[Pharmwaste] Estrogen mimics at low doses change how brain cells manage dopamine.

DeBiasi,Deborah dldebiasi at deq.virginia.gov
Wed Mar 4 11:19:18 EST 2009


Estrogen mimics at low doses change how brain cells manage dopamine. 

Mar 03, 2009 

Alyea, RA and CS Watson. 2009. Xenoestrogens alter dopamine transport
and trafficking. Environmental Health Perspectives


Synopsis by Michael D. Laiosa and Wendy Hessler 

For the first time, scientists find that extremely low levels of some
types of environmental estrogens disrupt specialized brain cells and
their ability to regulate brain chemistry. All of the EEs tested changed
the way cells released and reabsorbed dopamine, an important chemical
messenger that governs movement and pleasure.

J.P. Myers 

Warming a polycarbonate baby bottle will increase leaching rates of
bisphenol A. 
In some cases, the responses were stronger when natural estrogens were
mixed with one EE, as exposures most likely occur in people and animals.
These changes may explain how EEs contribute to nervous system diseases,
such as Parkinsons and schizophrenia, that are caused by abnormal
dopamine responses. 
Xenoestrogens and other estrogen mimics are environmental contaminants
that act in ways similar to -- but not exactly like -- natural hormones
such as estrogen. Exposure to these chemicals, particularly at very low
levels, can cause biological outcomes that are not predicted by
traditional experimental procedures.

Xenoestrogens, environmental estrogens, or simply, estrogen mimics are
natural and synthetic compounds found almost everywhere in the
environment. They can contaminate humans, animals, plants, soil, water
and air.

The widely variable substances are present in plastics, PCBs, pesticides
and herbicides, pharmaceutical products, and personal care products.
While the amounts found in these products are often extremely small, the
sheer volume of items containing them makes exposure unavoidable.

People around the planet are exposed to estrogenic compounds on a daily
basis. The constant exposure to low levels may contribute to the
potential to harm human health.

Mounting evidence suggests that exposure to low levels of some EEs --
especially during development -- can cause a number of effects that can
lead to disease and reproductive problems later in life. Effects seen at
lower doses may not occur at higher doses or those at middle doses may
not appear at the low or high exposures tested. These variations --
common with hormones and environmental disrupting compounds -- are known
as nonmonotonic dose responses. 

Prior laboratory studies show estrogen mimics can affect the brain by
altering important signaling chemicals that are regulated by estrogen

Dopamine is one of these specialized brain chemicals. Dopamine helps
brain and nerve cells communicate with one another. Its actions affect
heart/circulation (blood pressure), hormones (reward/pleasure) and nerve
function (movement). Dopamine is considered a neurotransmitter -- a
messenger that carries signals from one nerve cell to another -- and a
hormone -- a molecule that sends control messages to the hormonal

A number of diseases -- including Parkinsons, schizophrenia, attention
deficit disorder and addiction -- are attributed to problems with
dopamine levels in the brain.

What did they do?

The authors tested whether different types of environmental estrogens
(EEs) affect dopamine signaling in rat brain cells. They tested the
compounds by themselves and then combined with estrogen hormones, as
would occur in people and animals. Levels tested were low, similar to
what might be present in the brains of people in the general population.

Cells derived from rat brains, called PC12 cells, were exposed to six
estrogen mimics, five of which are commonly found in the environment.
The compounds represented three major types of EEs: pharmaceuticals
(diethylstilbestrol or DES), plastic additives (BPA, nonylphenol) and
pesticides (DDE, dieldrin and endosulfan).

After exposing the cells, changes in dopamine regulation were measured.
Normally, brain cells release dopamine in response to an electrical or
chemical stimulus. After a period of time, cells reabsorb the dopamine
and store it for the next stimulus and release. The researchers measured
both processes to determine if the estrogen mimics affected release,
uptake or both.

First, the authors measured how dopamine regulation changed through
time. A single, environmentally relevant dose (1nM or 1 part per
billion) of the estrogen mimics was added to cells. The amount of free
dopamine outside of the cells was measured every minute for up to 20

Second, they chose the time point at which dopamine release was maximum
for each of the estrogen mimics and used that time point to ask if the
maximum dopamine release changed using a range of doses for each

Finally, in arguably the most important experiment of the paper, the
authors tested two estrogen mimics in combination with the natural
estrogen hormone 17-beta-estradiol. This experiment replicates what
would most likely happen in people exposed to the chemicals.

Chemicals and normal hormones occur together in organisms. It is the
combination of the two (or more) that may have the most profound (and
realistic) impact on the chemical signals and ultimately, health.

What did they find?

In the first experiment, when compared to controls, treatment with 1 ppb
DES, DDE and dieldrin all caused a relatively slow but steady release of
dopamine, followed by either a leveling off or a reabsorption of
dopamine. Nonylphenol caused a slight release of dopamine, followed by a
rapid and dramatic reabsorption of the dopamine. Interestingly,
bisphenol A caused a biphasic response with two separate cycles of
dopamine release and reabsorption.

In the second experiment, the authors measured changes in dopamine
regulation at a single time point across a range of concentrations. All
of the estrogenic mimics had more activity in the middle concentrations
rather than at either the lower or higher levels (displaying a
non-monotonic dose response curve). Non-monotonic dose response curves
generally follow an inverted U shape, and are commonly seen at extremely
low concentrations of hormones or hormone mimics.

Finally, the authors tested how a dual exposure to either DDE or
bisphenol A and 17-beta-estradiol would affect dopamine regulation. The
insecticide DDE added with the estrogen increased dopamine release
across a range of doses.

Combining estrogen and bisphenol-A affected dopamine regulation in a way
not predicted by the individual responses to either estrogen or
bisphenol A. Specifically, while bisphenol A caused a rapid reabsorption
of dopamine at the lowest dose tested, bisphenol A and estrogen together
mediated dopamine release. Moreover, at an intermediate dose where
neither estrogen nor bisphenol A affected dopamine release, the
combination of the two caused significant dopamine release.

What does it mean?

Each of the five estrogenic chemicals tested affected in different ways
how rat brain cells release and reabsorb dopamine. All acted at very low
levels -- in the parts per billion to parts per trillion range (less
than a teaspoon mixed into an Olympic sized swimming pool).

The responses were not linear across the doses tested; that is they did
not increase steadily as doses increased. The most profound effects were
observed in the middle dose ranges of the EEs tested. The higher levels
did not affect dopamine in the same way. Dose response experiments that
show an inverted U response are referred to as non-monotonic and are
very common with xenoestrogen responses.

The EEs acted through hormone receptors on the surface of the cell
membrane, instead of through receptors inside the nucleus. Surface
receptors are much more sensitive to low levels of exposure and their
effects can take place much more rapidly than receptors inside the
nucleus.  During the past 5 years, the surface receptors have received
considerable attention because of their unique traits that better
explain how some of the effects seen when testing EEs occur.

Finally, when two of the xenoestrogens were tested in combination with
estrogen, the effects on dopamine regulation were different than when
each of the chemicals was tested individually. The results of these
experiments are most likely what is happening in the real world where
humans are exposed to mixtures of contaminants. Moreover, these
contaminants are interacting with and interfering with normal biological
regulatory factors, including, but not limited to, hormones.

If the observations found in this study using brain cells also occur in
the brains of animals and people, the implications are alarming.
Specifically, chemicals common in the products, air, water and food are
potentially capable of profoundly altering brain chemistry at extremely
low levels; levels that most humans and many animals are exposed to on a
daily basis.

Deborah L. DeBiasi 
Email:   dldebiasi at deq.virginia.gov 
WEB site address:  www.deq.virginia.gov 
Virginia Department of Environmental Quality 
Office of Water Permit Programs 
Industrial Pretreatment/Toxics Management Program 
PPCPs, EDCs, and Microconstituents 
Mail:          P.O. Box 1105, Richmond, VA  23218 (NEW!) 
Location:  629 E. Main Street, Richmond, VA  23219 
PH:         804-698-4028 
FAX:      804-698-4032 

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