Interaction between a semisynthetic diet and indole-3-carbinol on mammary tumor incidence in Balb/cfC3H mice.

This paper extends prior studies on the chemoprotective effect of indole-3-carbinol (I3C) on mammary and endometrial tumors in rodent models and focuses on the interplay between standard laboratory chow (Purina Lab Chow 5001), a high omega 6 fatty acid diet (AIN76A), and I3C on the incidence of mouse mammary tumor virus-induced (MMTV) mammary tumors in mice. While the protective effect of I3C was observed in mice maintained on the AIN76A diet from conception, a marked decrease in tumor incidence was observed, which was found to be directly related to the extent of time the mice were maintained on the Purina 5001 diet prior to the switch to the AIN76A control diet. This protective effect of the chow diet against MMTV-induced tumors has not been previously reported. The effects of the chow diet and I3C do not appear to be additive or synergistic.

Methionine restriction increases blood glutathione and longevity in F344 rats.

Little is known about the biochemical mechanisms responsible for the biological aging process. Our previous results and those of others suggest that one possible mechanism is based on the loss of glutathione (GSH), a multifunctional tripeptide present in high concentrations in nearly all living cells. The recent finding that life-long dietary restriction of the GSH precursor methionine (Met) resulted in increased longevity in rats led us to hypothesize that adaptive changes in Met and GSH metabolism had occurred, leading to enhanced GSH status. To test this, blood and tissue GSH levels were measured at different ages throughout the life span in F344 rats on control or Met-restricted diets. Met restriction resulted in a 42% increase in mean and 44% increase in maximum life span, and in 43% lower body weight compared to controls (P < 0.001). Increases in blood GSH levels of 81% and 164% were observed in mature and old Met-restricted animals, respectively (P < 0.001). Liver was apparently the source for this increase as hepatic GSH levels decreased to 40% of controls. Except for a 25% decrease in kidney, GSH was unchanged in other tissues. All changes in GSH occurred as early as 2 months after the start of the diet. Altogether, these results suggest that dramatic adaptations in sulfur amino acid metabolism occur as a result of chronic Met restriction, leading to increases in blood GSH levels and conservation of tissue GSH during aging.

Animal models of androgen-dependent disorders of the pilosebaceous apparatus. 1. The androchronogenetic alopecia (AGA) mouse as a model for male-pattern baldness.

The androchronogenetic alopecia (AGA) mouse if a mutant strain which expresses androgen-dependent baldness. Daily s.c. injection of testosterone (T) induced thinning of the hair coat along the upper dorsum after 4 weeks of treatment. After 12 to 14 weeks this diffuse alopecia eventually eveloped into a bald area which extended to the middorsum. Dihydrotestosterone was more effective than T in stimulating the onset of AGA. In this model, T produced the alopecia by decreasing the rate of hair growth, decreasing the duration of anagen, and markedly prolonging the duration of telogen. When applied topically at a concentration of 5%, cyproterone acetate delayed the progression of the T-mediated hair loss. However, this inhibitory effect occurred through systemic means as evidenced by decrease in the size of the submaxillary gland. Chronic feeding of androgen-treated female AGA mice with a diet containing 0.01% minoxidil also inhibited the development of alopecia. Skin and core temperatures were found to be higher in minoxidil-treated animals than in the placebo-treated controls. Minoxidil at a topical dose of 1% did not produce any effect. Increasing the dose to 2% caused a slight retardation of the development of alopecia. However, a 60% inhibition was observed at a topical dose of 5% minoxidil after 12 weeks of treatment (p less than 0.03). The data demonstrate that hair loss in the AGA mouse is androgen dependent and that this mutant strain can serve as a suitable model for the screening of compounds, such as antiandrogens and vasodilators, which may influence the balding process.

Synergistic antiandrogenic effects of topical combinations of 5 alpha-reductase and androgen receptor inhibitors in the hamster sebaceous glands.

The androgenic action of dihydrotestosterone (DHT) is antagonized by agents that compete with testosterone for the 5 alpha-reductase enzyme and by agents that block the binding of DHT to its receptor. The topical synergistic effect of 5 alpha-reductase (5 alpha RI) and androgen receptor inhibitors (ARI) was determined by measurement of the sebaceous gland size (SGS) of the ventral ear skin of the intact, sexually mature male Syrian hamsters. Progesterone (P), a 5 alpha RI, and spironolactone (SL), an ARI, produced a dose responsive decrease in SGS at topical concentrations of 0.01% to 5.0%. At concentrations of 1, 3, and 5%, P and SL combinations produced neither an additive nor synergistic inhibition of SGS. At very low concentrations of up to 0.10%, neither P nor SL alone produced any effect on SGS. When combinations of these two steroids were applied at low concentrations, SGS decreased unilaterally to approximately 50%. This synergy occurred best at a P:SL ratio of 1:2. The lower effective concentrations of P may be explained by its greater percutaneous absorption. Synergy was also demonstrated at low concentrations with other antiandrogens: cyproterone acetate, canrenone, hydroxyflutamide, and N-N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane- 17 beta-carboxamide. The use of anti-androgen combinations at low concentrations is of value because of the decreased risk of systemic side effects while maintaining potent topical efficacy.

Effects of toxic shock syndrome Staphylococcus aureus, endotoxin and tampons in a mouse model.

Synthetic tampons and toxic shock syndrome toxin-one (TSST-1)-producing strains of Staphylococcus aureus have been linked to an increased incidence of toxic shock syndrome (TSS). While recent reports attempt to define the tampon connection as the creation of an optimal environment for the production of TSST-1, the role of other factors in disease expression in an animal model remain under investigation. To understand the role of tampons and bacteria, pools of Swiss mice were inoculated with permutations of effluents from TSS strains of S. aureus and Escherichia coli grown inside tampons. Depending on tampon brand, when all 3 factors were combined mortality ranged from 20-100%. In controls inoculated with single effluents, or effluents from growth in the presence of cotton, no deaths were observed. Likewise, when hairless mice were inoculated with exotoxin, endotoxin, and tampon leachables, mortality was 100%. In the absence of any 1 component, mortality ranged from 0-40%. Lethal toxicity can be the result of enhancement, since animal death in apparent shock was observed in all pools containing the 3 components, and in all pools containing effluents of TSS S. aureus and E. coli grown in the presence of synthetic tampons, but not in their absence. A retrospective analysis of fatal vs non-fatal TSS in humans supports the hypothesis of enhancement.

The local antiandrogenic effect of the intracutaneous injection of progesterone in the flank organ of sexually mature male Syrian golden hamster.

The local antiandrogenic action of progesterone was investigated using the androgen-responsive flank organs of adult, sexually mature male Syrian golden hamsters. The effect of the unilateral injections of a micronized suspension of progesterone into the flank organs was analyzed by the measurement of the weight, area of surface pigmentation, and the cross-sectional area of the sebaceous glands. The weekly injections of 5 mg of progesterone for a period of 3 weeks produced approximately 50% reduction in all three parameters in comparison to the controls. The minimal effective dose of 1 mg per week was determined by the injection of progesterone at doses ranging from 0.1 to 5 mg. These effects were localized only to the treated flank organs since the values for the contralateral side were not significantly different from the controls. The local action of progesterone was further demonstrated by the absence of effect on the weight of seminal vesicles and testes of the treated animals in comparison to the controls.