hormone metabolism

The article also points out that there is abundant evidence that endocrine disruptors are a problem for aquatic species, but far less is available to know if these disruptors are also a threat to humans. The inference is that they are indeed important for human health as well, but direct evidence is still lacking.

So, I think I'll open up the topic by partially addressing the first mechanism in the above list. I haven't seen any reports indicating endocrine disruptors interact with protein hormones. I don't know if that's because this is an unlikely action, or because nobody has looked at these hormones. Rather, the focus is generally on thyroid hormones or steroid hormones (i.e., estrogens, androgens), and their receptors.

Thyroid hormones receptors have a different mechanism of action than do steroid hormone receptors, particularly with regard to coactivator and corepressor interactions with the transcriptional complex located at the hormone response element.

Are endocrine disruptors, in the context of hormone interactions, thought to interact primarily with the with receptor to induce a conformational change similar to that of an agonist or antagonist, or are there disruptors that act directly upon cofactor/transcriptional regulators binding to the hormone response element? I haven't come across anything that indicates anyone has looked beyond actions of disruptors as receptor ligands. Perhaps DocToxyn has seen or heard something that isn't published but known among toxicologists about this. Has anyone even looked at interactions beyond that of a ligand-receptor interaction?

I ask, because it's possible someone has looked and found they don't act at that level, so never published it. Or, it's possible nobody has gotten around to looking yet, considering this is a field still in its infancy.

PLease, let's try to keep this thread on-topic. However, by that, I mean general questions necessary to understand the topic are fair game. For example, if a more basic endocrinology tutorial is needed to understand the topic, or if you need further definitions of terminology used, ask away! And, please, feel free to bring in your own interests and expertise to this discussion. That's the whole point! This is a topic that is very interdisciplinary, so we can easily discuss any facet of this, including: endocrinology, toxicology, developmental biology, molecular biology, cancer biology, etc. Bonus points to those who take time to delve into the literature and use peer-reviewed sources as references.

 

[Astronuc]

Is the interest in EDC with respect to understanding harmful (toxological) effects from the environment or for treatment of a physiological anomaly? My interest seems directed toward general mechanism 1 - interaction with hormone receptors.

Would there be any useful to the understanding of contribution to EDC from the study of alpha and beta blockers?

Beta Blocker Drugs - The beta blockers (examples: atenolol, metoprolol, propranolol) act as competitive antagonists at the adrenergic beta receptors. The newer agents tend to be more selective for the cardiac (beta-1) receptors which allows for decreased systemic side effects. (from http://www.rxlist.com/bblock.htm )

which affects Adrenergic Receptors

"Cell-surface proteins that bind epinephrine and/or norepinephrine with high affinity and trigger intracellular changes. The two major classes of adrenergic receptors, alpha and beta, were originally discriminated based on their cellular actions but now are distinguished by their relative affinity for characteristic synthetic ligands. Adrenergic receptors may also be classified according to the subtypes of G-proteins with which they bind; this scheme does not respect the alpha-beta distinction."
from http://fred.hmc.psu.edu/ds/retrieve/fred/meshdescriptor/D011941

Alpha-1 Adrenergic Receptors - A subclass of alpha-adrenergic receptors (RECEPTORS, ADRENERGIC, ALPHA). alpha-1 Adrenergic receptors can be pharmacologically discriminated, e.g., by their high affinity for the agonist phenylephrine and the antagonist prazosin. They are widespread, with clinically important concentrations in the liver, the heart, vascular, intestinal, and genitourinary smooth muscle, and the central and peripheral nervous systems.
from http://fred.hmc.psu.edu/ds/retrieve/fred/meshdescriptor/D011942

Alpha-2 Adrenergic Receptors - A subclass of alpha-adrenergic receptors (RECEPTORS, ADRENERGIC, ALPHA). alpha-2 Adrenergic receptors can be pharmacologically discriminated, e.g., by their high affinity for the agonist clonidine and the antagonist yohimbine. They are found on pancreatic beta cells, platelets, and vascular smooth muscle, as well as both pre- and postsynaptically in the central and peripheral nervous systems.
from http://fred.hmc.psu.edu/ds/retrieve/fred/meshdescriptor/D018341

and then there are Catecholamine Receptors

Cell surface proteins that bind catecholamines with high affinity and trigger intracellular changes which influence the behavior of cells. The catecholamine messengers epinephrine, norepinephrine, and dopamine are synthesized from tyrosine by a common biosynthetic pathway.

The topic seems relevant to a family member who must take medication for treatment of an undiagnosed endocrine anomaly - periodic episodes of high catecholmines levels - which trigger high blood pressure and tachycardia (sometimes doubling or tripling of heart rate).

Also keep this handy - Core Endocrine Laboratory (Penn State)- http://www.hmc.psu.edu/medservices/labs/corendo.htm

 

[Moonbear]

Is the interest in EDC with respect to understanding harmful (toxological) effects from the environment or for treatment of a physiological anomaly? My interest seems directed toward general mechanism 1 - interaction with hormone receptors.

Generally, the term endocrine disruptor is used in relation to environmental contaminants/pollution, not therapeutic/pharmaceutical uses. However, there is a bit of a caveat, in that some of these pharmaceutical compounds are making their way into the environment via wastewater. There are also naturally ocurring endocrine disruptors, such as compounds produced by plants that act on animal hormone receptors. One example would be the compound genistein, which is produced by plants (soybeans), and functions as an estrogen antagonist in mammals.

I'll try to get back to the rest of your post later (I have a bit of a headache coming on at the moment, so am going to cut short my post until I resolve that).

 

[DocToxyn]

Wow, Moonbear, you sure jumped in with both feet on with this one! I'll start with a definition taken from the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC). "An endocrine disruptor is any exogenous chemical substance or mixture that alters the structure or function(s) of the endocrine system and causes adverse effects at the level of the organism, its progeny, or subpopulations of organisms, based on scientific principles, data, weight-of-evidence, and the precautionary principle." See http://www.epa.gov/scipoly/oscpendo/edspoverview/edstac.htm for the full overview of EDSTAC (if you've got a lot of time on your hands). I thought this def. might aid in our discussion of EDCs and please ask if any parts of that def. are confusing/unknown.

Generally, the term endocrine disruptor is used in relation to environmental contaminants/pollution, not therapeutic/pharmaceutical uses.

As Moonbear states most EDCs under investigation are of human origin and now lose in the environment, however the only proven human EDC is a drug prescribed in the 1950s to aid in the reduction of miscarriage, called diethylstilbestrol (DES). Adminstration of this drug caused nothing deletrious in the mothers but when their children began to mature and unusual number of cases of vaginal/cervical/uterine squamous cell carcinoma was found in female offspring. I think other adverse effects were found in male offspring.
An additional note on alterations in thyroid hormone function. PCBs have been demonstrated to cause reductions in serum thyroxine (T4) concentrations by several means including displacement of the T4 from its plasma carrier transthyretin (also called prealbumin). So perhaps this qualifies as one of the non-receptor mediated mechanisms for endocrine disruption that Moonbear is looking for. I'll look for some more as this tread goes along, but I've got a presentation to prepare for so if I don't check in for a few days, don't send the troops.

 

[Dayle Record]

http://www.protectingourhealth.org/press/2003/2003-0714-WP-cadmium.htm

 

[Moonbear]

Wow, Moonbear, you sure jumped in with both feet on with this one!

Ha ha, yes, I guess so. And I probably won't be on for about 2 weeks over the holidays to check in on the thread.

I'll start with a definition taken from the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC).

Great! Thanks for the definition. I think it's much clearer than my "off-the-cuff" definition.

As Moonbear states most EDCs under investigation are of human origin and now lose in the environment, however the only proven human EDC is a drug prescribed in the 1950s to aid in the reduction of miscarriage, called diethylstilbestrol (DES). Adminstration of this drug caused nothing deletrious in the mothers but when their children began to mature and unusual number of cases of vaginal/cervical/uterine squamous cell carcinoma was found in female offspring. I think other adverse effects were found in male offspring.

It may have been the site you quoted, or another, where one of the points made was that a difficult in classifying an endocrine disruptor is determining just when its effects become "adverse." In this case, the organizational effects (long-term developmental effects) are pretty clear-cut, whereas with many instances of probable endocrine disruptors, the effects are more activational (acute effects on a properly developed system). It may be that the effects are less disruptive in humans than in aquatic species, for example, because we can remove ourselves from the source of the contaminant and return to normal function, whereas the aquatic species are continuously exposed with no ability to escape the contaminant in their surroundings.

An additional note on alterations in thyroid hormone function. PCBs have been demonstrated to cause reductions in serum thyroxine (T4) concentrations by several means including displacement of the T4 from its plasma carrier transthyretin (also called prealbumin). So perhaps this qualifies as one of the non-receptor mediated mechanisms for endocrine disruption that Moonbear is looking for.

Yes, I think that would be a good example of a non-receptor mediated action. That's interesting to me for another reason. Transthyretin in the brain is postulated to be a mediator of seasonal reproduction, at least in hamsters (Brian Prendergast and Randy Nelson have published on this in PNAS about a year or two ago; very elegant work). They did some gene chip array studies and transthyretin was one of the few genes that was consistently associated with seasonal/photoperiodic reproductive status. We know that thyroid hormones are required for seasonal reproduction as well (my work and others who preceded me in the Karsch lab). It's much less clear-cut what role thyroid hormones play in reproduction in non-seasonal breeders. Don Pfaff's group has done work on that in mice, and the results are typically unsatisfying as mice do stop having estrous cycles if thyroid function is suppressed, but that could also be due to a general metabolic effect, so it has been difficult to narrow down the effect specifically to thyroid hormones, per se. Does PCB exposure affect reproductive cyclicity, or alter the timing of seasonal breeding? I suppose more is likely to be known about the former than the latter of those two.

 

[DocToxyn]

Does PCB exposure affect reproductive cyclicity, or alter the timing of seasonal breeding? I suppose more is likely to be known about the former than the latter of those two.

Yes, apparently they do. A group out of the Netherlands has consistantly produced nice work on the effects of PCBs and their hydroxylated metabolites on numerous endpoints, in this case developmental and reproductive indices in female offspring exposed in utero. http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=15310862 The metabolite appears to be quite good at extending the estrous cycle, I haven't pulled the whole article so I don't have any potential or proven mechanisms in front of me. Looks to be a nice example of what EDCs can do.

 

[xck]

!wo

Moonbea ,

Thank you so much for such an informative/interesting thread! Food for thoughts.

No time to comment but to say can't wait to re-check the "lefty" thread. (I am back from my moon~honey with the kids/grand-kids.) I think that was the one you/i/me were having phun with

 

[Astronuc]

"A World Wildlife Fund survey indicates that Americans consume about 13 billion liters of bottled water in a year, a number that continues to rise. Joel Schwartz is a professor at the Harvard School of Public Health who specializes in safe drinking water. He spoke with The Health Shows Dr. David Carpenter as part of our occasional series on environmental health."

Among the concerns about drinking water, Schwarz metioned that some plastics used in the bottles release phthalates (e.g. poly terephthalic acid (PTA polymer)). Apparently phthalates are endocrine disrupters, and apparently there is growing evidence that phthalates are effecting male fertility and fetal development.

 

[DocToxyn]

In line with the other thread started by cepheid, did Schwartz mention that the phthalates in water were found in the disposable plastic type bottles found in stores and vending machines or does they also, or predominantly, come from the re-usable nalgene-type bottles?

As evidence of industry reaction to phthalate concerns I know several of my children's toys (the squishy rubber teether kind) are labeled with "NO PHTHALATES" statements.

As an aside, I rotated through Dave Carpenter's lab as part of my graduate work. Nice guy with an excellent ability to communicate with people.

 

[Astronuc]

I believe Schwarz was referring to PET bottles specifically. The program was about quality of drinking water in general, and PET was just one concern. Infiltration of drinking water sources, e.g. by pesticides and agricultural run-off was another, as was the adequacy of testing.

The particular program in audio format can be found at:

http://healthshow.org/topics/environmental/

Look for :

December 2, 2004

Bottled up 6:03 min

A World Wildlife Fund survey indicates that Americans consume about 13 billion liters of bottled water in a year, a number that continues to rise. But is bottled water any safer than what comes out of the tap? Joel Schwartz is a professor at the Harvard School of Public Health who specializes in safe drinking water. He spoke with The Health Shows Dr. David Carpenter as part of our occasional series on environmental health.

 

[Reality_Patrol]

I'm curious about the known human EDC's. Other than the drug doc mentioned, are there any commonly found in water supplies that can be absorbed through the skin? I'm particularly interested in learning if there are any steroid hormone disruptors in this respect.

 

[DocToxyn]

As stated in my previous post, the only proven human EDC is diethylstilbestrol, a pharmaceutical, not an environmental contaminant. Having said that, there are numerous suspected human EDCs, identified by laboratory animal and/or epidemiological studies. They are considered suspected because the weight of evidence in human populations is lacking in some aspects.
To get to your question, depending on what water you are referring to, there may be EDCs present. If you are talking about municipal water you get piped into your house, there is probably very little to no endocrine disrupting activity. This is based mostly on the fact that a majority of these contaminants are not especially water soluble and therefore are at concentrations that are potentially detectable but not biologically relevant, i.e. not toxic. This statement has to be qualified with the fact that not all water sources are going to be the same and thus from area to area, EDC potential may vary, but water supply is not a major route of exposure, especially if you are talking about dermal absorption. As addressed in another thread, very little water, if any, passes through the skin and enters the circulatory system, thus the ability to carry toxicants along with it is not a factor. The most common route of exposure is consumption of contaminated food such as fish or meat and fat-containing products. If you want we can start up a thread, or continue this one, on the effects of steriod hormone receptor disrupting chemicals in wildlife, much more evidence there and some interesting effects too.

 

[Moonbear]

If you want we can start up a thread, or continue this one, on the effects of steriod hormone receptor disrupting chemicals in wildlife, much more evidence there and some interesting effects too.

Feel free to continue it in this thread. Since the original idea didn't exactly take-off as I hoped, might as well shift it as interests dictate.

 

[Reality_Patrol]

Doc, yes I'm interested in learning what's known about EDC's in wildlife. It's a useful starting point at least. Also, could you share a list of "suspected" human EDC's?

 

[DocToxyn]

I think the best way to address this is to provide a few articles on this topic to give you an introduction to the topic and serve as a starting off point as you delve further into things that interest you. If you don't have immediate access to these, check your library and they should be able to get them via inter-library loan, or I can come up with others or get them to you somehow. Either way they are a good place to start and please post any questions you have along the way.

Schantz and Widholm: Cognitive effects of endocrine-disrupting chemicals in animals. Environmental Health Perspectives 2001, 109 (12); 1197+.

Zala and Penn: Animal behaviours induced by chemical pollution. Animal Behaviour 2004, 68 (4); 649+.

Clotfelter et al.: The role of animal behaviour in the study of endocrine-disrupting chemicals. Animal Behaviour 2004, 68 (4); 665+.

EDCs, Brain and Behavior (entire journal): Environmental Health Perspectives 2002, vol 110 suppl. 3.

Lathers: Endocrine disruptors: a new scientific role for clinical pharmacologists? Impact on human health, wildlife, and the environment. Journal of Clinical Pharmacology 2002 vol. 42 (1):7+.

If that's not enough there are plenty more and I do realize the list may be slanted toward brain and behavior, but that's my particular subject (or bias ) and there's a strong argument for very subtle effects to be detected by examining such endpoints.

As far as a list of "suspected human EDCs", that's tough. The US EPAs Endocrine Disruptor Screening and Testing Advisory Committee (http://www.epa.gov/scipoly/oscpendo/edspoverview/edstac.htm ) has proposed to review over 15,000 chemicals for endocrine disrupting ability, European Union has come together on about 600 suspected EDCs, other agencies have their own lists. The problem is that EDCs are relatively new in toxicology and there is still no internationally accepted definition of what an EDC is. The short list of chemicals which I can come up with that are considered to be EDCs include: polyhalogenated aromatic hydrocarbons (PCBs, dioxin, benzo[a]pyrene), certain metals (tributyltin), many, many pesticides, fungicides, herbicides, bisphenol A, pthalates, synthetic hormones, nonylphenols...the list goes on and on.