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PCBs & Serotonin in the Brain
A Potential Cause of Depression and Other Emotional
Disorders
Introduction
Serotonin is a chemical neurotransmitter which
is affected by PCB exposures, as shown by the eight studies listed below.
Serotonin is involved in our body’s temperature regulation, sensory perception,
and mood control. It plays a major role in emotional behavioral disorders
such as severe depression, anxiety, suicide, impulsive behavior, and aggression.
Several prescription drugs, including the well-known Prozac and Paxil,
are used to treat depression because they increase serotonin levels in
the brain.
Could widespread world contamination with PCBs be a contributing
cause to emotional disorders, and could local residents in Northeast Wisconsin
face even higher risks?
About 15 percent of the U.S. adult population uses some
form of mental health service in any year, according to the U.S. Surgeon
General’s office. However, nearly half of all Americans who have a severe
mental illness fail to seek treatment, which means the true number of Americans
suffering from mental illness could be about 30% (… roughly 88,000,000
Americans.) A large portion are suffering from clinical depression
or other serious mood disorders, which could be linked to abnormal serotonin
levels in the brain. The annual economic and social costs of these disorders
are extremely high when such a large population is impacted.
One disturbing aspect of the following studies is that
even lower-chlorinated PCBs are toxic at relatively low doses, despite
frequent claims by experts and agency regulators that these are "less toxic"
or "non toxic" forms of PCBs. It may be that future research will discover
that each of the 209 kinds of PCBs is toxic in its own way.
These lighter-weight PCBs are more likely to mix with
water and volatilize (evaporate) into the air, so they’re more transient.
However, this ability to move around allows more people to be exposed through
breathing, skin contact and drinking, in addition to food consumption.
These lighter forms of PCBs also travel long distance by air, to concentrate
in cold regions and high altitudes where people and wildlife are at risk
far from the PCB sources. As the heavier, higher-chlorinated forms of PCBs
gradually break down (through de-chlorination) over time they turn into
the lighter-weight lower-chlorinated PCBs, which changes the nature of
their toxicity.
Links to More Information
The
Neurobiology of Depression --- A feature article in Scientific American
(an excellent explanation of the role of serotonin in
depression) --- June 1998; by Nemeroff; 8 pages --- accessible now
through their online Archives search.
The Center for
Mental Health Services
FIRST
SURGEON GENERAL'S REPORT ON MENTAL HEALTH, 1999
Dr.
Ivan's DEPRESSION CENTRAL
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Summary of Study Results
Keep in mind that not all studies are equal in size or
quality. Some examine the effects of old PCB commercial mixtures (which
had variable composition), or just one or two individual types of PCBs
(out of 209 possible.) This accounts for some of the varying results. It’s
clear that not all PCBs have the same effects. Some studies used high and
some used low doses of PCBs.
(Each entry represents one finding in a study. Some
studies had multiple findings.)
-
PCBs significantly alter serotonin, with likely affects on
behavior and locomotor activity
-
PCBs move into the brain by way of a saturable transport
system
-
neurochemical changes were evident following PCB exposure
in adulthood
-
findings are reversible and appear to be dependent on the
presence of PCBs in the nervous tissue.
-
PCBs have long-lasting effects on dopamine and serotonin
producing processes on offspring of PCB exposed mothers
-
PCBs affect dopamine and serotonin processes
-
PCBs induce serotonin release in human cells
-
some PCBs show synergistic effects (more than additive) when
more than one PCB type is present
-
PCBs specifically target the serotonergic nervous system
during embryonic development
-
various PCB types induce serotonin-release, at different
levels depending on the number and placement of chlorines on the PCB molecule
-
PCB exposure results in alterations in serotonin metabolism
but not dopamine metabolism in offspring of PCB exposed mothers, which
differs from PCB induced neurotoxicity in adult animals
-
serotonin metabolism was altered in adult offspring in a
complex fashion
-
prominent neurochemical alterations were found in the lateral
olfactory tract, prefrontal cortex and the brainstem.
-
neurochemical data could be interpreted as the result of
a primary lesion in the brainstem early in development.
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Studies Linking PCBs and Changes
in Serotonin
This is not a complete list of all studies on this topic.
For more studies,
visit the TOXNET
database operated by the National Library of Medicine (the source of these
abstracts).
Study #1 |
 |
-
PCBs significantly alter serotonin, with likely affects on
behavior and locomotor activity
-
PCBs move into the brain by way of a saturable transport
system
-
neurochemical changes were evident following PCB exposure
in adulthood
-
findings are reversible and appear to be dependent on the
presence of PCBs in the nervous tissue.
Adult male Wistar derived rats were given single oral doses
of corn oil or polychlorinated-biphenyls (PCBs) in corn oil, at levels
calculated to yield a final dose of either 500 or 1000 milligrams of total
PCBs per kilogram of body weight. Levels of PCBs were consistently higher
in brains of animals exposed at the higher dose level. Levels of PCBs in
the brains of animals receiving half the dose were higher than half the
level of PCBs in brains of animals receiving the full dose, and the authors
conclude that PCBs move into the brain by way of a saturable transport
system. The single dose was able to significantly alter serotonin
(5-HT) concentrations and metabolism in most of the brain areas that were
examined. This indicated that neurochemical changes were evident following
PCB exposure in the adult animal. While PCB levels in the brain regions
were able to be determined, it was not possible in most sections to correlate
changes in 5-HT concentrations or in 5-hydroxyindole-acetic-acid to 5-HT
ratios with concentration changes of PCBs. The magnitude of the changes
induced in 5-HT concentrations by PCB exposure are expected to cause changes
in behavior, with particular attention to locomotor activity, of the animal
so treated. The authors state that these findings are also reversible and
appear to be dependent on the presence of PCBs in the nervous tissue. (Seegal
et al, 1986)
Study #2
-
PCBs have long-lasting effects on dopamine and serotonin
producing processes on offspring of PCB exposed mothers
-
study used PCB 77
In the present experiment, drug discrimination was examined
in rats after maternal exposure to 3,3',4,4'-tetrachlorobiphenyl (PCB 77)
using apomorphine (APO) as the training drug at a dose reported to act
on dopamine D2 receptors. A group with maternal exposure to 6n-propyl-2-thiouracil
(PTU) was included as a positive control for effects induced by PCB 77
on thyroid hormones. On gestational day (GD) 19 reduced levels of free
and total thyroxine (FT4, TT4) and free triiodothyronine (FT3) were detected
in dams exposed to PCB 77 or PTU. In the offspring decreases in levels
of FT4 and TT4 were found in both treated groups on postnatal day (PND)
21, while reductions of FT3 were observed only in the PTU group. PTU-treated
rats needed more daily sessions for successful discrimination between apomorphine
and saline. There were no differences between groups in generalization
tests and sessions with the D2/D3 agonist quinpirole, the D2 antagonist
haloperidol plus APO, or with the GABAergic drug pentobarbital and only
minor differences in sessions with the D1 agonist SKF-38393. Differences
between controls and groups exposed to PCB 77 or PTU were detected in a
blocking test using the mixed serotonin 5-HT1A agonist and partial D2 antagonist
buspirone. This outcome suggests long-lasting effects by developmental
exposure to PCB 77 on the interaction between dopaminergic and
serotonergic
processes which may be mediated by effects on thyroid hormone levels. (Lilienthal
et al, 1997)
Study #3
-
PCBs affect dopamine and serotonin processes
-
study used PCBs 77 and 47
Previous experiments indicated that after treatment with
the dopamine D2 receptor blocker haloperidol the resulting catalepsy was
more pronounced in rats with maternal exposure to the coplanar PCB 3,3',4,4'-tetrachlorobiphenyl
(3,4-TCB) than in rats exposed to the ortho-chlorinated congener 2,4-TCB
and controls. In the present experiment drug discrimination in a standard
two-lever task was examined in rats maternally exposed to 3,4-TCB using
apomorphine at a dose reported to act on D2 receptors. Since impairment
of thyroid function is suggested to mediate neurobehavioural effects of
PCBs a group with perinatal exposure to propylthiouracil (PTU) was included
as a positive control. PTU-treated rats needed more daily sessions than
controls to reach the criterion for successful discrimination between apomorphine
and saline. Differences between controls and groups exposed to 3,4-TCB
or PTU were detected in a blocking test using the serotonin 5-HT1A agonist
buspirone which is also a partial antagonist to the D2 receptor. This outcome
suggests an effect of 3,4-TCB on the interaction between dopaminergic
and serotonergic processes. (Lilienthal el al, 1996)
Study #4
-
PCBs induce serotonin release in human cells
-
some PCBs show synergistic effects (more than additive) when
more than one PCB type is present
-
study used PCB 11, 40, 77, and 101
Incubation of human platelets with polychlorinated biphenyls
(PCB) induced and modulated cellular responses to a different degree. 3,3',4,4'-tetrachlorobiphenyl
(TCB) was a more potent inducer of platelet aggregation, serotonin release
and 12-HETE generation compared to the other PCB (2,2',3,3'-TCB, 3,3'-dichlorobiphenyl
(DCB), 2,2',4,5,5'-pentachlorobiphenyl(PCB)). 3,3',4,4'-TCB showed synergistic
effects, in combination with other PCB, such as an enhanced formation
of 12-HETE, when 3,3'-DCB and 2,2',3,3'-TCB were applied simultaneously.
The combined incubation of platelets with PCB and sodium fluoride (NaF),
an activator of G-proteins, resulted in a synergistic 12-HETE generation
compared to stimulation with NaF or PCB alone. Furthermore, when platelets
were incubated with the PCB the enzymatic steps controlling the metabolism
of the platelet-activating factor (PAF) were modulated. A direct relationship
between the extent of platelet activation and the chloro-substitut (Raulf
et al, 1991)
Study #5
-
PCBs specifically target the serotonergic nervous system
during embryonic development
-
study used PCB commercial mixture Aroclor 1254
Polychlorinated biphenyls (PCBs) are classified as persistent
organic contaminants that accumulate to toxic levels in the food chain
and pose a major threat to human health. Children exposed to PCBs in utero
have an increased risk for developmental deficits and learning delays.
Using Spisula as an experimental model we have shown that PCBs specifically
target the serotonergic nervous system during embryonic development.
Embryos were exposed to 1, 10 or 100 ppm of Aroclor 1254 or an acetone
vehicle control for 24, 48 and 72 hours, then fixed and labeled with anti-serotonin
and a rhodamine labeled secondary antibody. Confocal microscopy reveals
that the serotonergic cell bodies in the cerebropleural ganglion (CPG)
are affected by the presence of 100 ppm Aroclor 1254. At 24 hours post-fertilization
there is no significant difference in the size of the CPG or in the amount
of serotonin present in the untreated and treated embryos. At 48 hours
post-fertilization the CPG of embryos treated with 100 ppm Aroclor 1254
are significantly smaller than the untreated and control embryos (p = 5
x l0(-6)). The amount of serotonin present is not significantly different
among the experimental groups. At 72 hours there is a significant decrease
in both the size of the CPG and in the amount of serotonin present (p =
0.01 and 0.0005, respectively) in embryos treated with 100 ppm Aroclor
1254 when compared to the control group. Our results suggest that embryonic
exposure to environmentally relevant amounts of Aroclor 1254 leads to alterations
in the developing nervous system. (Kreiling et al, 2000)
Study #6
-
various PCB types induce serotonin-release, at different
levels depending on the number and placement of chlorines on the PCB molecule
The effects of various isomers of polychlorinated biphenyls
(PCBs) to induce and modulate the generation of lipoxygenase products from
different human cells under noncytotoxic conditions were studied. Various
PCB-congeners were potent inducers of platelet aggregation, serotonin-release
and 12-HETE-generation. Furthermore, when platelets were incubated with
the PCBs the enzymatic steps controlling the metabolism of platelet activating
factor (PAF) were modulated. Stimulation of human PMNs with the PCBs did
not induce generation of leukotrienes by themselves, but modulated the
subsequent opsonized zymosan or sodium fluoride (NaF) induced leukotriene
generation. With regard to lymphocyte function (e.g. proliferation, expression
of CD23 and CD25) the 3,3',4,4',-TCB isomere showed differential effects.
Our data show a direct relationship between the extent of cell stimulation
and chlorosubstitution-pattern of the PCBs. (Raulf et al, 1991)
Study #7
-
PCB exposure results in alterations in serotonin metabolism
but not dopamine metabolism in offspring of PCB exposed mothers, which
differs from PCB induced neurotoxicity in adult animals
-
study used PCB commercial mixture Aroclor 1254
The effect of maternal exposure to the commercial polychlorinated
biphenyl (PCB) Aroclor-1254 (Aroclor) on regional brain serotonin levels
in weanling and young adult rats was investigated. Pregnant Wistar-WU-rats
received daily oral doses by gavage of 0, 5, or 25mg/kg Aroclor from day
ten to 16 of gestation. Rats were sacrificed on day 21 or 90 postnatally.
Brain region levels of neurotransmitters were determined by high pressure
liquid chromatography. Neither dose of Aroclor affected maternal weight,
number of offspring, or postnatal mortality. Alterations in 5-hydroxytryptamine
(5HT or serotonin) metabolism occurred in the lateral olfactory
tract (LOT), prefrontal cortex, and striatum and dorsal hippocampus of
the offspring. The effects were characterized by increased concentrations
of hydroxyindole-acetic-acid (5HIAA), the principal metabolite of 5HT,
and increased 5HIAA/5HT ratios. The increases in 5HIAA levels and 5HIAA/5HT
ratios occurred largely on postnatal day 90 in the LOT and prefrontal cortex,
whereas the striatum and hippocampus showed only increases in 5HIAA. On
postnatal day 21, slight increases in 5HIAA levels occurred in the LOT
at the 25mg/kg dose. Other biogenic amines, norepinephrine, dopamine,
and homovanillic acid, were unaffected by maternal PCB exposure. The authors
conclude that exposure to Aroclor results in alterations in 5HT metabolism
but not dopamine metabolism, which differs from Aroclor induced neurotoxicity
in adult animals. (Morse et al, 1996)
Study #8
-
serotonin metabolism was altered in adult offspring in a
complex fashion
-
prominent neurochemical alterations were found in the lateral
olfactory tract, prefrontal cortex and the brainstem.
-
neurochemical data could be interpreted as the result of
a primary lesion in the brainstem early in development.
-
study used PCB commercial mixture Aroclor 1254
The underlying mechanisms of PCB-induced developmental neurotoxicity
are unclear, although it is a plausible hypothesis that pre- or postnatal
PCB exposure indirectly affects brain development by transiently reducing
the amount of thyroid hormone in the brain. We therefore examined the effects
of pre- and postnatal PCB exposure on thyroid hormone levels in the plasma
and brain of developing rats, the mechanisms involved in altered thyroid
hormone homeostasis and which brain regions and cell types were affected.
The results indicate that when pregnant rats are exposed to Aroclor 1254,
there is a substantial accumulation of the hydroxylated PCB metabolite,
2,4,5,3',4'-pentachloro-4-biphenylol (4-OH-pentaCB) in the fetal plasma
and brain. The accumulation of 4-OH-pentaCB in the plasma is probably responsible
for the dramatic reductions in plasma and brain T4 concentrations by blocking
the transport of thyroid hormone to the fetus. However, the fetal brain
may be able to compensate for the decreases in T4, by increasing the conversion
of T4 to T3. Despite the lack of an observed effect of maternal PCB exposure
on brain T3 levels in the offspring, the levels of a neurotypic protein
(synaptophysin) and a glial protein (glial fibrillary acidic protein, GFAP)
as well as serotonin metabolism were altered in the brain of adult
offspring in a complex fashion. The most prominent neurochemical alterations
were found in the lateral olfactory tract, prefrontal cortex and the brainstem.
The neurochemical data could be interpreted as the result of a primary
lesion in the brainstem early in development. (Morse et al, 1995).
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Upcoming Study
THOMAS PM. MECHANISMS OF REPRODUCTIVE NEUROENDOCRINE TOXICITY
Crisp Data Base National Institutes Of Health. Author Address: UNIV. OF
TEXAS AT AUSTIN, 750 CHANNELVIEW DRIVE, PORT ARANSAS, TX 78373-5015
The actions of representatives of two classes or reproductive
toxicants, a heavy metal (lead), and a polychlorinated biphenyl mixture
(Aroclor 1254), on the serotonin (5-HT)-gonadotropin releasing hormone
(GnRH)-gonadotropin (GtH) neuroendocrine pathway controlling GtH secretion
will be investigated in an extensive teleost model of reproductive endocrine
function and endocrine toxicology, the Atlantic croaker (Micropogonias
undulatus). Currently, the sites and mechanisms of xenobiotic interference
with the reproductive neuroendocrine pathway are poorly understood. Therefore,
the following overall hypothesis will be tested: that lead and Aroclor
1254 alter GtH secretion by disrupting different components of the 5-HT-GnRH-GtH
stimulatory neuroendocrine pathway controlling reproduction. Preliminary
results in croaker and other vertebrate species suggest that Aroclor 1254
acts primarily on the 5- HT component, whereas lead may act on the GnRH
and GtH (pituitary) components of the neuroendocrine system. Therefore
all three components of the system will be investigated using multiple
indices of neuroendocrine function after exposure to the model compounds.
Parallel studies will be conducted with several neuropharmacological agents
which either mimic the xenobiotic-induced disturbances or reverse them.
Parallel disturbances of GtH secretion will be interpreted as evidence
that the model compound has the same primary site of action as the neuropharmacological
agent. Specific objectives are to: 1. Compare the actions of Aroclor 1254
and the neuropharmacological agents on separate components of the 5-HT-GnRH-GtH
pathway and GtH secretion; correlate PCB accumulation with the degree of
neuroendocrine disruption. 2. Compare the actions of lead and the neuropharmacological
agents on separate components of the 5-HT-GnRH-GtH pathway and GtH secretion;
correlate lead accumulation with the degree of neuroendocrine disruption.
The proposed research on the effects of the model compounds on components
of a major neuroendocrine system controlling reproduction, the 5-HT-GnRH-GtH
pathway, should provide valuable new information on the mechanisms and
targets of reproductive neuroendocrine disruption by xenobiotics in vertebrates.
The further evaluation of this non- mammalian model of reproductive neuroendocrine
toxicology will facilitate comparisons of the mechanisms of endocrine disruption
by chemicals among a broader range of vertebrates and thus provide a more
accurate prediction of their long term reproductive hazards to humans.
In addition this teleost model should be valuable as a sentinel of pollution
damage to aquatic ecosystems and the potential reproductive hazards of
environmental contamination to human populations.
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References
Kreiling JA, Stephens RE, Reinisch CL. Polychlorinated biphenyls target
serotonergic neuronal development in Spisula solidissima (surf clam) embryos.
FASEB J 2000 May;14(8):A1476. Author Address: Marine Biological Laboratory,
Woods Hole, MA.
Lilienthal H, Weinand-Harer A, Winneke G. Drug discrimination in rats
following maternal exposure to a coplanar PCB or propylthiouracil. Toxicologist
1996 Mar;30(1 Pt 2):227. Author Address: Medical Institute of Environmental
Hygiene, Dusseldorf, Germany.
Lilienthal H, Weinand-Harer A, Winterhoff H, Winneke G. Effects of maternal
exposure to 3,3',4,4'-tetrachlorobiphenyl or propylthiouracil in rats trained
to discriminate apomorphine from saline. Toxicol Appl Pharmacol 1997 Sep;146(1):162-9
Author Address: Department of Biological Psychology, Heinrich-Heine-University,
Auf'm Hennekamp 50, Duesseldorf, D-40225, Germany.
Morse DC, Brouwer A, van den Berg KJ, Seegal RF. Prenatal exposure to
polychlorobiphenyls: PCB metabolism, thyroid hormone homeostasis and brain
development in the rat. Neurotoxicology 1995 Fall;16(3):535. Author Address:
Department of Toxicology, Agricultural University, Wageningen, The Netherlands.
Morse DC, Seegal RF, Borsch KO, Brouwer A. Long-Term Alterations in
Regional Brain Serotonin Metabolism Following Maternal Polychlorinated
Biphenyl Exposure in the Rat. Neurotoxicology, Vol. 17, Nos. 3/4, pages
631-638, 38 references, 1996
RAULF M, KOENIG W. In vitro effects of polychlorinated biphenyls on
human platelets. IMMUNOLOGY; 72 (2). 1991. 287-291. Author Address: Lehstruhl
fuer Med. Mikrobiologie Immunologie, Arbeisgruppe Infectabwehrmechanismen,
Ruhr-Universitaet Bochum, Universitaetsstr. 150 MA 01/240, 4630 Bochum
1, Germany.
RAULF M, KOENIG W. Effects of polychlorinated biphenyls (PCB) on cellular
functions in vitro. ALLERGOLOGIE; 14 (9). 1991. 352-359. Author Address:
Berufsgenossenschaftliches Forschungsinstitut Arbeitsmedizin, Inst. Ruhr-Univ.
Bochum, Gilsingstrasse 14, W-4630 Bochum 1.
Seegal RF, Brosch KO, Bush B. Regional Alterations in Serotonin Metabolism
Induced by Oral Exposure of Rats to Polychlorinated Biphenyls. Neurotoxicology,
Vol. 7, No. 1, pages 155-166, 30 references, 1986
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