Transcript Fertility, pregnancy outcome and metals

Mechanisms of male
reproductive toxicity
Markku Sallmén
Finnish Institute of Occupational Health
Time trends in male reproductive
health
Declining semen quality
 Increasing incidence of hypospadias
and cryptorchidism
 Increasing incidence in testicular cancer
in Northern European countries
including Estonia and Finland

=> are there common causal environmental
factors behind?
Timing of male reproductive
hazards

The adult life:
most studies on male reproductive
health have focused on this period

Prenatally (examples):
ionizing radiation, cadmium, oestrogens
(diethylstilbestrol, DES)
Sex-dependent differences in
germ cell kinetics

Male: germ cells undergo expensive
mitosis during fetal development, but do
not enter meiosis before puberty

Female: germ cells initiate their first
meiotic division before birth
Prenatal events
O
E
Synthesis of Müllerian
Inhibiting Substance
in fetal Sertoli cells
Postnatal manifestations
Proliferation of
Sertoli cells
Impaired
spermatiogenesis
Normal germ
cell division
Testicular
cancer
Regression of
Müllerian
ducts
Cryptorchidism
S
T
R
O
G
Synthesis of
Testosterone in fetal
Leydic cells
E
Poor virilization
N
S
Adapted from Bonde and Giwercman (1995)
Site of action of male
reproductive toxicants
Affected site
Exposure
Epididymis
Epicholorohydrin, Chlorometahane
Spermatid
Chlorometahane
Spermatocyte
Heat
Spermatogonium
DBCP
Sertoli cell
Phtalate esters, dinitrobenzene
Leydig cells
Ethanol
Capillary
Cadmium
Adapted from Bonde and Giwercman (1995)
Severity of the damage and site
of action
Affected site
Effect
Spermatogonium
azoospermia without recovery
Spermatocyte and
decreased capacity to reproduce
Spermatids
transient (stem cells unaffected)
Epididymial or testicular
transient impairment of sperm
spermatozoa
motility, decreased viability
Adapted from Bonde and Giwercman (1995)
Severity of the damage and site
of action
Affected site
Effect
Sertoli cells
number and morphology of
sperm cells, may be irreversible
Leydig cells
reduced testosterone and thus
disturbance of Sertoli cell function
Hypothalamus - Pituitary axis
disturbed endocrine homeostasis,
reduced semen quality
Adapted from Bonde and Giwercman (1995)
Male-mediated developmental
toxicity
gene mutation
 chromosomal abnormalities
 spontaneous abortion
 congenital malformations
 cancer

Male-mediated developmental
toxicity: mechanisms

Direct germ-cell effects by either genetic
or epigenetic mechanisms

Indirect effects by transmission of
agents to the mother via seminal fluid
and maternal exposure to toxicants
brought home by the father
Male-mediated developmental
toxicity: mechanisms

Seminal fluid transfer:
methadone, cyclophosphamide

Household contamination:
lead, beryllium, polychlorinated
biphenyls
Epigenetic mechanisms

Change in gene activity during
development (without gene or
chromosomal mutations!)

genomic imprinting for example through
change in DNA methylation or removal
of proteins that control imprinting
Epigenetic mechanisms

5-azazytidine, a non-mutagenic
chemical

exposure in vitro has caused 10-30% of
previously inactive genes to become
reactivated
corresponds about 1 million-fold increase over
spontaneous reversion rates
Lead: proposed mechanisms of
developmental toxicity
Seminal fluid transfer
 Household contamination
 Direct toxic effects on sperm
 Mutations
 Epigenetic effects
 Effects on chromatin stability

Lead: epigenetic effects
Gandley et al. Environ Research 1999
 Fertility was reduced in male rats with
PbB 27-60 µg/dl
 Changes in 2-cell gene expression with
PbB 15-23 µg/dl
Lead may affect fetal development in
the absence of decreased fertility
Lead: effects on chromatin
stability
 Chromatin
structure altered at rather low
exposure
 Lead and other cations (mercury,
copper) may replace zinc in chromatin
structure
=> Failure or delay in sperm chromatin
decondensation in fertilitzation process
=> reduced fertility or DNA damage
possible