et al. reveal large differences among strains of mice in
their sensitivity to endocrine disruption by estrogen. Most dramatically,
they found that one strain of mice used widely in laboratory experiments
and selectively bred for large litter sizes is remarkably resistant
to developmental disruption by estrogen.
strain, the CD-1 strain developed by Charles Rivers laboratories,
has been used very widely in toxicological testing. It appears that
selection for large litter size, done because large litters increase
the economic efficiency of certain procedures in laboratory work,
may inadvertently have lowered estrogen sensitivity, making this
strain highly inappropriate to use in testing the potency of endocrine
disruptors. Spearow et al.'s concern "is that the
use of laboratory animals selected for large litter size in product
safety testing might underestimate the role of estrogenic agents
in disrupting juvenile reproductive development in other genotypes."
Spearow et al. used estrogen in these experiments, it is
reasonable to assume that similar variability exists in responsivity
to estrogen-mimicking contaminants.
paper is important for two reasons.
it clearly and compellingly documents that genetic differences
can affect sensitivity to endocrine disruption. "Monitoring
endocrine disruption will therefore require consideration of both
susceptibility genotype and environmental exposure."
it indicates that uses of the least sensitive strain is highly
inappropriate for regulatory studies attempting to establish risks
resulting from exposure to endocrine disruptors. "Use of
an animal model with a highly resistant genotype to assess deleterious
effects of estrogenic agents on reproduction may be misleading
and could mask our appreciation of how global exposure to estrogenic
xenobiotics threatens wildlife, domestic animals, and our own
did they do? Spearow et al. measured the responses of
mice of four different genetic strains to exposure to estrogen in
different amounts beginning at the age of 22-23 days after birth.
Estrogen exposure was via silastic implants of varying sizes. They
then measured developmental disruption on day 43 after birth. Developmental
endpoints examined were aspects of the size, structure and function
of the testis.
did they find? Estrogen exposure affected development in all
strains of mice, but least so in the CD-1 strain, a strain widely
used in toxicological experiments. The variation in sensitivity
they observed differed depending upon the endpoint measured. For
example, CD-1 males were 16 times more resistant to to the suppressive
effects of estrogen on gonadal function, but over 450 times more
resistant to the effects of estrogen on sperm formation.
of estrogen (estradiol) on testicular morphology and function
(as measured by the percentage of seminiferous tubules with
elongated spermatids). CD-1 shows only a slight decline compared
to the other 2 strains. Even very low doses of estradiol disrupt
testicular development in C17 and B6 strains.