DEVELOPMENTAL EXPOSURE TO DIETHYLSTILBESTROL ELICITS DEMETHYLATION OFESTROGEN-RESPONSIVE LACTOFERRIN GENE IN MOUSE UTERUS

Alteration of DNA demethylation in five CpG sites (-547, -533, -475, - 464, and -454) immediately upstream from the estrogen response element of lactoferrin promoter was determined in the uteri of immature (17-d ay-old) and mature (21- and 30-day-old) mice treated neonatally with D ES, Only the CpG/-464 was found to be abnormally demethylated by dieth ylstilbestrol (DES) treatment in the mature uteri. This abnormal demet hylation occurred in specific response to DES in neonatal mice, becaus e DES injected into the 30-day-old mature mice did not demethylate CpG /-464. This site, however, remained methylated in the neonatally DES-t reated/ovariectomized mice, indicating that this DES-elicited demethyl ation is under hormonal control. Thus, neonatal DES treatment appeared to imprint an abnormal, site-specific demethylation of CpG/-464, whic h requires ovarian hormones to occur in adult mice, Moreover, the deme thylation was maintained in uterine tumors of the neonatally DES-treat ed mice, This mode of demethylation is reminiscent of uterine tumor fo rmation, which also depends on both neonatal DES exposure and ovarian hormone stimulation in adulthood, Thus, neonatal DES treatment may ind uce tumor formation as well as demethylation through a common cellular process.