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Autoimmunity
Immune enhancement
Immune suppression
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