Dr Shantakumari Rajan

Faculty of Health Sciences

UiTM Puncak Alam
shanta@[Link]

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Lesson Outcomes:

At the end of the lesson, undergraduates should be able

to:
 Describe endocrine disrupting chemicals and their effects

 Explain non-toxic transgenerational effects of toxicants

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 Carcinogens

 Endocrine Disruption

 Fetal development and Susceptibility windows

 Epigenetics

 Transgenerational effects

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Carcinogens
 Carcinogens are agents that can cause cancer.
→ Substances and exposures
 Carcinogens do not cause cancer in every case, all the time.

 Substances labelled as carcinogens may have different

levels of cancer-causing potential.
 Some may cause cancer only after prolonged, high levels of
exposure.

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 for any particular person, the risk of developing cancer
depends on many factors, including how they are exposed
to a carcinogen, the length and intensity of the exposure,
and the person's genetic makeup.
 Some carcinogens do not affect DNA directly, but lead to
cancer in other ways.
 Some may cause cells to divide at a faster than normal rate,
which could increase the chances of DNA changes and
mistakes.

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 In industry, there are many potential exposures to
carcinogens.
 Generally, workplace exposures are considered to be at
higher levels than for public exposures.

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Stages in Carcinogenesis
Initiation by Physical Means
 Ionizing radiation

 Nonionizing radiation
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Initiation by Biological Agents
 Human viral pathogens
 oncogenic retroviruses (HIV)
 DNA viruses (Epstein-Barr, HSV-2, papilloma, HBV)

 Bacteria, biotransformation (Helicobacter pylori)

 Endoparasites (Schistomsoma spp.)

 Inhibition of Tumour suppressor genes

 Activation of oncogenes

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Predisposing Factors - Genetic
 Metabolism, biotransformation

 Predisposition to initiation

 Inaccurate repair mechanisms

 Immunodeficiency
Predisposing Factors - Dietary
 Caloric intake

 Protein deficiency, high fat

 Carotenes and retinoids - deficiency

 Tocopherols - deficiency

 Selenium (glutathione peroxidase) - deficiency

 Zinc deficiency

 Flavanoids (enzyme inhibition) - deficiency

 TESTING OF CHEMICAL CARCINOGENS

 It has not been economically feasible to test all the

compounds to which people may be exposed.
 Criteria for selection include:
A. Compounds related to known carcinogens
B. New compounds that are to be placed in the
environment
C. Compounds that are indicated by epidemiological
surveys to be associated with an increased incidence of
cancer

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Classification by International Agency for Research on
Cancer (IARC)

 Group 1: Carcinogenic to humans

 Group 2A: Probably carcinogenic to humans

 Group 2B: Possibly carcinogenic to humans

 Group 3: Unclassifiable as to carcinogenicity in humans

 Group 4: Probably not carcinogenic to humans

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2-Year Toxicology and Carcinogenesis Rodent Studies
 Carcinogenicity studies have a different design from
chronic toxicity studies.
 They require larger groups of animals typically 50 per sex
per group
→ statistical significance
→ to prevent a “false negative” conclusion
 Sprague-Dawley strain of rat / hybrid mice

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 Studies in rodents along with studies in human populations
(epidemiology studies) are the best means currently
available for identifying potential human hazards.
 Chemicals recognized by the International Agency for
Research on Cancer (IARC) as human carcinogens
essentially all cause cancer when adequately tested in at
least one species of laboratory animals.

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Endocrine Disruption
 Many chemicals, both natural and man-made, may mimic or
interfere with the body’s hormones, known as the
endocrine system.
 These chemicals called endocrine disruptors, are linked
with developmental, reproductive, brain, immune, and
other problems.
 found in many everyday products– including plastic bottles,
metal food cans, detergents, flame retardants, food, toys,
cosmetics, and pesticides.

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 Endocrine disrupting chemicals cause adverse effects in
animals. But limited scientific information exists on
potential health problems in humans.
 People are typically exposed to multiple endocrine
disruptors at the same time, assessing public health effects
is difficult.
 Some endocrine-disrupting chemicals are slow to break-
down in the environment. That characteristic makes them
potentially hazardous over time.

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How do people encounter endocrine-disrupting
chemicals?
 People may be exposed to endocrine disruptors through
food and beverages consumed, pesticides applied, and
cosmetics used.
 In essence, your contact with these chemicals may occur
through diet, air, skin, and water.
 The body’s normal endocrine functioning involves very
small changes in hormone levels
 Low doses of endocrine-disrupting chemicals may be
unsafe and cause significant developmental and biological
effects.
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 Endocrine disruptors can mimic or partly mimic naturally
occurring hormones in the body → potentially producing
overstimulation.

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 Endocrine disruptors can 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.
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 Endocrine disruptors can bind to a receptor within a cell
and cause inactivation

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Known endocrine disruptors

Arsenic PCBs
Bisphenol A Dioxin
Cadmium atrazine
Fluoride Lead
Triclosan Nickel
PAHs Phthalates
PBDE Parabens
DEHP DDT

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 Adverse effects have been reported for humans exposed to
relatively high concentrations of certain EDCs.
 However, whether such effects are occurring in the
community at concentrations present in the ambient
environment, drinking water, and food remains unclear.
 Considerable scientific uncertainty regarding actual cause
and effect
 Small disturbances in endocrine function, particularly
during highly sensitive stages of the life cycle (e.g.,
development, pregnancy, lactation) can lead to profound
and lasting effects

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Fetal development

 Various toxicants pose a

significant hazard to
foetuses during
development.

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 structural abnormalities, altered growth, functional
deficiencies, congenital neoplasia, or even death for the
foetus
 Toxic substances that are capable of causing structural
congenital abnormalities can be termed teratogens
 The embryonic period, during which organogenesis takes
place, occurs between implantation at around 14 days to
around 60 days postconception.
 This is usually the most sensitive period to teratogenesis
when exposure to a teratogenic agent has the greatest
likelihood of producing a malformation.

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What are the critical periods in prenatal development?
Body System Especially Sensitive Development up to …
Central nervous Postnatal, through to
4th to 8th weeks
system/Brain adulthood
)
Heart 5th to 9th weeks 12th week
Upper limbs 6th to 10th weeks 12th week
Eyes 6th to 10 weeks Term
Lower limbs 6th to 10th weeks 12th week
Teeth 9th to 11th weeks Term
Palate 9th to 11th weeks 16th week
External genitalia 9th to 11th weeks Term
Ears 6th to 11th weeks 13th week
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 Environmental causes of human malformations account for
10% or fewer of malformations, most of these
environmentally induced malformations are related to
maternal disease states.
 Fewer than 1% of all human malformations are related to
drug exposure, chemicals, or radiation.
 Known environmental pollutants – lead, radiation, mercury

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Lead and Low birth weight (Zhu et al., 2010; Zhang et al., 2015)

 linked with infant survival

 Blood lead levels associated with both a decreased birth

weight and length
 maternal age also causes a decreased birth weight with the
same lead concentrations
 older women are more sensitive to the additional
insult of lead exposure

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 BPA and ADHD symptoms (Braun et al., 2009 & 2011)

 ADHD - inattention, impulsivity, and hyperactivity

 Children with ADHD are at increased risk for conduct

disorder or antisocial behaviour
 maternal urine was collected during gestation and at birth
to measure the level of BPA
 children behaviour were followed up at 3 years of age

 Gestational BPA exposure was associated with higher

scores for measures of anxiety, hyperactivity, emotional
control, and behavioural inhibition
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Epigenetics
 the study of how your behaviors and environment can
cause changes that affect the way your genes work.
 heritable changes in gene expression or phenotype
occurring without changes in DNA sequence
 DNA methylation, histone modifications, and microRNA
(miRNA) expression, can change genome function under
exogenous influence.

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 DNA methylation is a process by which methyl groups are
added to DNA.
 Two of DNA's four nucleotides, cytosine and adenine, can be
methylated.
 DNA methylation is one of several epigenetic mechanisms
that cells use to control gene expression.

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 hypermethylation and
hypomethylation of
DNA can result from
exposure to
exogenous chemicals.
 alter gene expression

 are mitotically
inheritable and
therefore can be long
lasting

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 Generally more methylation means less transcription of the
gene, but even this is not consistent across all genes.
 Whether its "beneficial or detrimental" depends on the
gene and cell function

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 Cadmium exposure

 cadmium can also inhibit DNA

methylation in proto-oncogenes
⇨ inducing oncogene
expression and resulting in
cell proliferation

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Transgenerational effects
 During early development (e.g., embryonic and foetal),
epigenetics serves as a key mechanism controlling cell and
tissue
 The resulting change is normally permanent and
unidirectional, preventing a cell from reverting to a stem
cell or converting into a different cell type.

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 During subsequent life stages or critical windows of
differentiation, epigenetics serves to bring about the
orderly expression or inactivation of sets of transcribable
genes that ultimately define the mature phenotype of a cell
or tissue at the specific developmental stages (e.g., puberty,
pregnancy, aging).

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 Transgenerational epigenetic inheritance is the idea
that epigenetic marks (i.e., DNA methylation, histone
modifications) can be acquired on the DNA of one
generation and stably passed on through the gametes (i.e.,
sperm and eggs) to the next generation.
 environmental exposures can change the way your DNA
works (without changing the DNA itself) and this could be
passed on to your offspring.

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Vinclozolin and male reproductive system
 one-time transient exposure of pregnant rats to
vinclozolin
 male offspring exhibited male infertility, accelerated
aging, behavioral abnormality, and prostate diseases
 epigenetic, trancriptomic, and genetic changes that
persisted through three generations.
 unique patterns of DNA methylation in genes persisted
in F1 through F3 offspring (inherited)
Anway et al., 2005
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 PAH exposure and immunity

 prenatal PAH exposure was significantly associated with

genomic hypomethylation in umbilical cord white blood cell
 hypermethylation of the ACSL3 5′-CGI was found to be
significantly associated with maternal airborne PAH
exposure and with a parental report of asthma symptoms in
children prior to age 5
Herbstman et al., 2009; Perera et al., 2009

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Toxicants take many routes through the environment