Toksikologi pada Organ 3

(Sistem Imun Reproduksi dan Perkembangan)

Tim Pengampu Toksikologi Veteriner

FAKULTAS KEDOKTERAN HEWAN
UNIVERSITAS BRAWIJAYA
2020
Tujuan Pembelajaran
 Memahami dan menjelaskan tentang
pengaruh senyawa toksik pada sistem
imun, reproduksi dan perkembangan
Sistem imun
Immunotoxicity
 The study of toxic effects of chemicals (or in some
cases physical agents such as radiation) on the
immune systems
The Immune System
 The immune system is a very complex and
regulated organ system
 Involving the cooperation and interaction of a
number of different cell types, cell products,
tissues, and organs.
 The immune system consists of :
 Primary (i.e., thymus and bone marrow
 Secondary (i.e., spleen, lymph nodes, and gut-
associated) lymphoid tissue, and various
circulating immunocompetent cells
Scenarios by which chemicals, drugs and other
xenobiotics may lead to alterations in immune
function

(House et al., 2006)

Cellular components of the immune system and their functions in
mammals
Major cytokines involved in
Immune Responses
The main symptoms caused by immunotoxic
agents
Hypersensitivity

• Drug hypersensitivity is a cause of morbidity and to a lesser extent

mortality.

Autoimmunity

• occur as a result of tolerance loss or induction of sensitivity.

Immune enhancement

• causes over stimulation of the immune response

• can lead to gross inflammation and tissue damage.

Immune suppression

• lowers the activity of the immune system : including surveillance,

e.g. the elimination of tumour cells.
• This type of response can give recurrent infections with increased
severity and neoplastic cell growth.
Mechanism
Direct Effect of Xenobiotics
 Affect immune function (humoral, cell-mediated,
innate, or host resistance)
 The size, composition (e.g., alterations in the
numbers, or differentiation and maturation of B-
or T-lymphocytes)
 Architecture of lymphoid organs
 Hematological parameters
 Cytokine production and/or release
 The expression of receptors or ligands on the
surface of immune cells
 Receptor mediated signal transduction
Example of immunotoxic effects of
Mycotoxins in domestic or food animals
Metals evaluated in domestic or food
animals for immunotoxic potential
Contaminants in feed that may influence
immune response in domestic or food
animals
Clinical or toxicological tests indicate of
compromised immunologic response
SISTEM REPRODUKSI DAN
PERKEMBANGAN
 Mechanism of Toxicity
Developmental toxicity depends on the stage of
embryonic development and factors that modify the
toxicity of the xenobiotic
These factors are
 fetal and parental genotypes
 the maternal environment
 the placenta
 A. CRITICAL PHASE OF INTRAUTERINE
DEVELOPMENT
 The critical period of intrauterine development is
that time during development at which the embryo
or fetus has the greatest sensitivity to noxious
influences.

 Since the critical period is known for many organs in

several species, hypotheses about cause of a
specific defect can be made
Each organ, or organ system, has a particular critical period, hence exposure to
xenobiotics at different times of Development is likely to produce lesions in different
organ systems depending on their critical period
B. MODIFYING FACTORS

1. Embryo and Fetus

a. Embryonic and fetal genotype
b. Embryonic and fetal pharmacokinetics

2. Mother
a. Maternal physiologic state
b. Maternal pharmacokinetics
3. Father
a. Direct effect on the sperm
b. Abnormalities in seminal fluid.

4. Placenta
a. Placental transfer of teratogens.
b. Placental pharmacokinetics
 1. Embryo and Fetus
a. Embryonic and fetal genotype
 Species differences in expression of defective development
following xenobiotic exposure have been clearly shown in
experiments using some compounds.
 The classic example is thalidomide,  teratogenic in
humans, nonhuman primates, and certain rabbit strains, but
nonteratogenic in rodent species and chicken embryos
 Similarly, glucocorticoids are teratogenic in mice, but not in
rats
 Species differences in teratogenic response are probably a
manifestation of the pharmacokinetic properties of the
teratogens, the individual rate of teratogen transfer across
the placenta, and species-specific differences in sensitivity
inherent in target cells or their receptors.
b. Embryonic and fetal pharmacokinetics
 In addition to phylogenetic differences, variability exists
among species in the ontogeny of the monooxygenase
system.
 Unlike most laboratory animals, human fetal liver and
adrenal glands possess cytochrome P-450, NADPH-
cytochrome C reductase, NADPHcytochrome P-450
reductase, cytochrome b 5, and NADH-cytochrome C
reductase as early as 6-8 weeks of gestation
 Laboratory animals with shorter gestation periods show
this activity earlier.
 Since these enzymes are capable of affecting sidechain
hydroxylation, aromatic hydroxylation, N-demethylation,
nitroreduction, and, to a limited extent, glucuronic acid
conjugation, a human fetus can metabolize many
foreign compounds to which it is exposed
2. Mother
a. Maternal physiologic state
 Alterations in material homeostasis must be severe to
affect the fetus, since the needs of the fetus are
usually met at the expense of the mother
 Approximately 3.5% of all congenital malformations in
humans relate to :
 thyroid disorders (hyperthyroidism—fetal goiter and
tracheal obstruction; hypothyroidism— cretinism,
deafness, and mental retardation)
 diabetes (caudal regression syndrome)
 phenylketonuria (microcephaly, mental retardation, and
congenital heart disease)
 virilizing tumors (pseudohermaphroditism)
 malnutrition (abortion, stillbirths, neonatal deaths, and
neural tube defects).
b. Maternal pharmacokinetics
 Absorption decreases during pregnancy, in part
because of reduced gastrointestinal motility and
decreased gastrointestinal metabolism of
substances.
 In addition, the volume of distribution markedly
increases during pregnancy, because of increased
total body water and body fat.
 This increase in volume, along with decreased
absorption, leads to decreases in the initial blood
concentration of blood-borne xenobiotics.
 3. Father
a. Direct effect on the sperm
 Teratospermia is the induction of microscopic
pathological changes in the sperm.
 This alteration may follow exposure to some substances.
 For example, paternal poisoning with lead sufficient to
cause clinical toxicity results in teratospermia, which
may result in reduced fertility and reduced birth weights
of the offspring.
 Direct action of compounds on sperm may reduce
ribosomal activity, impair protein synthesis, and reduce
their RNA content.
 In addition, some compounds may produce
anatomical abnormalities, chromosomal damage, or
alterations in sperm motility
b. Abnormalities in seminal fluid

 Xenobiotics dissolved in the seminal fluid can induce :

 secondary morphological abnormalities in sperm
 impaired sperm motility
 impaired viability
 Dissolved toxins may also have some influence on the
uterus, either by direct action or through systemic
absorption.
 Subsequent effects on the timing of implantation,
distribution of implantation sites, and placentation are
possible; these compounds may be directly toxic to
the developing embryo
 4. Placenta
a. Placental transfer of teratogens.
 The rate at which xenobiotics are transported across the
placenta determine whether toxic levels reach the fetus.
 The major physicochemical factors affecting
transmembrane passage apply to the placenta
 lipid solubility
 molecular size and weight
 Ioniccharge
 structural configuration
 However, the placenta produces steroids and hormones
and has diverse and complex functions, thus dispelling
the concept that the placenta is just a semipermeable
membrane.
 Since most drugs are absorbed by the process of passive
diffusion, as the lipid solubility increases, the rate of
transport also increases
Placental pharmacokinetics
 Placental metabolic capabilities play a minor role
in the modulation of fetal drug exposure, since
enzyme activities are minimal
 A generalized decrease in nutrient transport has
been observed when xenobiotics such as
cadmium and trypan blue bind to the placenta.
 The placenta does not appear to act as a sink for
chemicals, but sequestration of certain substances
can obstruct its function.
 For example, cortisone exposure decreases
glucose transport and methyl mercury inhibits
amino acid transport.
Classes of reproductive toxicants
1. Agents that interfere with the activity of hormones at
their receptors
 Clomiphene and tamoxifen
 Oral contraceptives
 Xenoestrogens (genistein and other isoflavones in clover,
soybeans, alfalfa, fruits and vegetables)
 Pesticides (DDT, PCBs, dioxin, kepone)

2. Agents that interfere with steroid hormone

metabolism
 Inhibitors: danazol, ketoconazole, metyrapone,
aromatase inhibitors
 Inducers: methoxychlor, heptochlor, chlordane, DDT, and
other organochlorine pesticides, dioxin
 Classes of reproductive toxicants
3. Agents that affect Sertoli cells in the testes
 Dibromochloropropane
 Monoethylhexylphthalate
 n-Hexane
 Tetrahydrocannabinol

4. Agents that affect Leydig cell function

 Cadmium
 Inhibitors of androgen synthesis
Classes of reproductive toxicants
5. Agents that affect germ cell chromosomes/DNA
 Mercury, lead, cadmium
 Alkylating agents and other cytotoxic agents
(cyclophosphamide, chlorambucil, busulfan,
methotrexate, adriamycin, cytosine-arabinoside,
vincristine, vinblastine)
(Plumlee, 2004)
(Plumlee, 2004)