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 immunotoxicagents

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

Hypersensitivity

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

Autoimmunity

• causes over stimulation of the immune response

• can lead to gross inflammation and tissue damage.

Immune enhancement

• 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.

Immune suppression

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 Fetusa. Embryonic and fetal genotype

Species differences in expression of defective developmentfollowing 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 monooxygenasesystem.

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 sidechainhydroxylation, 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. Mothera. 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. Fathera. 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, oralterations 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. Placentaa. 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 hormonemetabolism

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

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)

Classes of reproductive toxicants

(Plumlee, 2004)

(Plumlee, 2004)