Spearow 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.

This 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."

While Spearow et al. used estrogen in these experiments, it is reasonable to assume that similar variability exists in responsivity to estrogen-mimicking contaminants.

This paper is important for two reasons.

• First, 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."
• Second, 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 species."

What 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.

What 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.

Effect 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.

from Spearow et al. 1999

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