persistent organic pollutant

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Environmental Toxicology
Persistent organic pollutants How do persistent
pollutants affect living organisms
By ANWAR KEMAL
June, 2022
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Environmental toxicology Persistent organic
pollutants
How do persistent pollutants affect living
organisms
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Outline of the presentation

• Introduction
• Detoxifying enzymes
• Persistent pollutants effects and research at
  different biological levels
• Hydoxymetabolites
• Methylsulphonyl metabolites
• Dioxins
• Effect on thymus and immune system
• Foetal damage and skin changes
• Role in the development of cancer
• Effects on sex hormone

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Introduction

• Many persistent pollutants seem to be capable of
  triggering a long chain of disturbances in an
  organism.
• The most apparent changes are the secondary
  results 0f primary effect.
• Secondary effects can in turn pave the way for
  further consequences-such as emaciations or
  infection.
• Signalling and regulatory systems sensitive to
  chemical interference.
• The search for the basic mechanisms by which POP
  cause damage needs to focus on the extremely
  intricate processes that takes place at the
  molecular level, within and between individuals
  cells populations.

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Introduction . . .
Populations
Understanding effects of persistent pollutants
Secondary effects of molecular level disturbance
Individuals
Tissues organs
Cells
Molecules
Primary effect of foreign substances
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Introduction . . . Contd

• Initially, the influence of a foreign substance
  on an organisms assumes of the form of
  disturbances at the molecular level.

Endocrine and related organs
Pituitary gland
Thyroid gland
Thymus
Adrenal gland
Pancreas
Testicles
Ovaries
Kidney
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Role of Detoxifying Enzymes

• Most species have developed methods of achieving
  the chemical transformation.
• Animals respond to harmful substance by
  developing enzymes which metabolize and detoxify
  the chemicals.
• The most important of this kind belong to a large
  family referred to as cytochrome p450s.
• Normally levels of these enzymes are relatively
  low, but in certain cases liver cells can react
  to an input of a foreign substance by
  forming/releasing a large quantity of a suitable
  cytochrome p450.
• Usually, the net effect that a molecule reacting
  with cytochrome p450nenzyme that it has an oxygen
  atom attached to it.
• This can render stable compounds considerably
  less stable and more reactive, paving the way for
  further chemical changes.

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Persistent molecules effects and research at
different biological events.

• Once oxidized, originally lipid-soluble
  substances can combine with polar molecules and
  thus become water-soluble and they are then
  rapidly excreted in urine or faces.
• Certain foreign substances when oxidized by
  cytochrome p450, are converted in to reactive
  metabolites which are more toxic that the
  original compounds.
• some metabolites are genotoxic they can react
  with DNA to form adducts.
• The adducts are gradually released from the chain
  replaced with links of the original type. E.g.
  PAHs, such as benzopyrene

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Persistent molecules effects and research at
different biological events

• Hydroxy metabolite effects on hormone transport
• Most persistent pollutants become so reactive
  following oxidation that they immediately undergo
  further chemical changes, long before they can
  come into contact with DNA molecules with cell
  nuclei.
• neither PCBs nor dioxins appear to have any
  appreciable genotoxic effects
• Substitution of hydroxy or hydroxyl OH groups for
  the O2 atoms added by the detoxifying enzymes.
• The hydroxy (or phenol metabolites thus produced
  are more soluble in water than the original
  compounds)

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Hydroxy metabolite effects on hormone transport .
. . Contd

• Some hydroxy metabolites of PCB are retained in
  living organisms.
• They can also accumulate in the fetuses of
  pregnant animals.
• The OH group of hydroxy metabolites usually
  located at one end of the molecule between two
  chlorine atoms.
• A similar structure is found in thyroid hormone
  thyroxine (T4), which contains an OH group placed
  between two iodine atoms.
• This structure fits a particular site on protein
  molecules in blood.

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FIG. 1. GC/ECD chromatograms of methylsulfonyl
PCB metabolites in the livers of rats (A), guinea
pigs (B), and hamsters (C) after exposure to
Kanechlor 500 (100 mg/kg i.p.).  
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Hydroxy metabolites and the thyroid hormone

• The protein concerned, transthyretin (TTR), is
  able to pickup the thyroxine produced in the
  thyroid gland and carry it to other parts of the
  body via the blood stream.
• Several metabolites with structure in question
  bind at least ten times more strongly to TTR than
  the thyroxine itself.
• this is why these metabolites are retained so
  effectively in the body
• The transfer of thyroid hormones to foetus and
  brain can be partly supplanted by a transfer of
  toxic contaminants.
• High concentration of hydroxy metabolites and
  also certain biochemical changes have been
  observed in the brains of rat fetuses.

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Methyl sulphonyl metabolites

• Methylsulphonyl metabolites of PCBs are retained
  fairly efficiently in the body, partly because
  they are reasonably soluble in lipids.
• In humans, a protein similar to Methylsulphonyl
  causes respiratory symptoms.
• Certain methylsulphonyl metabolites of PCBs also
  accumulate in the renal cortex, liver, prostate
  gland or brains of mammals/birds.
• DDE, too, can be metabolized to a persistent and
  lipid soluble methylsulphonyl compound.
• Methylsulphonyl-DDE builds up in the adrenal
  cortex

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Methyl sulphonyl metabolites . . . Contd

• Experiments in mice
• In their adrenal gland, it is transformed in to a
  reactive metabolite that can attack the cells
  own proteins.
• This transformation is catalyzed by cytochrome
  p450-IIB.
• The gene for the construction of this particular
  enzyme is only expressed in the adrenal cortex,
  but the reactive metabolite forms in such
  quantities that it can have toxic effects.

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Methyl sulphonyl metabolites . . . Contd

• In humans, adrenal gland secrete hormones which
  regulate metabolism and kidney function.
• If metabolites of persistent pollutants
  accumulate in sufficient quantities to damage the
  adrenal cortex, therefore, there is a clear risk
  of far-reaching disturbances in the body.
• Most of the adverse effects of persistent
  pollutants on Baltic seals observed in recent
  decades appear to form part of a wide-ranging
  disease complex (known as hyperadrenocorticism)

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Dioxins

• Dioxins cause damage by transmitting false
  information by acting as chemical messengers.
• They bind effectively to a specific receptor, a
  protein in the cytoplasm known as Ah/dioxin
  recetor.
• The binding of dioxin to this receptor triggers a
  chain of reactions, the end result of which is
  that the receptor binds to a DNA sequence after
  entering the cell nucleus.
• One of the possible binding sites on the DNA
  molecule is the regulatory region for a gene
  (CYP-1A1) which holds the blue prints for an
  enzyme of the cytochrome p450 type.

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Dioxins . . . Contd

• Dioxins give rise to a whole complex of
  pathological changes.
• The symptoms can vary from one spp. to the other.
• They exhibit a characteristic pattern, a pattern
  that is produced by all the substances which bind
  to the Ah receptor.
• The dioxin congener TCDD is one of the compounds
  that is attracted most strongly to this receptor
  and which is thus toxic at the lowest doses.
• Several other dioxins have a similar structure
  but generally do not bind quite as strongly to Ah
  receptors as TCDD and larger doses therefore have
  to be given to achieve a comparable effect.

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Dioxins . . . Contd

• Certain PCB congeners also have a dioxin like
  structure and causes dioxin like toxicity.
• The most marked such effects are associated with
  congeners which entirely lack chlorine at the
  ortho positions and which are comparatively flat.
• however, PCBs with one chlorine atom in such
  positions also have something of a dioxin like
  effect, as do some PAHs and PCNs.

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Dioxins . . . Contd

• How do Dioxin-like compounds affect the thymus
  and immune system?
• High acute toxicity_ the most widely noted
  property of dioxin and dioxin-like compounds.
• In certain spp., very small single doses can
  result in death.
• death is preceded by gradual emaciation and
  normally does not occur until several weeks after
  exposure, even the doze is well-above the lowest
  lethal level.
• Symptoms include a marked reduction in the size
  of thymus.

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Dioxins . . . Contd

• How do Dioxin-like compounds affect the thymus
  and immune system?
• A key role performed T-lymphocytes
• Immature T-cells are formed in the bone marrow
  but subsequently migrate to the thymus which has
  the task of promoting their proliferation and
  teaching them to distinguish between the bodys
  own tissues and foreign cells/substances.
• Mature T cells leave the thymus and are carried
  to ther part of the body.
• Activated T-cells constantly patrol all the
  tissues of the organism.

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Dioxins . . . Contd

• How do Dioxin-like compounds affect the thymus
  and immune system?
• A key role performed T-lymphocytes
• Dioxin-like substances also result in the
  reduction of T-cells in the body making more
  susceptible to infection.
• Long-term damage occur if an individual exposed
  at the foetal stage in early life, when thymus
  activity is most intense and most important.

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Dioxins . . . Contd

• How do Dioxin-like compounds skin changes and
  foetal damage?
• Cause accelerated or derailed cell
  differentiation.
• Chloracne_is a characteristic symptom of dioxin
  poisoning in human beings, apes and few other
  spp.,
• Can be described as a result of abnormal
  differentiation of the cells of the epidermis of
  the skin.
• This change primarily manifested in increased
  production keratin.
• a contributory factor is that the cells in the
  sebaceous glands attached to the hair follicles
  and thickening and hardening of the epidermis.
• During the foetal period, disruption of cell
  differentiation can result in serious
  deformations.

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Dioxins . . . Contd

• Role in the development of cancer
• TCDD is one the most toxic pollutants known.
• None of the dioxin or dioxin-like compounds
  appear to be capable of triggering mutations.
• Unlike PAHs, they are unable to initiate the
  development of tumours.
• They paly a decisive role at later stage in the
  process.
• It is as a promoter that dioxins are so effective
  in causing tumours.
• tumour initiation can be the work of a moment,
  promotion is a time-consuming and protracted
  process

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Dioxins . . . Contd

• Role in the development of cancer
• Repeated or continuous intake of dioxins or other
  tumour promoting compounds is needed if tumour is
  really to become established.
• If promotion continues for long enough an
  initially benign tumour can begin to grow in a
  completely uncontrolled fashion and give rise to
  metastases.
• i.e, secondary tumours_the process has then moved
  from promotion to the progression stage and can
  no longer be stopped.

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Dioxins . . . Contd

• What are the underlying mechanisms of tumour
  promotion
• One possibility is that the exchange of
  substances which normally takes place between
  cell is blocked.
• Initiated cells normally kept in check by the
  chemical influence of neighbouring cells.
• But control is lost if the channels in the cell
  membrane are reduced in number or cease to
  function
• Experiments with TCDD and a dioxin-like PCB
  congener have shown that these substances bring
  about a marked reduction of connexin levels in
  rats liver tissues.

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Dioxins . . . Contd

• What are the underlying mechanisms of tumour
  promotion
• DDT and non-dioxin like PCBs can also reduce this
  chemical exchange of information between cells
  but in different way.
• An inability to promote tumour development has
  been demonstrated in a large number non-then are
  any thing like as active in this respect as the
  most toxic dioxins.

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Dioxins . . . Contd

• How disturb vitamin A metabolism and disrupt
  liver function
• Retinol
• Before vitamin A store din the liver, it has to
  be converted in to an ester, which is done with
  the help of an esterifying enzyme.
• Dioxins inhibit the action of esterifying enzyme
  and storage of vitamin A.
• At the same time, the enzymes activity in the
  kidneys increases and both kidney and blood
  levels of vitamin A rise.

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Dioxins . . . Contd

• How disturb vitamin A metabolism and disrupt
  liver function
• Retinol
• vitamin A metabolism disturbance result in
  numerous pathological changes including foetal
  damage, growth, disorders, sterility and
  increased keratin production in the epithelial
  tissue.
• Also increase risk of tumour promotion
• Other persistent organic pollutants, including
  DDT, lindane, chlolroparaffins and PBDs can also
  reduce vitamin A levels in the liver.

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Dioxins . . . Contd

• How disturb vitamin A metabolism and disrupt
  liver function
• Retinol
• Hydroxy metabolites of PCBs have a partly
  different impact on levels of vitamin A.
• such metabolites can bind to the carrier protein
  TTR and thus disturb thyroxine transport.
• One of the proteins which carries vitamin A to
  different parts of the body is normally coupled
  to TTR, but it has been found that this coupling
  does not work if the TTR molecule is carrying a
  hydroxy metabolite rather than thyroxin.
• Thus, where as dioxin-like substances raise blood
  levels of vitamin A, hydroxy-PCBs lowers.

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Dioxins . . . Contd

• How disturb vitamin A metabolism and disrupt
  liver function
• Retinol
• A condition known as hepatic porphyria can be
  caused by dioxin- like compounds.
• It is due to disruption of the process where by
  the liver produces haem.
• The result is the build up of porphyrins
  substance which represent an intermediate stage
  in the production of haem.
• The associated symptoms can include sensory
  disorders, paralysis and psychological effect.

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Dioxins . . . Contd
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Effects on sex hormones

• Natural breakdown of oestrogen in the body takes
  place under the influence of enzymes of c. P450
  type and it is conceivable that toxic pollutants
  could accelerate this process by inducing such
  enzymes.

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Effects on sex hormones

• Although originally an estrogen was defined as a
  compound that increase the uterine weight in the
  rats, in recent times, the ability to bind to the
  estrogen receptor has become the standard.
• However, the receptor is also the site for
  chemicals to exert their anti-estrogenic actions.
  
• In nature there are some 300 natural compounds,
  and even more anthropogenic compounds, which have
  estrogenic or anti-estrogenic activity.

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Effects on sex hormones

• The realization that hormones in physiological
  amounts could reach the environment, even after
  treatment of the sewage water, strengthened the
  search for the presence of pharmaceuticals and
  endocrine disruptor compounds in water sources.
• This led to the PPCP (Pharmaceutical and Personal
  Care Products) which came to include the
  steroidal estrogens and pharmaceuticals contained
  in sewage effluent.
• This initiated a world-wide search to determine
  the hormones and pharmaceuticals present in
  sewage water effluent, surface and ground water.

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Thank You