Topic 7 & 8.pptx

PPT 10-hr. General Industry – PPE v.03.01.17
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Created by OTIEC Outreach Resources Workgroup
TOPIC 7
Target Organs

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LEARNING OUTCOMES
By the end of this topic, you should be able to:
1. Explain toxicants and their exposure in the human body;
2. Describe the human body in a physiological perspective; and
3. Explain toxicants and its disruptions to our physiological system.

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INTRODUCTION
• Gandhi once quoted “It is health that is real wealth and not pieces of gold and
silver”. Surprisingly, it is true; there is no meaning of wealth without good
health in our daily life.
• However, because the world has changed so much, we are facing many types
of toxicants, both natural and man-made, which disrupt our health.
• Even though the medical field has evolved and many good medicines have
been created, we are still facing many chronic diseases caused by exposure
toward toxicants which disrupt our body’s physiological functions.

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7.1 TOXICANTS AND THEIR EXPOSURE IN THE
HUMAN BODY
•The father of toxicology, Paracelsus, once said “all substances are poisons, there is none that is
not a poison, and the right dose differentiates a poison and a remedy”. Looking at the world
nowadays, we can find varieties of chemicals in our daily life. The big questions are how the
chemical enters the body; how it is distributed; how it is metabolised; and how it is excreted
from the body.
•To understand and answer this question, we must first understand toxicology. The basic
understanding should include four important stages. These four important stages in toxicology
that we should understand in order to relate the toxicant, exposure toward it and its effect are:
(a) Absorption of toxicant:
(i) Route of entry;
(ii) Duration of exposure; and
(iii) Degree of exposure.

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Cont.
(b) Distribution of toxicant:
(i) Local distribution; and
(ii) Systemic distribution.
(c) Metabolism of toxicant:
(i) Metabolism of the toxicant in our body; and
(ii) Disruption of biochemical pathway.
(d) Excretion of toxicant:
(i) How will the toxicant be excreted in our body?

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7.2 OUR HUMAN BODY IN PHYSIOLOGICAL
PERSPECTIVE
•Have we ever wondered what makes up our body? Through the advances and evolution of
modern technology, we can discover the complex human body. Basically, a cell is the basic
unit in our body. We can see many types of cells in our body such as smooth cells, squamous
cells etc. Combination of many cells to perform certain functions will form the organ. Skin,
eye and heart are examples of the organs in our body.
•A system, on the other hand, is combination of a few organs to complete one particular task
in our body. For example, the integumentary system consists of skin and the components of
the skin that perform the integumentary tasks in our body.
•We could summarise the human body organisation as depicted in Figure 7.1.

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Cont.
Figure 7.1: Organisation in human body

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Cont.
• How are we going to relate our body to the toxicants that are present in
our surrounding? Basically, as we have stressed earlier, we are exposed
to many chemicals nowadays.
• Just imagine the excessive amounts of preservatives and flavouring
substances in our food that we eat today which might become hazardous
to our body.
• The exposure also might come from our occupation specifically or
environment generally. Now, let us discover our body system briefly
and common effects of toxicants to it.

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7.3 TOXICANTS AND THEIR DISRUPTIONS TO OUR
PHYSIOLOGICAL FUNCTION
•Through this subtopic, we will briefly learn about how toxicants
affects our:
(a) Respiratory system;
(b) Integumentary system;
(c) Circulatory system;
(d) Liver;
(e) Kidney; and
(f) Reproductive system.

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7.3.1 Effects of Toxicants on the Respiratory System
•We inhale and exhale air every day, but do we know what system is responsible
for it? What is the purpose of it? The respiratory system is the one responsible for
the inhaling and exhaling of air in our body.
•We might ask ourselves the purpose of inhaling and exhaling in our body. This
can be explained through five basic functions of the respiratory system. They are as
follows:
(a) Providing an extensive area for gas exchange between the air and the circulating
blood.
(b) Moving air to and from the exchange surfaces of the lungs.
(c) Protecting respiratory surfaces from dehydration, temperature changes or other
environmental variations and defending the respiratory system and other tissues
from invasion by pathogens.

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(d) Producing sounds involved in speaking, singing
and non-verbal communication.
(e) Providing olfactory sensations.
Basically, the component of the human respiratory system consists of
two parts which are as below:
(f) Upper respiratory system (nose, nasal cavity, paranasal sinus and
pharynx); and
(g) Lower respiratory system (bronchioles, alveoli of the larynx (voice
box), trachea (windpipe), bronchi and lungs.

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Refer to Figure 7.2 to get a better understanding.
Figure 7.2: The anatomy of respiratory system

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(a) It is a paired organs located in the thoracic cavity; enclosed and protected by the
pleural membrane (two layers)
(i) Parietal pleura (outer layer) - attached to the wall of the thoracic cavity; and
(ii) Visceral pleural (inner layer) - covering the lungs.
(b) The lungs are between the pleurae ă the pleural cavity - which are filled with
lubricating fluid.
(c) Each lung is a blunt cone, with the tip, or apex, pointing superiorly.
(d) The lungs have distinct lobes separated by deep fissures.
(e) The right lung has three lobes and the lobes are separated by two fissures.
(f) The left lung has two lobes and the lobes are separated by one fissure.
(g) The lungs consist of numerous numbers of alveoli.

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•The alveoli can be described as follows:
(a) Alveoli are tiny thin-wall sacs where gas exchange occurs.
(b) Each lung contains about 150 million alveoli, and their abundance gives the lung an open,
spongy appearance.
(c) An extensive network of capillaries is associated with each alveolus.
•Many respiratory problems arise from its exposure toward varieties of
chemical in our daily life. Among these problems include:
(a) Irritation (ammonia, chlorine, hydrogen fluoride, sulphur dioxide);
(b) Asbestosis (asbestos);
(c) Silicosis (silica, sand blasting activities);
(d) Oedema (phosgene, tetrachloroethylene, nickel);

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Cont.
(e) Occupational induced asthma (particulate matter, dust);
(f) Pneumonia;
(g) Emphysema;
(h) Bronchitis; and
(i) Lung cancer (carcinogenic substances).
•Protection for respiratory system against these toxicants can be taken by applying the
dental mask, dust mask, half face piece, full face piece, PAPR, SCBA and air line.

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7.3.2 Effects of Toxicants on the Integumentary System
•What is the integumentary system? What organs are included in this integumentary system
and how do they function? Do we know what common problems will occur when it is
exposed to toxicants such as chemicals? Let us find the answers to all these questions.
•The integumentary system is actually a large, highly complex organ or a structurally
integrated organ system. It makes up 16 per cent of our total body weight and its 1.5 to 2m2
surface is continuously abused, abraded, attacked by microorganisms, irradiated by
sunlight and exposed to environmental chemicals.
•Two major components of the integumentary system are:
(a) Cutaneous membrane; and
(b) Accessory structure.

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• General functions of the integumentary system are:
(a) Protection;
(b) Excretion;
(c) Temperature regulation;
(d) Synthesis of vitamin D; and
(e) Cutaneous sensation.
•Our skin is undeniably the primary defence to any exposure. It goes against scar, biological
microorganisms, chemicals and many other substances. We can see many effects that
commonly affect the skin due to exposure to chemicals such as skin burn, irritation and skin
cancer.
•Protection for the integumentary system includes glove, apron and covering all on oneself.

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7.3.3 Effects of Toxicants on the Circulatory System
•“Oh dear, my hand is bleeding” - this may be a common experience that we might
face in our daily lives when our hands or other parts of the body get injured
accidentally.
•The question is do we know what is the purpose of the blood? Which system in our
body is responsible for it? To answer this question, the next step is to read the
content of this subtopic.
•Blood is actually one of the main parts in the circulatory system. Without it, the
circulatory system might not function well or not even work at all and can be fatal.
That is the reason why excessive bleeding could pose a serious risk to the victim.
•So we know that blood is a part of the circulatory system in our body. In this
subtopic, we will learn more on the circulatory system.

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•The circulatory system is an organ system that passes nutrients (such
as amino acids, electrolytes and lymph), gases, hormones and blood
cells to and from cells in the body to help fight diseases, stabilise body
temperature and pH, and to maintain homeostasis.
•There are three important components of the circulatory system which
are:
(a) Heart;
(b) Blood; and
(c) Blood vessel.
Let us discuss further.

(a) Heart
• Our heart is like a muscular pump that pushes blood to all parts of our body. It
provides the force that powers the cardiovascular system and is able to pump
approximately five to six litres (about 1.5 gallons) of blood per minute, even when we
are at rest.
• The size of the heart is that of a person’s clenched fist, and it weighs 280 to 340
grams. It is hollow and roughly conical in shape, the narrow end pointing downward
to the left, situated between the lungs. The diagram of the heart can be referred to in
Figure 7.3.
Figure 7.3: The diagram of the heart
Source: http://science6shms.pbworks.com/w/page/24477490/Heart%20Diagram

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(b) Blood
•Blood actually is a type of connective tissue in the form of fluid. It is a part of
extracellular fluid within the cardiovascular system. The average adult has approximately
five litres (about 10 pints) of blood. Blood is made up of both liquid and solid
components: the liquid portion is called plasma, while the solid portion consists of red
blood cells, white blood cells and platelets.
•Basically blood consists of 55 per cent plasma and 45 per cent blood cells (which include
erythrocytes, leukocytes and thrombocytes). The basic components of blood can be
divided into the following:
(i) Plasma - the liquid portion;
(ii) Platelets - the clot forming components;
(iii) White blood cells - the infection fighters; and
(iv) Red blood cells - the oxygen transporters.
•The function of the blood is for transportation, regulation and protection.

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•The common effects of toxicants on the circulatory system include:
(a) Methemoglobinemia;
(b) Anaemia;
(c) Aplastic anaemia;
(d) Drug induced autoimmune haemolytic anaemia;
(e) Drug induced nonautoimmune haemolytic anaemia;
(f) Haemolytic anaemia (lead poisoning);
(g) Leukaemia (benzene);
(h) Drug induced cardiovascular disease; and (i) Heart cancer.

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3.4 Effects of Toxicants on the Liver
The human body’s detoxifying site is liver’s most prominent function.
Sometimes we might ingest foreign substances such as weak poisons and
drugs. Do you know that the little warriors inside our body will try to detoxify
it in order to prevent it from harming our body?
Yes, it truly is one of the little warriors that work hard to detoxify all those
harmful substances that enter our body.
•So, in this subtopic, structure of the liver and the effects of toxicants on it will
be explained through the following questions.
(a) What is our liver structure like?
(b) What are the effects of toxicants on our liver?

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•So let us find the answers here.
(a) What is our liver structure like?
• Let us see the overview of our liver structure in Figure 7.4.
Figure 7.4: General overview of the liver Source:
http://www.merckmanuals.com/home/liver_and_gallbladder_disorders/biology_of_the_liver_and_gallbladder/overview_of_the_liver_
and_gallbladder.html

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•The processes for liver metabolism are as follows:
(i) Cytochrome P450 mono oxidase;
(ii) Glucuronidation;
(iii) Sulfation; and
(iv) Glutathione-S-Transferase.
(a) What are the effects of toxicants on our liver?
•According to a study by Proper and Schaffer (1959), damage to the liver which is caused by chemicals can be
explained through a few classifications which are:
(i) Zonal hepatocellular alteration without inflammatory reaction:
• Necrosis and steatosis.
(ii) Intrahepatic cholestasis:
• Bilestasis.
• Dilatation of the canaliculi with subsequent loss of microvilli.
(iii) Focal necrosis.
(iv) Hepatic necrosis with inflammatory reaction.
(v) Unclassified.
(vi) Hepatocarcinogen.
–

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•There are few factors that are involved in liver injury which include:
(i) Biotransformation of toxicant:
• To more active metabolite (Eg. Chloroform  phosgene) lead to depletion of hepatic
glutathione and alkylation of macromolecules.
(ii) Alteration of hepatic blood flow:
• Haemorrhagic necrosis by Dimethylnitrosamine.
• Coagulative necrosis by Carbon Tetrachloride.
(iii) Potentiation of Hepatotoxicity:
• Ethanol - increase damaging properties of haloalkanes.
• Acetone and other form of ketones potentiate Carbon
(iv) Tetrachloride (CCl4) hepatotoxicity.
• n-hexane intermediate potentiate chloroform toxicity.
• Diabetic state enhances hepatotoxicity of Carbon Tetrachloride (CCl4), chloroform.

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•The liver injury usually comes through few mechanisms which include:
• Accumulation of lipids  Protein synthesis  Lipid peroxidation  Calcium homeostasis 
Immunologic reaction  Cholestasis  Cirrhosis  Carcinogenesis
•The mechanism can be explained by:
(a) Accumulation of Lipids
(i) Accumulation of advance beneficiary notice of non-coverage (AbN) amount of fat
predominantly in parenchymal cells and decrease plasma lipid and lipoprotein.
• Interfere with synthesis of the protein moiety;
• Coupling phase of triglycerides (TG) secretion;
• Impaired released of Very Low Density Lipoprotein (VLDL);
• Increase synthesis of TG;
• Inhibition of Beta oxidation of Fatty Acids; and
• Increase mobilisation of Fatty Acids from adipose tissue.
(ii) CCl4 , ethionine, phosphorus, tetracycline.

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(b) Protein Synthesis (Lead to Necrosis)
(i) Inhibit incorporation of amino acid into liver protein.
(ii) Ethionine, Carbon Tetrachloride (CCl4), dimethylnitrosamine.
(iii) Ethionine - replace methionine cause decrease adenosine triphosphate (ATP) synthesis
and inhibition of (ribonucleic acid) RNA synthesis.
•
(i) Dimethylnitrosamine - loss of mRNA.
(ii) CCl4 - ribosome.
(iii) Galactosamine - decrease synthesis of RNA.

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(c) Lipid Peroxidation
(i) Peroxidation cleavage of unsaturated Fatty Acids and release of carbonyl compound.
(ii) CCl4 ------- formation of free radicals
• Alteration of ER;
• Loss of G6P activity enzyme;
• Loss of protein synthesis; and
• Loss of capacity to form and excrete VLDL.
(d) Calcium Homeostasis
(i) Accumulation of Calcium (Ca2+) in the liver leads to cell death (influence cell
metabolism, motility and division).
(ii) Activation of molecular Oxygen (O2) (oxidative stress) at plasma membrane,
endoplasmic reticulum, mitochondria, cytosol.
• Carbon Tetrachloride (CCl4 ), bromobenzene, adriamycin

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(e) Immunologic Reaction
(i) Covalent binding with hepatic protein.
(ii) Mainly by many drugs such as phenytoin, sulfonamides, erythromycin.
(f) Cholestasis
(i) Decrease microvilli canaliculi.
(ii) Golgi apparatus dilated and vacuolated.
(iii) E.g. Manganese.

(a) Cirrhosis
(i) Chronic morphological alteration of the liver (appear as nodules).
(ii) Mechanism:
• Single cell necrosis + deficiency in repair mechanism of residual cells.
• Alteration of intrahepatic vasculature.
(iii) Enhance by deficiency in protein, vitamin B12 , folic acid;
(iv) E.g. - CCl4, aflatoxin, alcohol (ethanol);
(v) Chronic liver disease;
(vi) Damage of liver tissue, scarring of the liver (fibrosis - nodular regeneration);
(vii) Progressive decrease in liver function;
(viii)Excessive fluid in the abdomen (ascites);
(ix) Bleeding disorders (coagulopathy);
(x) Increased pressure in the blood vessels (portal hypertension); and
(xi) Brain function disorders (hepatic encephalopathy).

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Take a look at Figure 7.5 where an example of healthy liver and liver scarred by cirrhosis is
displayed.
Figure 7.5: Healthy and cirrhosis liver

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(a) Carcinogenesis
(b) Initiation, promotion and progression.
(ii) Pseudofetal configuration of liver cells
• Increase foetal isozyme, alfa feto protein, foetal antigen.
(iii) Examples of carcigonesis are as follows:
• Vaflatoxin B1;
• Dimethylnitrosamine;
• Dimethylbenzoanthracene;
• Dimethylaminoazobenzene;
• Organochlorine pesticide;
• Polychlorinated biphenyl; and
• CCl4.

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(i) Angiosarcoma
(i) Uncommon malignant neoplasms characterised by rapidly proliferating,
extensively infiltrating anaplastic cells derived from blood vessels and
lining irregular, blood-filled spaces.
(ii) Malignant endothelial vascular neoplasms that affect a variety of sites.
(iii) Angiosarcomas are aggressive and tend to recur locally, spread widely, and
have a high rate of lymph node and systemic metastases.
(iv) The rate of tumour-related death is high.

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7.3.5 Effects of Toxicants on the Kidney
•The kidney is one of the vital organs in the excretory system of our human body.
It is also involved in the thermoregulation for our body, performs the filtering
system in order to ensure our blood is free from harmful substances, ensures good
regulation of our urinary system, as well as, ensures our body is in a good state.
•Many people nowadays are heavily dependent on artificial machines which
replace the function of their malfunctioned kidney at a high expense and cost.
Thus, to prevent it from happening to us, it is wise to really understand how our
kidney’s function and the possible threat of toxicants to our kidneys.

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•In order to understand the kidney and its functions in the human body, as well
as to understand the effects of toxicants on it, this subtopic will detail out:
(a) How does our kidney look like?
(b) What are the functions of our kidney?
(c) What are the common effects of toxicants on our kidney?
•Let us proceed to find the answers.
(a) What is the structure of our kidney? Three primary components:
(i) The tubular elements;
(ii) The glomerulus; and
(iii) The vascular element.
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A general overview of the kidney and its other sections and parts can be seen in
Figure 7.6 to 7.8.
Figure 7.6: General overview of the kidney
Source: http://bharathgramaarogya.net/urosymptoms.htm
Figure 7.7: Cut section of kidney (vascular elements - renal arteries)
Source: http://kidneycares.com/forPatients.aspx

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(b) What are the functions of our kidney?
(i) Excretion of waste;
(ii) Acid-base homeostasis;
(iii) Osmolality regulation;
(iv) Blood pressure regulation; and
(v) Hormone secretion.
(c) What are the common effects of toxicants on
our kidney?
•There are many types of nephrotoxicants that can threaten
our kidney. These include:
(i) Heavy metals;
(ii) Halogenated hydrocarbons;
(iii) Petroleum hydrocarbons; and
(iv) Therapeutic agents.
Figure 7.8: Basic functional unit in our kidney (tubular ă tubule and glomerulus)
Source: http://www.ratical.org/radiation/vzajic/8thchapter.html

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•Common heavy metal such as mercury, cadmium, chromium, arsenic, gold, lead, iron,
antimony, uranium and thallium could pose risk to our body. The effects are categorised as:
(i) Most-potent nephrotoxicants;
(ii) Low dose - glucosuria, polyuria;
(iii) High dose - renal necrosis, anuria, death;
(iv) Similar damage by similar mechanisms; and
(v) Histologically - necrotic proximal tubules, protein casts plug tubular lumen.
•We will now take a look at how mercury affects the kidney. Mercury is recognised in many
forms such as HgĈ, Hg+, Hg++, MeHg and PhHg. The toxicity it causes varies with types.
The kidney and the GI tract are targets of suicide using Hg salts. This will cause proximal
tubule damage and renal failure. One can see the effects in 24 to 48 hours after a large dose of
1 to 4g. Chronic effects can also be seen in the proximal tubule, though the onset is longer.
Primary toxicity is neurological. Renal toxicity is most likely due to dealkylation or
dearylation back to the Hg salt.

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•The initial stage of the effects of this toxicant in the kidney starts with low renal blood flow
and glomerular filtration rate (GFR). Tubular dysfunction will then set in, where there are
sodium and glucose excretion and loss of secretory function. In the ultrastructural
alterations, there will be loss of proximal tubular. The brush border enzymes decrease
within 15 minutes, and within eight hours. The membrane clumps in cytoplasm which will
be followed by vacuolisation of plasma membrane. This will ultimately lead to
mitochondrial rupture (necrosis).
•
•The progression to disease can be seen through the following:
•
(i) ATP production decreased - Mercury binding to sulfhydrals in mitochondrial enzymes;
(ii) Altered Ca2+ homeostasis- Hg effects blocked by Ca2+ uptake blocker;
(iii) Phospholipid derangements - lead to decreased membrane function resulting in further
free Ca - a cascading effect; and (iv) Leads to necrotic injury of the tubule.

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7.3.6 Effects of Toxicants on the Reproductive System
The reproductive system is important to ensure of offspring production in any living being. It ensures that our genes will be
passed on to the next generation and ensures the survival of the human population.
Let us take a look at the male reproductive system as in Figure 7.9.
Figure 7.9: Male reproductive system
Source: http://healthfitnesscentre.blogspot.com/

•The function the male reproductive system is for the production of spermatozoa after
puberty for fertilisation with the ovum from the female, coitus process and the production of
androgens. Basic components of this system include:
(a) Testis;
(b) Penis;
(c) Urethra;
(d) Prostate gland;
(e) Seminal vesicle; and
(f) Vas deferens.
• The sperm production (as in Figure 7.10) in the testis originates from indifferent gonads
during the embryonic phase. It contains 200 to 300 lobules which are separated by septum.
Each lobule has four seminiferous tubules. Blood is supplied from the testicular artery and
drains through the pampiniform plexus into the testicular vein. The seminiferous epithelium
contains sertoli cells (sustentacular cells) and germ cells. Meanwhile, the Leydig cells exist
in between tubules and produce spermatozoa and androgens.

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•This is divided into two compartments: extratubular and intratubular.
(a) Extratubular - vascular and interstitial divisions (inclusive of lymphatic channels and
Leydig cells); and
(b) Intratubular - basal and adluminal divisions. This compartment is located in the
seminiferous tubules.
Figure 7.10: Sperm production

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•The effects of toxicants on the male reproductive system through lead, EDB,
carbon disulphide and drug abuse are as explained in the following.
(a) In lead, effect begins at 40 μg/dL of blood lead level. The occupational exposure
will decrease sperm count totals and increase abnormal sperm frequencies. In
long-term exposure, sperm concentrations, total sperm counts and total sperm
motility may diminish. There is also a decrease in the function of prostate and
seminal vesicles as well as in sexual drive and impotence. These effects could
be the result of direct testicular toxicity of lead but as the duration of exposure
increase, the hypothalamic-pituitarytesticular axis could be disturbed. However
it is unclear how long these effects may last in humans after lead exposure
ceases.

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(b) EDB (Ethylene Dibromide or 1,2-dibromoethane) is a colourless, water
soluble liquid and used as pesticide and gasoline additive absorbed through
the lungs, digestive tract and skin.
It is extensively metabolised to 2bromoacetaldehyde (toxic) and excretion occurs
primarily in the urine. It will result in testicular atrophy which is a medical
condition in which testes was diminished in size and loss of function were
observed in rodents exposed to 37 to 41mg/kg/day, five days a week for a period
of 53 to 61 weeks.
Study show that those workers exposed to EDB have more sperm with tapered
heads and fewer sperm per ejaculate.

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(c) Carbon Disulphide is a clear, colourless or faintly yellow and liquid at
room temperature and used primarily as solvent in the viscose rayon and
cellophane. Study in rats show that male rats exposed to approximately
610ppm (1,900mg/mò) for six hours per day, five days per week for 10
weeks resulted in significant reduction in sperm counts by the seventh
week.
However, caudal epididymal sperm counts were not depressed and the testes
appeared histologically normal. Carbon disulphide does not exert a direct
effect on the testes, but may interfere with sperm transport and ejaculation.

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(d) Drug Abuse affects the three stages of male sexual function
which are erection, ejaculation and orgasm.
Anti-depressants, testosterone antagonists and stimulants of
prolactin reduce libido in men.
Anti-hypertensive drugs which act on the sympathetic nervous
system-induce impotence in some men.
Cocaine, heroin and high doses of cannabinoids also reduce the
libido, while opiates may delay or impair ejaculation.

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We will now move on to the female reproduction system which you can refer to in Figure 7.11.
Figure 7.11: Female reproductive system (Source: http://fau.pearlashes.com/anatomy/Chapter%2042/Chapter%2042.htm)

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•The basic component of female reproductive system includes the ovary, oviduct,
uterus, cervix and vagina.
•The ovary developed from gonadal cortex. During foetal development, oogonia are
formed by mitosis followed by meiosis with the production of millions of oocytes.
Atresia occurs due to hypoxia resulting in less number of oocytes. Women are born
with a fix number of oocytes. Its function is to produce ova as well as two hormones:
progesterone and oestrogen.
•The oviduct floats in mesosalpinx. It consists of four segments:
(a) Fimbriae - at the periphery of oviduct, functions to assist in supporting uterus.
(b) Infundibulum - funnel-shaped structure near ovary, functions to catch ovulated ovum.
(c) Ampulla - distal oviduct and is enlarge, functions as site of fertilisation.
(d) Isthmus - proximal oviduct and is narrow, functions to connect oviduct to uterine
cavity.

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•The uterus is a simplex form in human. There are three layers which are the serous
membrane (perimetrium), myometrium (thickest) and endometrium. Its function is for
embryo implantation and to support and house the foetus throughout pregnancy.
•The cervix is the sphincter muscle situated between the uterus and vagina. Most cervixes
have annular ring structure. It contains goblet cells that secrete mucous and consistency
varies with menstrual cycle. Mucous consistency can be used to detect fertility. It functions
to stop entry of bacteria into uterine cavity. The cervical canal usually closes and only
opens during parturition. The cervix also functions to form a cervical plug during
pregnancy.
•The vagina is divided into two parts which are the vestibule (external) and posterior
vagina (internal). The hymen is a thin connective tissue which forms a transverse fold to
partially close vaginal opening in virgins. It functions to accept ejaculated semen from
penis during coitus. It also has an acidic environment to kill bacteria and foreign bodies.

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•The effects of toxicants on the female reproductive system include exposure to
the common reproductive toxicants such as heavy metal, polycyclic aromatic
hydrocarbon, halogenated polycyclic hydrocarbons, organic solvents and
pharmacological agent.
(a) Polycyclic Aromatic Hydrocarbon (PAH)
(i) Produced by cigarette smoke;
(ii) Ovarian toxicity and oocyte destruction;
(iii) Caused by reactive electrophilic metabolites generated by parent
hydrocarbon; and
(iv) Inducers of hepatic enzyme including microsomal monooxygenases and
transferase.

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(b) Halogenated Polycyclic Hydrocarbon
(i) Includes DDT, PBB and PCB;
(ii) DDT will cause damage to uterus and affect fertility;
(iii) Cause an estrogenic response in rats; and
(iv) Thickening of the endometrium and increase in uterus weight competitive
inhibition of the binding of estradiol to receptors sites in uterus.
(c) Organic Solvents
(i) Carbon disulphide causes irregular menstrual flow;
(ii) Benzene alters the ovarian function; and
(iii) Carbon tetrachloride alters the ovarian function.

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(d) Pharmacology Agents
(i) Adverse effect on the menstrual cycle;
(ii) Mediated through binding to steroid receptor and exertion of
estrogenic or anti-estrogenic effects;
(i) Stimulation of an increase in serum prolactin level;
(ii) Direct toxic effect on the ovary; and
(iii) Examples are oral contraceptives and tricyclic anti-depressants.

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END OF TOPIC 7

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TOPIC 8
Endocrine Disruption and Mutagenic
Pollutants

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LEARNING OUTCOMES
•By the end of this topic, you should be able to:
1.
Describe the endocrine system and mutagen;
2.
Describe the characteristics of endocrine disruptors;
3.
Explain the types of mutation; and
4.
Discuss the effects of endocrine disruptors and mutagens to human.

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INTRODUCTION
•What is the endocrine system? Although we rarely think about them, the glands
of the endocrine system and the hormones they release influence almost every
cell, organ and function of our bodies. The endocrine system is instrumental in
regulating mood, growth and development, tissue function and metabolism, as
well as sexual function and reproductive processes.
•
• In general, the endocrine system is in charge of body processes that happen
slowly, such as cell growth. Faster processes like breathing and body
movement are controlled by the nervous system. However even though the
nervous system and endocrine system are separate systems, they often work
together to help the body function properly.

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8.1 THE ENDOCRINE SYSTEM
• The foundations of the endocrine system are hormones and glands. As the body's chemical
messengers, hormones transfer information and instructions from one set of cells to
another.
• Although many different hormones circulate throughout the bloodstream, each one affects
only the cells that are genetically programmed to receive and respond to its message.
Hormone levels can be influenced by factors such as stress, infection and changes in the
balance of fluid and minerals in blood.
• A gland is a group of cells that produces and secretes, or gives off, chemicals. A gland
selects and removes materials from the blood, processes them and secretes the finished
chemical product for use somewhere in the body.
• Some types of glands release their secretions in specific areas. For instance, exocrine
glands, such as the sweat and salivary glands, release secretions in the skin or inside of the
mouth. Endocrine glands, on the other hand, release more than 20 major hormones
directly into the bloodstream where they can be transported to cells in other parts of the
body.

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• The major glands that make up the human endocrine system are the
hypothalamus, pituitary, thyroid, parathyroids, adrenals, pineal body and
the reproductive glands, which include the ovaries and testes (see Figure
8.1).
• The pancreas is also part of this hormone-secreting system, even though
it is also associated with the digestive system because it also produces
and secretes digestive enzymes.
• Although the endocrine glands are the body's main hormone producers,
some non-endocrine organs - such as the brain, heart, lungs, kidneys,
liver, thymus, skin and placenta - also produce and release hormones.
• Take a look at Figure 8.1 to see the major glands and non-endocrine
organs.

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•Once a hormone is secreted, it travels from the
endocrine gland through the bloodstream to target cells
designed to receive its message. Along the way to the
target cells, special proteins bind to some of the
hormones. The special proteins act as carriers that
control the amount of hormone that is available to
interact with and affect the target cells.
•Also, the target cells have receptors that latch onto
only specific hormones, and each hormone has its own
receptor, so that each hormone will communicate only
with specific target cells that possess receptors for that
hormone. When the hormone reaches its target cell, it
locks onto the cell's specific receptors and these
hormone-receptor combinations transmit chemical
instructions to the inner workings of the cell.
Figure 8.1: Major glands and non-endocrine organs of the
endocrine system

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•When hormone levels reach a certain normal or necessary amount, further
secretion is controlled by important body mechanisms to maintain that level of
hormone in the blood.
•This regulation of hormone secretion may involve the hormone itself or another
substance in the blood related to the hormone.
•For example, if the thyroid gland has secreted adequate amounts of thyroid
hormones into the blood, the pituitary gland senses the normal levels of thyroid
hormone in the bloodstream and adjusts its release of thyrotropin, the pituitary
hormone that stimulates the thyroid gland to produce thyroid hormones.
•Another example is parathyroid hormone, which increases the level of calcium
in the blood. When the blood calcium level rises, the parathyroid glands sense
the change and decrease their secretion of parathyroid hormone. This turnoff
process is called a negative feedback system.

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8.2 ENDOCRINE DISRUPTORS
•Endocrine disruptors are chemicals that may interfere with the body’s endocrine
system and produce adverse developmental, reproductive, neurological and immune
effects in both humans and wildlife. A wide range of substances, both natural and man-
made, are thought to cause endocrine disruption, including:
(a) Pharmaceuticals;
(b) Dioxin and dioxin-like compounds;
(c) Polychlorinated biphenyls;
(d) DDT and other pesticides; and
(e) Plasticisers such as bisphenol A.
•Endocrine disruptors may be found in many every day products such as plastic bottles,
metal food cans, detergents, flame retardants, food, toys, cosmetics and pesticides.

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•A few researches and studies have been carried out to determine whether exposure to
endocrine disruptors may result in human health effects including lowered fertility and
an increased incidence of endometriosis and some cancers. Research shows that
endocrine disruptors may pose the greatest risk during prenatal and early post-natal
development when organ and neural systems are forming.
•Exogenous substances which cause adverse health effects in an intact organism or its
progeny subsequent to changes in endocrine function are called endocrine disruptors
(EDs) or endocrine disrupting chemicals (EDCs). Over recent years, a number of
coincident observations have led scientists to the conclusion that chemical substances
in the environment may be interfering with the endocrine systems of humans and
various animals.
•These so-called endocrine disruptors may be responsible for a range of dysfunctions in
the reproductive system of humans and a variety of animals in the wild. The wildlife
effects are well documented and some can be reproduced experimentally.

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•The human effects are more difficult to definitively associate with environment
chemicals and some effects are controversial. However, there is considerable interest in
the area which is potentially of great importance.
•It is widely accepted that chemicals that are capable of causing endocrine disruption
have been released into the environment. These chemicals may act as oestrogen mimics,
as anti-oestrogens or as anti-androgens.
•The end result is a change in the hormone balance which may result in a variety of
physiological and pathological effects. The debate, however, is whether the
concentrations of these chemicals is sufficient to cause all of these effects undoubtedly
observed in animals and the effects suspected as being related in humans.

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8.3 REVIEW OF HORMONAL FUNCTION
•The endocrine system is a system of glands that produces chemical messengers
(hormones) and the receptors in tissues that respond to them. Examples include the
thyroid, pituitary and adrenal glands, plus the male and female reproductive systems.
•The endocrine system is composed of ductless glands that secrete hormones into the
blood stream to act at distant sites. Together with the nervous system, the endocrine
system is responsible for the integration of many different processes which allow
complicated organisms to function as a unit (maintain homeostasis).
•Hormones can be proteins, polypeptides, amino acids or steroids. The most well-
known hormones are the sex steroids oestrogen, produced in the ovaries, and
testosterone, produced in the testes. Oestrogen and testosterone are also produced in
the adrenal glands of both sexes. Other hormones include thyroxin, produced in the
thyroid, and insulin, produced in the pancreas. The pituitary and hypothalamus in the
brain release a variety of hormones that affect other organs, including the sex glands.

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•From the blood, hormones interact with cells by binding to special proteins called
receptors. The binding is specific, like a key in a lock. When enough binding sites are
occupied, then a message is passed on to the target cell nucleus unmasking genetic
information which results in physiological reactions ultimately responsible for
stimulating or regulating proper metabolism, development, growth, reproduction and
behaviour.
•For example, in women oestrogen works in this way to control the menstrual cycle,
and in men testosterone controls sperm production. Hormones are released into the
blood in very small amounts. Their levels are controlled by the rate of release, and the
rate of degradation, usually by the liver or kidneys.
•Timing of hormone release is often critical for normal function. This is especially true
during foetal development. Precise hormone control is important, as too much or too
little at the wrong time can result in dysfunction of one or several body systems.

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8.4 CHARACTERISTIC OF AN ENDOCRINE
DISRUPTOR
•The endocrine system is a complex communication system between chemical
signals and their targets responsible for regulating internal functions of the body.
Any substance that alters the function of this system is termed an endocrine
disruptor. Endocrine disruptors or commonly referred to as “Endocrine Disrupting
Chemicals” (EDCs) and can alter the endocrine function by a variety of different
mechanisms:
(a) By mimicking the sex steroid hormones oestrogen and androgen by binding to
their natural receptors either as agonists or antagonists.
(b) By altering the synthesis and breakdown of natural hormones.
(c) By modifying the production and functioning of hormone receptors.

•8.4.2 Sources of Endocrine Disruptors
•Chemicals capable of acting as endocrine disruptors are ubiquitous in our environment. They
can be found in:
(a) The natural environment (air, water, soil);
(b) Food products (soybeans, legumes, flax, yams and clover);
(c) Plants (phytoestrogens are chemicals naturally found in plants that can act as endocrine
disruptors and are present in fruits, veggies, beans and grasses);
(d) Household products (breakdown products of detergents and associated surfactants,
including nonylphenol and octylphenol);
(e) Pesticides (o,p’-DDT, endosulfan, atrazine, nitrofen and tributyl tin);
(f) Plastics (bisphenol A, phthalates);
(g) Pharmaceuticals (drug oestrogens - birth control pills, DES, cimetidine);

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Cont.
(h) Industrial chemicals (polychlorinated biphenyls (PCBs), dioxin and
benzo(a)pyrene);
(i) By-products of incineration, paper production and fuel combustion; and
(j) Metals (cadmium, lead, mercury).
•We are exposed to these various endocrine disruptors by eating and drinking them,
breathing them, and using them whether at home or at work.

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8.5 MODE OF ACTION
•Here, we discuss the mode of action associated with endocrine disruptors.
•8.5.1 Interaction with Lipids or Amino Acids
•Most EDs may interact with the effects of lipids (steroid) or amino acid derived (thyroid)
hormones, while a few interact with peptide/protein hormone synthesis or signalling. However,
effects of EDs through steroid receptors on peptide/protein hormones are common.
•8.5.2 Direct Effect on Genes
•Other less well explored mechanisms of action of EDs are direct effects on genes. Oestrogens
and EDs with estrogenic action were, for example, suggested as causing DNA damage, thereby
promoting malignant differentiation of affected cells. A troubling new aspect is their epigenetic
impact; the amount of methylation of genes occurring early in life may have profound effects
years later and may even be transgenerationally inherited.

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•8.5.3 EDs Interference
•Most EDs interfere with reproduction. They act as either agonists or antagonists
of the steroidal sex hormones, oestrogens or androgens. A number of EDs
interfere with the daily necessity of coping with internal or environmental stress
and other adverse events.
•Fortunately, very few EDs exert a life-threatening impact through interference
with hormone systems necessary to maintain basic life-sustaining mechanisms.
Nevertheless, the effects of some EDs may be life-threatening because they may
interfere with the normal functions of organs or cause malignancies of these
organs.
•Figure 8.2 shows the mechanism of action of endocrine disruptors.

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Figure 8.2: Mechanism of action of endocrine disruptors
Source: www.hormones.gr/pdf/HORMONES%202010%209-15.pdf

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8.6 HORMONES AND CANCERS
•There are a number of effects on the human reproductive system that have been observed and
documented. Although some are contentious, some are clearly established. There has been an
undeniable increase in testicular cancer and breast cancer since 1945, particularly in certain
countries.
•Most scientists do not believe that hormones cause or initiate cancer, but some hormones may
promote cancer growth. This promotion may result in cancer that appears at a younger age than
expected, or in a cancer that grows at a faster rate. These findings suggest that chemicals that
act like hormones may also promote cancers. In women, oestrogen is thought to play a role in
the promotion of some forms of breast cancer. Based on a single epidemiological study, the
presence of DDE, a metabolite of DDT, has been associated with increased risk of breast
cancer. However, more recent studies provide strong evidence that there is no relationship
between DDE exposure and breast cancer. Other studies suggest that specific phytoestrogens
and certain PCBs and dioxins can block oestrogen from promoting some forms of breast cancer.

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• Speculated health effect from EDCs can be seen as below:
• Reproductive effects/birth defects;
• Cancer;
• Low sperm count/sexual dysfunction;
• Heart disease;
• Cognitive disorders;
• Sex reversal;
• Premature puberty; and
• Altered immune function.

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8.7 TESTING ESTROGENICITY
•Although oestrogen is often considered the female hormone, oestrogen hormones play
important developmental and sexual function roles in both women and men. However ensuring
proper oestrogen levels is also important for other reasons. Altered levels in women can signal
pregnancy or menopause or more serious medical problems in men. Oestrogen tests can be
conducted at a doctor's office, but many kits are also available for at-home testing. Oestrogen
can be either good oestrogen 2 (methoxyestrone) which is cancer protective or bad oestrogen
16 (hydroxyestrone) which is cancer causing.
•There are three different types of oestrogen:
(a) Estradiol E2: Predominant type of oestrogen in a menstruating woman;
(b) Estriol E3: Predominant type of oestrogen in a pregnant woman; and
(c) Estrone E1: Predominant type of oestrogen in a post-menopausal woman.

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•Oestrogen tests may be used for a variety of reasons:
(a) Estrone levels may be elevated in patients with polycystic ovarian syndrome and
endometriosis. Tests may be used to aid in the diagnosis of an ovarian tumour, Turner
syndrome and hypopituitarism. In males, it may help in the diagnosis of the cause of
gynecomastia or in the detection of oestrogen-producing tumours.
(b) Estradiol levels are used in evaluating ovarian function. Estradiol levels are increased in
cases of early (precocious) puberty in girls and gynecomastia in men. Its main use has
been in the differential diagnosis of amenorrhea - for example, to determine whether the
cause is menopause, pregnancy or a medical problem. In assisted reproductive technology
(ART), serial measurements are used to monitor follicle development in the ovary in the
days prior to in vitro fertilisation. Estradiol is also sometimes used to monitor menopausal
hormone replacement therapy. A doctor may sometimes order a total oestrogen test.
This test measures oestrone and estradiol together but does not measure estriol.

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(c) Estriol may sometimes be ordered serially to help monitor a high risk pregnancy.
When it is used this way, each sample should be drawn at the same time each day.
An unconjugated estriol test, one that measures estriol that is not bound to a protein, is one
of the components of the triple or quad screen. Decreased levels have been associated with
various genetic disorders including Down syndrome, neural tube defects, and adrenal
abnormalities.
It is ordered during pregnancy, along with maternal alpha-fetoprotein (AFP maternal),
human chorionic gonadotropin (hCG), and inhibin-A tests, to assess the risk of carrying a
foetus with certain abnormalities.

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8.8 MUTAGEN
A mutagen is a natural or man-made agent (physical or chemical) which can alter the structure or
sequence of DNA. Characteristics of mutagens can be seen as follows:
(a) Causing DNA damage that can be converted to mutations.
(b) Physical mutagens
(i) High-energy ionising radiation;
(ii) X-rays and γ-rays - strand breaks and base/sugar destruction;
(iii) Non-ionising radiation; and
(iv) UV light - pyrimidine dimers.
(c) Chemical mutagens
(i) Base analogues - direct mutagenesis
(ii) Nitrous acid - deaminates C to produce U
(iii) Alkylating agents
(iv) Arylating agents indirect-lesion mutagenesis
(v) Intercalators: e.g. EB

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8.9 MUTATION
•A mutation is a process by which the heredity constitution of a cell is altered,
ultimately resulting in a genetically altered population of cells or organism. Although
mutations can occur in the RNA of viruses and the DNA of cytoplasmic organelles,
the mutations of greatest interest occur within genes in the nucleus of the cell.
•The human body is estimated to contain more than 10 trillion cells, and at some stage
in its life cycle contains a full complement of the genes needed by the entire
organism.
•Genes, composed of DNA in the nucleus of cells, are clustered together in
chromosomes. In the chromosomes of all but the most primitive organisms, DNA is
combined with protein.
The definition of mutation can be summed up as:
Permanent, heritable alterations in the base sequence of DNA.

80
•DNA, the molecular basis of heredity in higher organisms, is made up of a double helix held
together by hydrogen bonds between purine and pyrimidine bases,
•e.g. between adenine (A) and thymine (T), and between guanine and cytosine (C).
•The highly specific complementarity of these bases enables DNA to act as a template for its
replication by DNA polymerases, as well as the synthesis of RNA transcripts by RNA
polymerases (see Figure 8.3).
•For the information contained in DNA to be biologically expressed, the sequence of the
nucleotides in a gene is converted into a sequence that determines the enzymatic and structural
properties of the protein thus formed.
•DNA clearly plays a pivotal role in the expression and perpetuation of life. However, it is also
a critical target for the action of many mutagenic environmental chemicals; lesions in DNA
may occur through the action of physical or chemical agents found in the environment.
Occurrence of mutation, however, depends on the nature of the initial lesion and the response
of cells to the DNA damage.

81
Figure 8.3: The structures of the five bases in DNA and RNA
Mutation happens due to several reasons:
(a) DNA Fails to Copy Accurately
Most of the mutations that people think matter to evolution are "naturally occurring”. For example, when a cell divides, it makes a copy
of its DNA - and sometimes the copy is not quite perfect. That small difference from the original DNA sequence is a mutation.
(a) External Influences can Create Mutations
Mutations can also be caused by exposure to specific chemicals or radiation. These agents cause the DNA to break down. This is not
necessarily unnatural - even in the most isolated and pristine environments, DNA breaks down. Nevertheless, when the cell repairs the
DNA, it might not do a perfect job of the repair. So, the cell would end up with DNA slightly different than the original DNA and
hence, a mutation.

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8.10 TYPES OF MUTATION
•There are many different ways that DNA can be changed, resulting in different types of
mutation. They are:
(a) Substitution
• A substitution is a mutation that exchanges one base for another (e.g., a change in a single
"chemical letter" such as switching an A to a G as in Figure 8.4). Such a substitution could:
(i) Change a codon to one that encodes a different amino acid and cause a small change in
the protein produced. For example, sickle cell anaemia is caused by a substitution in the
beta-haemoglobin gene, which alters a single amino acid in the protein produced.
(ii) Change a codon to one that encodes the same amino acid and causes no change in the
protein produced. These are called silent mutations.
(iii) Change an amino-acid-coding codon to a single "stop" codon and cause an incomplete
protein. This can have serious effects since the incomplete protein probably would not
function.

83
Figure 8.4: Change of codon
Illustrations of codon changes can be further seen in Figures 8.5, 8.6 and 8.7.
Figure 8.5: Illustration of codon changes

84

85
(b) Insertion
• Insertion is “the addition of one or more bases in a DNA region”. Insertions are
mutations in which extra base pairs are inserted into a new place in the DNA (as in
Figure 8.8).
•
Figure 8.8: Insertions of extra base pairs

86
(c) Deletion
• Deletion is “the loss of one or more bases in a DNA region”. Deletions are
mutations in which a section of DNA is lost, or deleted (as in Figure 8.9).
Figure 8.9: Illustration of deletion

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(d) Frame shift
• Since protein-coding DNA is divided into codons three bases long, insertions and deletions can alter a gene so
that its message is no longer correctly analysed.
• These changes are called frame shifts. For example, consider the sentence, "The fat cat sat." Each word
represents a codon. If we delete the first letter and analyse the sentence in the same way, it does not make
sense. In frame shifts, a similar error occurs at the DNA level, causing the codons to be analysed incorrectly.
This usually generates shortened proteins that are as useless as "hef atc ats at" is uninformative.
Figure 8.10: Illustration of frame shift

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8.11 EFFECT OF MUTAGENS
•Mutagens cause changes to the DNA that can affect the transcription and replication of the
DNA, which in severe cases can lead to cell death. The mutagen produces mutations in the
DNA, and deleterious mutation can result in abnormal, impaired or loss of function for a
particular gene, and accumulation of mutations may lead to cancer.
•Different mutagens act on the DNA differently. Powerful mutagens may result in
chromosomal instability, causing chromosomal breakages and rearrangement of the
chromosomes such as translocation, deletion and inversion. Such mutagens are called
clastogens.
• Mutagens may also modify the DNA sequence. The changes in nucleic acid sequences by
mutations include substitution of nucleotide basepairs and insertions and deletions of one or
more nucleotides in DNA sequences.

89
•Although some of these mutations are lethal or can cause serious disease, many have minor
effects as they do not result in residue changes that have significant effect on the structure
and function of the proteins.
•Many mutations are silent mutations, causing no visible effects at all, either because they
occur in noncoding or non-functional sequences, or they do not change the amino-acid
sequence due to the redundancy of codons.
•Some mutagens can cause aneuploidy and change the number of chromosomes in the cell.
However, some propose that low levels of some mutagens may stimulate the DNA repair
processes and therefore may not necessarily be harmful.

90
8.11.1 Types of Mutagens
•The types of mutagens are as follows:
(a) Ionising Radiation
• Nuclear radiation, X-rays, gamma rays (e.g. medical treatment) associated with
development of cancers (e.g. leukaemia, thyroid cancer and skin cancer).
(b) Viruses and Microorganisms
• These integrate into human chromosome, upset genes and can trigger cancer.
(c) Environmental Poisons
• Organic solvents such as formaldehyde, tobacco, coal tars, benzene, asbestos, some dyes.
(d) Alcohol and Diet
• High alcohol intake increases the risk of some cancers. Diet high in fat and containing
burned or highly preserved meat.

91
8.11.2 The Effects of Mutations
•The effects of mutations are:
(a) Not all are harmful;
(b) Survival advantage;
(c) Most common among bacteria and viruses but also seen in insects; and
(d) If there is no selective pressure, it may remain in population

92
8.11.3 Harmful Mutations
•Harmful mutations can be seen as:
(a) Cystic fibrosis and sickle cell anaemia;
(b) Dysfunctional proteins; and
(c) Albinism - caused by mutation in gene of enzyme pathway of melanin.
•8.11.4 Beneficial Mutations
•Beneficial mutations include:
(a) Bacteria - antibiotic resistance through mutation, transfer between bacterial species;
(b) Superbugs such as methicillin resistant Staphylococcus (MRSA) have arisen this way; and
(c) RNA viruses - such as HIV - mutate its protein coat so that the host human is unable to
make antibodies quick enough against it.

93
8.11.5 Neutral Mutations
•Neutral mutations are:
(a) Neither harmful or beneficial to the organism but may be important in an
evolutionary sense;
(b) Silent mutations; and
(c) Virtually impossible to detect because no observable effect.

94
8.12 INDUCTION OF MUTATION
•An induction of mutation is a mutation that is produced by treatment with a physical or
chemical agent that affects the deoxyribonucleic acid molecules of a living organism.
Mutations which are artificially induced with the help of mutagenic agents are called induced
mutations.
• Remember that the previous notes had mentioned that some mutations arise as natural
errors in DNA replication (or as a result of unknown chemical reactions); these are known
as spontaneous mutations. The rates of such mutations have been determined for many
species. Example, E. coli has a spontaneous mutation rate of 1/108 (one error in every 108
nucleotides replicated).
• Humans have a higher spontaneous mutation rate: between 1/106 and 1/105 (probably as a
result of the higher complexity of human replication).

95
•Mutations can also be caused by agents in the environment; these are induced
mutations. Induced mutations increase the mutation rate over the spontaneous rate.
Looking at a single mutation in an individual, one cannot tell if the mutation is
spontaneous or induced.
•Induced mutations can only be discerned by looking at the mutation rate in a
population, and comparing it to the spontaneous mutation rate for the species. If the
observed mutation rate is higher, then induced mutations can be assumed. Agents in the
environment that cause an increase in the mutation rate are called mutagens.

96
•8.12.1 Causes of Inductions
•Induced mutations on the molecular level can be caused by:
(a) Chemicals
(i) Hydroxylamine NH2OH.
(ii) Base analogues (e.g. BrdU).
(iii) Alkylating agents (e.g. N-ethyl-nitrosourea) These agents can mutate both replicating and non-replicating
DNA. In contrast, a base analogue can only mutate the DNA when the analogue is incorporated in
replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to
transitions, transversions or deletions.
(iv) Agents that form DNA adducts (e.g. ochratoxin metabolites).
(v) DNA intercalating agents (e.g. ethidium bromide).
(vi) DNA crosslinkers.
(vii) Oxidative damage.
(viii)Nitrous acid converts amine groups on A and C to diazo groups, altering their hydrogen bonding patterns
which leads to incorrect base pairing during replication.

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(b) Radiation
• Ultraviolet radiation (non-ionising radiation).
• Two nucleotide bases in DNA - cytosine and thymine - are most vulnerable to radiation
that can change their properties. UV light can induce adjacent pyrimidine bases in a DNA
strand to become covalently joined as a pyrimidine dimer. UV radiation, particularly
longer-wave UVA, can also cause oxidative damage to DNA.
• Mutation rates also vary across species. Evolutionary biologists] have theorised that higher
mutation rates are beneficial in some situations, because they allow organisms to evolve
and therefore adapt more quickly to their environments.
• For example, repeated exposure of bacteria to antibiotics, and selection of resistant
mutants, can result in the selection of bacteria that have a much higher mutation rate than
the original population (mutator strain).

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END OF TOPIC 8

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