Mechanisms of male reproductive toxicity

1
Mechanisms of male reproductive toxicity

• Markku Sallmén
• Finnish Institute of Occupational Health

2
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
• gt are there common causal environmental factors
  behind?

3
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)

4
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

5
Prenatal events
Postnatal manifestations
O E S T R O G E N S
Synthesis of Müllerian Inhibiting Substance in
fetal Sertoli cells
Proliferation of Sertoli cells
Impaired spermatiogenesis
Normal germ cell division
Testicular cancer
Regression of Müllerian ducts
Cryptorchidism
Synthesis of Testosterone in fetal Leydic cells
Poor virilization
Adapted from Bonde and Giwercman (1995)
6
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)
7
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)
8
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)
9
Male-mediated developmental toxicity

• gene mutation
• chromosomal abnormalities
• spontaneous abortion
• congenital malformations
• cancer

10
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

11
Male-mediated developmental toxicity mechanisms

• Seminal fluid transfer
• methadone, cyclophosphamide
• Household contamination
• lead, beryllium, polychlorinated biphenyls

12
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

13
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

14
Lead proposed mechanisms of developmental
toxicity

• Seminal fluid transfer
• Household contamination
• Direct toxic effects on sperm
• Mutations
• Epigenetic effects
• Effects on chromatin stability

15
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

16
Lead effects on chromatin stability

• Chromatin structure altered at rather low
  exposure
• Lead and other cations (mercury, copper) may
  replace zinc in chromatin structure
• gt Failure or delay in sperm chromatin
  decondensation in fertilitzation process
• gt reduced fertility or DNA damage possible