George H. Gass

Strain differences in the response of the mouse to diethylstilbestrol

BALB/c StCrlfC3Hf/Nctr, C57BL/6/, C57BL/6 X BALB/c F1 hybrid (B6CF1), and monohybrid-cross offspring from the breeding of B6CF1 mice were examined with respect to uterine, vaginal, and thymus responses to diethylstilbestrol (DES). About 400 mice of each genetic population were used. Weanling mice were fed DES at dietary concentrations of 2.5 to 1,000 ppb (microgram/kg feed) for 6 days and were killed by cervical dislocation about 20 hr after removal of the feed. C57BL/6, B6CF1, and the monohybrid-cross offspring did not differ in the uterine-weight response to DES, but the slope of the dose-response line was shallower for the BALB/c than for the other strains. Dietary DES concentrations of 250 ppb or more inhibited the uterotrophic response in all populations. Vaginal cornification occurred at lower concentrations of DES in the C57BL/6 strain than in the B6CF1 animals. BALB/c and monohybrid-cross offspring were indistinguishable from each other in their vaginal response to Des and were less sensitive to DES than the other mouse populations. The use of ethanol or corn oil as the solvent for mixing DES into the diet had no apparent effect on the uterine weight or vaginal response in any of the mice. DES depressed thymus weight in a dose-related fashion at dietary concentrations of 100 ppb and above in all genetic populations.

Doisynolic-type acids—Uterotropically potent estrogens which compete poorly with estradiol for cytosolic estradiol receptors

Doisynolic acids, a class of seco-steroid acids some of which exhibit greater uterotropic estrogenicity than estradiol-17 beta, are D-ring cleavage products of steroidal estrogens formed by fusion with KOH above 200 degrees C. We have found that electron-transfer reactions between estrone or estradiol and CCl4 or CBrCl3 in KOH-t-BuOH at 25 degrees C rapidly provide 16,16-dichloro- or -dibromodoisynolic acid, respectively, the former approaching estradiol in uterotropic potency. Simple esters from these highly hindered tertiary carboxylic acids, easily prepared via phase-transfer-catalyzed alkylations, also rival estradiol in uterotropic activity. Unlike natural steroidal estrogens or their commonly used artificial equivalents (DES, hexoestrol, ethynylestradiol, etc.) whose uterotropic activity is accompanied by substantial binding affinity for cytosolic estradiol receptors, these highly uterotropic doisynolic-type acids and esters exhibit binding affinities for this receptor of only about 1% that of estradiol-17 beta as determined by the usual competitive binding-inhibition studies with [3H]estradiol. Other highly uterotropic carboxylic acids may exhibit similar characteristics. These unusual results leave open the possibilities that uterotropic seco-steroid and related carboxylic acids undergo some unknown metabolic activation, are exceptionally persistent estrogens, bind to a cytosolic receptor site other than the conventional (type I) estradiol site, or bind directly to type I or type II nuclear receptor sites. At dosages of 1000 times those required for a uterotropic effect, the doisynolic-type acids (24 doses over an 8-week period) were neither toxic nor carcinogenic.

The effect of age on serum proteins in mice

The relation of serum protein levels to age was investigated in the Swiss mouse. The present study demonstrates for the first time a dynamic age-dependent relationship between the various serum proteins. Total serum protein displayed a nonlinear change, decreasing from 10 to 136 days of age and thereafter increasing with advancing age with a peak at 465 days of age. Globulin concentration increased throughout the life span while albumin decreased for the first 136 days, after which it rose and peaked at 465 days of age. The relative percentage of each serum protein undergoes a significant non-constant, non-linear and non-quadratic change with increasing age. The patterns displayed by the various globulin fractions are strikingly similar to each other and tend to be inversely related to the pattern displayed by albumin. The relative percentage of each globulin fraction displayed a biphasic change with a peak at 200 days and a trough at 500 days of age.

Nonneoplastic changes induced in female c3h mice by chronic exposure to diethylstilbestrol or 17β‐estradiol

The long-term nonneoplastic effects of estrogenic diets were studied in female C3H/HeJ and C3HeB/FeJ mice. C3H/HeJ mice received diets containing 0, 10, 100, or 500 ppb diethylstilbestrol (DES) or 100, 1000, or 5000 ppb 17 beta-estradiol (E2) from 6 to 110 wk of age. C3HeB/FeJ females were fed diets containing nominal concentrations of 0, 10, 100, or 500 ppb DES from 6 to 136 wk of age. Responses of both strains to DES were qualitatively identical. Histological changes in the reproductive tract induced or increased by DES in both strains and by E2 in C3H/HeJ mice included stromal mucoid changes in the vagina and cervix, epithelial keratinization in the vagina, and glandular hyperplasia in the uterine horns. Increasing doses above 10 ppb DES or 100 ppb E2 increased the prevalence and, in some cases, severity of these responses. Dose-responses to DES for these endpoints were virtually indistinguishable in the two strains. At 10 ppb DES or 100 ppb E2 there were minimal or no observable effects. When the nonneoplastic dose-response data were compared with neoplastic dose-response data previously reported, no consistent relation between doses causing neoplastic and nonneoplastic responses was seen for the two estrogens.

Caffeine ulcerogenesis: A mechanism study in vivo

Abstract Gastric, submucosal administration of caffeine induced hydrochloric acid secretion in the rat. Evidence obtained from bilaterally vagotomized rats treated with parasympatholytic agents indicated that caffeine stimulation is mediated via intramural myenteric plexuses within the stomach. It is concluded that the primary mode of action of caffeine in ulcerogenesis in the rat is augmentation of gastric secretion. The spontaneous secretion of gastric acid in fasting rats was confirmed.