of Thyroid Hormones
of xenobiotics with thyroid hormone receptors and the effect on
thyroid hormone levels
A, TM Meerts, JJ van Zanden, EAC Luijks, I van Leeuwen-Bol, G Marsh,
E Jakobsson , Å Bergman and A Brouwer. 2000. Potent Competitive
Interactions of Some Brominated Flame Retardants and Related Compounds
with Human Transthyretin in Vitro. Toxicological
Sciences 56: 95-104.
flame retardants are commonly used in a wide variety of products
and processes, including plastics, paints, electronic parts and
is now revealing that contamination by several types of these compounds
is extraordinarily widespread. Ilonka et al. observe that
the chemical structures of some flame retardants is quite similar
to the structure of thyroxine (T4), a human thyroid hormone. They
conduct competitive binding experiments to measure the potency of
brominated flame retardants to intefere with thyroid hormone function.
Their results "indicate that brominated flame retardants,
especially the brominated phenols and tetrabromobisphenol A, are
very potent competitors for T4 binding to human transthyretin in
vitro and may have effects on thyroid hormone homeostasis in vivo
comparable to the thyroid-disrupting effects of PCBs."
AO, K Kow, J Chen and JA McLachlan. 1999. Potential Mechanisms
of Thyroid Disruption in Humans: Interaction of Organochlorine Compounds
with Thyroid Receptor, Transthyretin, and Thyroid-binding Globulin
Environmental Health Perspectives 107: 273-278
compounds are well known to alter the thyroid hormone system by
decreasing serum thyroid hormone levels in several species including
humans. Cheek et al. examine the ability of PCBs, DDT and its metabolites,
and several organochlorine pesticides (acetochlor, alachlor and
methoprene) to bind to human thyroid hormone receptors and thyroid
hormone transport proteins. Hydroxylated organochlorine have a high
affinity to thyroid transport proteins, but their affinity to thyroid
receptors was unknown prior to this study. Out of all the compounds,
only hydroxylated PCBs bound to the human thyroid receptor, but
had a greater binding affinity to the thyroid transport protein,
transthyretin. These findings help to narrow the scope of the investigation
into the mechanism by which organochlorine compounds alter the thyroid
N, W Karmaus, H Kruse and J Witten. 1999. Exposure to Polychlorinated
Biphenyls and Levels of Thyroid Hormones in Children Environmental
Health Perspectives 107(10) October
et al. present findings on the impact of living near a toxic
incineration plant with license to burn PCB contaminated material
on thyroid hormone levels in children. The study reports a significant
positive association between the PCB congener 118 and thyroid stimulating
hormone, and a significant negative correlation between five PCB
congeners (138, 153, 180, 183 and 187) to the thyroid hormone, triiodothyronine
(unbound to a protein) in children between 7-9 years of age. This
thyroid hormone makes up about 9% of the thyroid hormones secreted
from the thyroid. The study found no significant correlation with
PCB and thyroxine, which accounts for 90% of the thyroid hormones.
However, they did report an association between cadmium and increasing
levels of thyroid stimulating hormone and decreasing levels of thyroxine.
authors examined two areas north and southeast of the region in
immediate proximity to the incinerator for comparison. The levels
of both thyroxine and triiodothryonine were significantly decreased
in the incinerator region, as compared with the two other regions.
F. 1998. Effects of environmental synthetic chemicals on thyroid
function. Thyroid 8:827-855.
an ambitious review of the literature from laboratory experiments,
wildlife observations and human epidemiology, Françoise Brucker-Davis
concludes that wildlife data clearly demonstrate thyroid disruption
by synthetic chemicals. Studies of fetal exposure to contaminants
known to be thyroid disruptors in humans demonstrate impacts also,
particularly with respect to subsequent cognitive function in childhood,
but the mechanisms of action are not clear. More...
DA, LJ Guillette Jr., DB Pickford, HF Percival and AR Woodward.1998.
Sex Steroid and Thyroid Hormones Concentrations in Juvenile Alligators
(Alligator Mississippiensis) From Contaminated and Reference Lakes
in Florida, USA Environmental Toxicology and Chemistry 17(3):
hormones play important roles in growth and reproductive capacity
in reptiles. Removal of the thyroid in lizards and geckos can result
in the inhibition of spermatogenesis that can be restored with the
administration of thyroxine. Exposing geckos with an intact thyroid
to triiodothyronine also results in the suppression of spermatogenesis,
suggesting that the normal functioning of reproductive organs is
dependent on a specific range of thyroid hormone levels.
et al. examine sex steroid and thyroid hormone levels in juvenile
alligators of three lakes in Florida. Two of the lakes are highly
contaminated; Lake Apopka experienced a chemical spill in 1980,
and the other, Lake Okeechobee has a combination of chemical sources,
but has had no major spill. The third lake, Lake Woodruff, is used
as a reference lake.
levels of thyroxine and triiodothyronine were examined, as well
as the relationship of the thyroid hormones to alligator size. The
concentrations of thyroid hormones in alligators differed in all
three lakes. Thyroxine levels were elevated in Lake Okeechobee compared
to the reference lake. In the reference lake, thyroid hormone levels
had a strong negative correlation to alligator size. Thyroxine levels
in the males of the contaminated lakes were negatively correlated
to size, but there was no clear relationship in the females. Triiodothyronine
levels of the females in Lake Apopka had a negative relationship
to size, but there was no correlation in the males of either contaminated
lake to triiodothyronine.
results clearly indicate the alteration of the thyroid hormone system
in alligators living in contaminated lakes. There are two significant
questions that emerge from this study; first, if thyroid hormone
levels are abnormal during a juvenile state is this an indication
of embryonic exposure and is, therefore, a permanent alteration;
and second, will the alteration of thyroids have a significant impact
of the reproductive potential of this cohort of alligators?
JF. 1998. Changes in Thyroid Hormone Economy Following Consumption
of Environmentally Contaminated Great Lakes Fish Toxicology and
Industrial Health 14(1/2): 41-58
et al. conduct a comparative review of studies on experimental mice
and rats exposed to environmental contaminants via a diet of contaminated
fish from the Great Lakes, or through direct exposure to PCB mixtures
or polyhalogenated aromatic hydrocarbons (PHAHs), and the subsequent
impact on the thyroid hormone system. They report that the thyroid
responses of experimental rats and mice fed the PHAHs were similar
to those of rats and mice fed contaminated fish from the Great Lakes.
finding is significant because the thyroid responses of the experimental
animals fed contaminated fish were at exposure levels of mixed PHAHs
"several orders of magnitude lower than those applied in the
classical toxicology studies." Moreover, because Great Lakes
fish are contaminated with a combination of compounds, the impact
on the thyroid hormone system may be due to some synergistic mechanisms.
of thyroid hormone alteration on behavior and brain development
Porterfield and CE Hendrich. 1993. The Role of Thyroid Hormones
in Prenatal and Neonatal Neurological Development-Current Perspectives
Endocrine Reviews 14(1): 94-106
Porterfield and SA Stein. 1994. Thyroid Hormones and Neurological
Development: Update 1994 Endocrine Reviews 3(1):357-363
comprehensive reviews by Susan P. Porterfield examine the role of
thyroid hormones on normal brain development, and the impact of
thyroid hormone abnormalities on the fetal brain.
critical period for thyroid hormones in brain development occurs
in humans in late gestation to 1-2 years of age (in rats this period
is equivalent to 18 days of gestation to 21 days neonatal). Thyroid
deficiency (hypothyroidism) at birth has several implications on
the brain and middle ear development. Too much or too little of
these hormones can result in the decrease of cells in the mature
brain, can impair neurological development and can alter middle
ear development. Untreated congenital hypothyroidism will result
in severe mental retardation and hearing loss. Subtle effects of
treated congenital hypothyroidism include learning disabilities,
speech and memory problems, and poor coordination and balance. Similar
behavioral and neurological problems emerge in children whose mothers
had thyroid hormone deficiency or hyothyroxinemia during pregnancy.
JD, Pedersen LG 1987. Do residue levels of polychlorinated biphenyls
(PCBs) in human blood produce mild hypothyroidism? Journal
of Theoretical Biology 129(2):231-41.
are nearly ubiquitous environmental contaminants, occurring in most
human adipose tissue and blood samples. It has recently been recognized
that PCBs and related compounds share important structural properties
with thyroid hormones and can bind thyroid hormone binding proteins.
It is reasonable that such specific binding interactions can modulate
the distribution of these compounds in the body and alter hormone-protein
interactions that are responsible for the maintenance of normal
thyroid status. Most of the available evidence indicates that the
levels of free thyroid hormones in plasma are a reflection of the
maintenance of normal thyroid status in any individual. A theoretical
model for the transport of thyroid hormones in blood has been extended
to estimate the modulating effects of PCBs on free thyroid hormones.
Using conservative assumptions based on experimental data, our calculations
indicate that PCB concentrations normally found in humans can effect
significant increases in free thyroxine levels in serum by competing
with serum thyroid hormone binding proteins. Experimental data are
discussed which support the proposal that antagonist binding of
PCBs to thyroid hormone binding proteins in serum could produce
varying degrees of hypothyroidism. The biological result is compatible
with the "equilibrium hypothesis" in which thyroid hormone redistributes
between specific and nonspecific binding proteins rather than emphasizing
the importance of free hormone as the active moiety.