Endocrine disruptors and

hormonal cancer (testis, ovary,

prostate, uterus, mammary
gland)

Stan Cornelia Paula

Cluj-Napoca
2016
1. Endocrine disruptors

Endocrine disruptors are chemicals that, at certain doses, can interfere with endocrine (or
hormone) systems. These disruptions can cause cancerous tumors, birth defects, and other
developmental disorders. Any system in the body controlled by hormones can be derailed by
hormone disruptors. Specifically, endocrine disruptors may be associated with the development
of learning disabilities, severe attention deficit disorder, cognitive and brain development
problems, deformations of the body (including limbs), breast cancer, prostate cancer, thyroid and
other cancers, sexual development problems such as feminizing of males or masculinizing effects
on females, etc.
Found in many household and industrial products, endocrine disruptors are substances
that "interfere with the synthesis, secretion, transport, binding, action, or elimination of natural
hormones in the body that are responsible for development, behavior, fertility, and maintenance
of homeostasis (normal cell metabolism)." They are sometimes also referred to as hormonally
active agents, endocrine disrupting chemicals or endocrine disrupting compounds.
The Endocrine Society released a statement on Endocrine-Disrupting Chemicals (EDCs)
specifically listing these biological aspects as being affected if exposed to EDCs.:

Obesity
Diabetes
Female reproduction
Male reproduction
Hormone-sensitive cancers in females
Prostate cancer in males
Thyroid
Neurodevelopment and neuroendocrine systems

The critical period of development for most organisms is between the transition from a
fertilized egg into a fully formed infant. As the cells begin to grow and differentiate, there are
critical balances of hormones and protein changes that must occur. Therefore, a dose of
disrupting chemicals may do substantial damage to a developing fetus. The same dose may not
significantly affect adult mothers.
Studies in cells and laboratory animals have shown that EDCs can cause
adverse biological effects in animals, and low-level exposures may also cause similar effects in
human beings.

2. How do endocrine disruptors work?

From animal studies, researchers have learned much about the mechanisms through
which endocrine disruptors influence the endocrine system and alter hormonal functions.
Endocrine disruptors can:

Mimic or partly mimic naturally occurring hormones in the body like estrogens (the
female sex hormone), androgens (the male sex hormone), and thyroid hormones, potentially
producing overstimulation.
Bind to a receptor within a cell and block the endogenous hormone from binding. The
normal signal then fails to occur and the body fails to respond properly. Examples of
chemicals that block or antagonize hormones are anti-estrogens and anti-androgens.
Interfere or block the way natural hormones or their receptors are made or controlled, for
example, by altering their metabolism in the liver.

3. Synthetic Endocrine Disruptors

Diethylstilbestrol (DES) is considered an EDC because it was
released into the environment while being used to accelerate weight gain in cattle and poultry.
DES is the best known ED with strong estrogenic activity. It was first synthesized in 1938 and
has since been widely used worldwide for medical zindications including pregnancy toxemia and
preterm labor. However, an increase in breast cancer incidence was observed in mothers exposed
to DES. It was also shown that the incidence of cervical cancer, ovarian germ cell cancer,
cervical or vaginal dysplasia, and vaginal clear-cell adenocarcinoma was increased in female

infants born to mothers exposed to DES. The production or marketing of this chemical is
prohibited since 1997.
Experiments in mice revealed that prenatal and neonatal DES blocked stromal induction
of stratification of the vaginal epithelium, and resulted in the development of simple columnar
epithelium, which is normally present in the uterus. Most of the vaginal epithelium, however,
becomes stratified upon discontinuation of diethylstilbestrol exposure, but islands of noninduced epithelium end up developing glands similar to those found in the endometrium which
persist throughout adult life. These ectopic glands are believed to be the tissue where clear cell
carcinoma of the vagina originates (Kurita et al. 2004).
McLachlan et al. (1980) demonstrated that prenatal DES exposure in mice resulted in
neoplasias of the uterus and genital tract abnormalities. A high incidence of uterine
adenocarcinomas (Newbold et al. 1990) and male reproductive tract tumors could also be
produced after acute neonatal exposure to DES. Studies suggest that the carcinogenic effects of
DES may be transmitted to succeeding generations (Newbold et al 2000; Walker and Kurth
1995).
Remarkably, perinatal diethylstilbestrol exposure results in altered arrangement of the
myometrium, a phenomenon involving wnt-7a expression in the epithelium and thought to be
mediated through mesenchymalepithelial interactions. These alterations manifest as a
thickening and disorganization of the myometrium that provides the substratum for neoplastic
organization (Miller et al. 1998).
In addition, fetal exposure of rodents to DES increases their susceptibility to development
of mammary cancer in adult hood (Rothschild et. al 1987).

Tamoxifen, a pharmacological agent used in the treatment of breast cancer, is a

partial estrogen agonist and antagonist. In utero exposure to tamoxifen also increased the
incidence of mammary tumors in rodents when the exposed offspring were challenged with
dimethylbenzantracene (a laboratory carcinogen) at puberty (Hilakivi-Clarke et al. 2000).

Genistein is a naturally occurring phytoestrogen found in most soy products.

Although early reports suggested beneficial effects of such isoflavenoids, other studies correlate
high levels of phytoestrogen intake with adverse health effects. Hilakivi-Clarke et al. (2000)
demonstrated an increase in carcinogen-induced mammary cancer in female rat offspring after
injecting genistein to the rat mother, suggesting that an elevated estrogenic environment in utero
could increase significantly breast cancer risk. Newbold et al. (2000) injected neonatal mice with
genistein (increased bioavailability) and observed an incidence of adenocarcinomas of the uterus
similar to that previously observed for DES.
Exposure of late-gestation dams to genistein resulted in enhanced sensitivity of the pups
to DMBA-induced mammary tumors at sexual maturity. The model used to demonstrate the
prenatal effects of tamoxifen and genistein on the DMBA induction of breast tumors in the adult
was used by Brown et al. (1998) with TCDD. These investigators exposed rats prenatally to a
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single oral dose of TCDD, crossfostered the animals to eliminate lactation exposure, and treated
the pups at sexual maturity with DMBA. The prenatal TCDD treatment led to twice as many
mammary tumors several months later. This raises the question of how prenatal TCDD increases
the sensitivity of the pups to DMBA-induced mammary cancer. Brown and co-workers did not
observe any effects on estrus cyclicity or any evidence of clear estrogenicity of the dioxin
treatment, but did note an increased number of terminal end bud structures at the time of DMBA
exposure, suggesting that TCDD delayed gland maturation.
The PBBs (polybrominated biphenyls), possessing multiple endocrine
modulatory effects including estrogenic perturbation, are associated with an increase in liver
tumors in both rats and mice after prenatal exposure (Chhabra et al. 1993b). They belong to a
class of toxic chemicals known as polyhalogenated aromatic hydrocarbons (PHAHs), which
includes the polyhalogenated dibenzo-p dioxins, dibenzofurans, biphenyls, and naphthalenes.
The members can be chlorinated, brominated, or have mixed chloro-bromo substitution. The
PHAHs provide the best examples of persistent EDCs in the environmental setting.
Multiple examples of endocrine disruption caused by members of this class have been
observed in wildlife (fish, birds, and mammals) and domestic animals (cows, sheep, horses,
chickens), as well as in a host of laboratory animals, with representatives from all vertebrate
classes including nonhuman primates (Birnbaum L.S. 2000). For example, the disruption of
reproduction in trout of the Great Lakes in the United States has been associated with exposure
to dioxin (U.S. EPA 1993), and the lack of reproduction of wild mink has been attributed to
environmentally relevant dietary levels of polychlorinated biphenyls (PCBs) (Brunstrom et al.
2001).
The xenoestrogen Bisphenol A( BPA) is one of the EDCs that has been most
thoroughly studied. BPa is found in various consumer products including baby bottles, reusable
water bottles and reusable food containers, polyvinyl chloride stretch films, papers, cardboards
and in the epoxy resins lining the insides of food cans.
Rats exposed prenatally to environmentally relevant doses of BPA show an increased
number of intraductal hyperplasias (precancerous lesions) that appear during adulthood while
high doses induce the development of carcinomas in situ (Durando et al 2007). Animals exposed
during fetal life to BPA develop palpable tumors during early adulthood when treated at 50 days
of age with nitrosomethy urea, a chemical carcinogen. Exposure to BPA during nursing followed
by exposure at 50 days of age to dimethylbenzantracene resulted in an increased number of
tumors per rat and a decreased latency period compared with animals not exposed to BPA during
nursing. Regardless of the rat strain, exposure routes and levels, and timings of exposure to BPA,
all studies show an increased susceptibility to mammary gland neoplasia that manifests during
adulthood (Murray et al. 2007).

At puberty, an increased sensitivity to estradiol was observed in the mammary glands of

animals exposed fatally to BPA, which led to the induction of progesterone receptors in epithelial
cells and to increased duct lateral branching (Muoz-de-Toro et al. 2005).
As a side-note, neoplasias that result from exposures to BPA and DES during
embryogenesis and organogenesis usually appear after sexual maturity is complete.

Dioxins are byproducts of combustion and of multiple industrial processes. They have
been identified as a class 1 carcinogen by the International Agency for Research on Cancer and
have also been identified as reproductive and endocrine toxicants (Steenland et al. 2004).
The prototype chemical for this class is dioxin, or 2,3,7,8tetrachlorodibenzo-pdioxin (TCDD). Often called the most toxic man-made
compound, dioxin can cause a host of effects. Although essentially all vertebrates are sensitive to
its effects, not every effect may occur in all species. In addition, many of the responses are
developmental stage- or sex-dependent.
In cell culture studies, TCDD, by binding to the aryl hydrocarbon receptor, interacts with
estrogen receptors, and thus behaves either as an estrogen agonist or antagonist. Furthermore, in
mice, TCDD blocks estrogen-induced responses in several tissues (Fenton et al. 2002). TCDD
exposure during organogenesis alters mammary gland morphogenesis as evaluated by the
persistence of terminal end buds in exposed rats (Brown et al.1998). These transient structures
are considered the loci where cancer forms. exposure of these rats to the carcinogen
dimethylbenzantracene at puberty increases their tumor incidence and shortens the latency period
as compared to animals not exposed to TCDD.
Male rodents exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in intrauterine life
were found to experience problems in masculinization of internal and external genitalia, descent
of testicles, androgen production and in spermatogenesis.

Conclusions
In conclusion, it is worth noting that for EDs, to cause impairment of endocrine
functions, time of exposure is as important as dose, duration and age at exposure. Moreover, a
single chemical substance may result in multiple endocrine system dysfunctions via several
mechanisms. A systems biology approach should be adopted to tackle this complexity due to the
fact that endocrine disrupting chemicals act additivelytheir multiple and complex effects are
dose-dependent and contextual

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