Abstract
Purpose: :
The higher incidence of age–related cataracts in women, epidemiological studies examining estrogen exposure and cataract risk, and studies in animal models suggest that estrogen may be protective in the lens. However, there is only limited information on how estrogen and its receptors (ERα and ERß) function in the lens. For this reason, the present study was designed to examine whether estrogen receptors (ER) are required for maintenance of lens transparency and/or may have a cataract–protective role.
Methods: :
To examine whether the loss of ER will induced cataracts, slit–lamp examination were performed on aging mice lacking expression of ERα (αERKO), ERß (ßERKO), or both (αßERKO). We also examined cataract development in the ERKO mice crossbred with our transgenic model, ERΔ3 mice. In this model, the dominant negative ERα repressor, ERΔ3, is expressed in ocular and non–ocular tissues. Cortical cataracts form spontaneously in ERΔ3 females producing sufficient levels of estrogen to activate the dominant negative repressor (since estrogen is required to form inhibitory dimers with ERα, ERß, or itself). This inducible model allows us to investigate whether ERα and/or ERß may have a role in ERΔ3–induced cataracts.
Results: :
Regardless of their genotype, spontaneous cataracts are not detectable in αERKO, ßERKO, αßERKO, or wild–type (WT) male or female mice up to 12 months of age. Thus, based on our current data, the lack of ER does not cause cataracts to form; however, these data do not rule out their potential role in protection against cataract–inducing agents. In contrast, cataracts are evident in all genotypes of αERKO, ßERKO, and αßERKO females crossbred with the ERΔ3 model, but not in males or WT mice. These results suggest that ERΔ3 repressor homodimers (formed in the presence of estrogen) may be sufficient to block estrogen action to result in cataract development.
Conclusions: :
Our data suggests that expression of ERα or ERß are not required to maintain lens transparency in transgenic mice or to induce cataracts via the ERΔ3 repressor. These and future studies are needed to define the role of the ER in the lens to assess estrogen’s potential as cataract protective therapy.
Keywords: transgenics/knock-outs • cataract • receptors: pharmacology/physiology