Showing papers by "Worcester Foundation for Biomedical Research published in 1977"

The effect of an aromatase inhibitor 4-hydroxy-4-androstene-3 17-dione on estrogen-dependent processes in reproduction and breast cancer.

Abstract: 4-Hydroxy-f-androstene-3,17-dione (4-OH-A) when tested at various concentrations was found to inhibit markedly the conversion of 4-andorstene-3,17-dione to estrogens inhuman placental and rat ovarian microsomes. To obtain evidence that estrogen biosynthesis could also be reduced in vivo with 4-OH-A, rats were treated sc at a dose level of 50 mg/kg body weight. After 3 h the ovarian veins were cannulated and blood collected. Estradiol concentrations in the plasma were reduced by 80% compared to control values during the proestrous surge and on Day 4 of pregnancy. 4-OH-A was also found to be effective in controlling estrogen-dependent reproductive and neoplastic processes. In rats treated from Day 2-7 of pregnancy, implantation of fertilized ova was completely prevented in some rats, while in others either implantation was delayed or the development of implants was retarded. 4-OH-A treatment of rats having estrogen-dependent breast tumors induced by 7,12-dimethylbenz(a)anthracene caused 80% of the tumors to regress significantly in 4 weeks of treatment; 42% of these regressed completely.

Effects of experimentally-induced chronic hyperprolactinemia on testosterone and gonadotropin levels in male rats and mice.

Abstract: We have examined testicular and pituitary function in inbred CD-F rats and DBA/2J mice with chronic hyperprolactinemia induced by grafting 4 anterior pituitaries from adult females of the same strain under the kidney capsule. Eight rats were given pituitary isografts and 9 were sham-operated; blood samples were collected at 4-7 week intervals, and the animals were killed 6 months later. One month after surgery, PRL levels in grafted rats were elevated (348 +/- 15 vs. 94 +/- 11 ng/ml; P less than 0.001), LH levels were depressed (16 +/- 3 vs. 59 +/- 9 ng/ml; P less than 0.001), but T levels were not affected (1.0 +/- 0.1 vs. 1.1 +/- 0.2 ng/ml). The elevated PRL levels in grafted animals did not decline during the subsequent 5 months, while LH levels increased slightly, and T levels remained indistinguishable from those in the controls. At the time of autopsy, FSH levels were reduced in grafted rats (230 +/- 40 vs. 501 +/- 108 ng/ml; P less than 0.05). Multiple pituitary isografts did not affect the weight of the testes or the ventral prostate, but increased the weight of the seminal vesicles (P less than 0.001). In 11 mice examined 5.5 months after receiving pituitary isografts, plasma PRL levels were dramatically elevated (330 +/- 35 vs. 27 +/- 2 ng/ml; P less than 0.001), but plasma T levels and testicular weight were not different from those observed in 12 sham-operated controls. The weight of the seminal vesicles in grafted mice was increased (P less than 0.01). In both rats and mice, chronic hyperprolactinemia did not affect plasma testosterone levels or testes weight and increased seminal vesicle weight.

Testicular LH binding in the hamster: modification by photoperiod and prolactin.

Abstract: Suppression of testicular weight and activity induced in the hamster by light deprivation can be partially reversed by treatment with prolactin (PRL). The present study investigates the possibility that the stimulatory effect of PRL in this preparation may be mediated through increased LH binding. on LH binding while PRL alone or in combination with LH+FSH increased binding to levels greater than the long light controls. Peripheral testosterone concentrations reflected the level of LH binding.

Cannabinoids inhibit testosterone secretion by mouse testes in vitro

Abstract: Addition of delta-9-tetrahydrocannabinol or cannabinol to an incubation medium containing decapsulated mouse testes caused a significant reduction in the accumulation of testosterone in the medium. This result suggests that the reported effects of cannabis on male sexual and reproductive function may result from direct inhibition of testicular steroidogenesis by both psychoactive and nonpsychoactive constituents of marihuana.

Effects of Estrogens on Testicular Testosterone Production in vitro

Abstract: It has been suggested that treatment with estradiol (E2) in vivo decreases testosterone (T) production by a direct inhibitory effect on testicular steroidogenesis. To examine this possibility, decapsulated mouse and rat testes were incubated in Krebs-Ringer bicarbonate buffer containing glucose, hCG and various concentrations of E2 or diethylstilbestrol (DES). At the concentration of 50 Mg/mI, both E2 and DES significantly reduced the accumulation ofT in the incubation medium. Lower doses of free estrogens were ineffective in this system, except for an inhibitory action of 5 Mg DES/mi in the incubations of mouse testes. The possibility that esters of E1 can also influence testicular steroidogenesis directly, was examined by incubating mouse testes with various concentrations of E2 3-mono-benzoate (E2 B). Addition of 5 or 50 zg E2 B per ml produced a pronounced inhibition of T accumulation in this system, while 0.5 Mg E2 B per ml had a slight but statistically significant inhibitory effect. When decapsulated mouse testes were incubated with 50 Mg/mi of DES or E2 B in the absence of hCG, T accumulation was inhibited only by DES.

Effects of prolactin (PRL) on pituitary and testicular function in mice with hereditary PRL deficiency.

Abstract: Hereditary dwarf mice (Snell dwarf, dw/dw and Ames dwarf, dfldf) are genetically prolactin-deficient and sterile. Treatment with prolactin (PRL) stimulates testicular growth and activity, and induces fertility in these animals. To elucidate the mechanism of this action of PRL, and to identify the possible physiological functions of this hormone during sexual maturation, we have examined the effects of treating male dwarf mice with PRL on plasma and pituitary levels of LH and FSH, on the concentration of testosterone (T) in testes and plasma, and on T production in response to hCG in vitro. Both Snell and Ames male dwarf mice had a significantly lower concentration of FSH in the pituitary and the peripheral plasma, and of LH in the pituitary, than did the normal adult males of the same strain. Treatment with ovine PRL, or with a PRL-producing ectopic homograft of the anterior pituitary from a normal animal, produced a significant elevation in plasma FSH levels in male dwarf mice of both strains. The same i...

Action of pancreatic DNase: requirements for activation of DNA as a template-primer for DNA polymerase ∝

Abstract: Pancreatic DNase requires both Ca2+ and Mg2+ for its activity as measured by formation of an activated DNA template for in vitro DNA polymerase alpha assay and by the hyperchromic shift. Mn2+ can partially satisfy the Mg2+ requirement of the DNase for activation of DNA but the resulting template is only 50% as active in the DNA polymerase assay. When precautions are taken to avoid divalent ion contamination, pancreatic DNase is not active in the presence of Ca2+ or Mg2+ alone. analysis of the DNA by sucrose gradient centrifugation shows that only in the presence of Ca2+ plus Mg2+ or Mn2+ does pancreatic DNase produce extensive strand breaks in the DNA. The activated DNA template that yields maximal DNA polymerase activity is low molecular weight material of 30,000 to 50,000 daltons.

Malignancy and transformation: expression in somatic cell hybrids and variants.

Abstract: Publisher Summary This chapter reviews the genetic basis for the regulation of the expression of transformed or tumor cells in vitro and in vivo. It focuses on the studies involving somatic cell hybrids and phenotypic revertants derived from transformed cells and cell lines that display temperature-dependent expression of transformed characteristics. The role of genetic factors in tumorigenesis and in vitro transformation is well documented. This association exists for a variety of virological, chemical, and physical agents known to induce tumors. The phenomenon of cell fusion permits the introduction of the entire genome of one cell into another. The capability to generate and select for hybrid cells of appropriate properties offers opportunities to study the genetic regulation of tumor cells. It is also observed that suppression of malignancy can occur in intraspecies cell hybrids between a malignant and a nonmalignant cell. Suppression occurs with a large variety of tumors of different origin and at different initiation events.

Reproductive and endocrinological features of male rats after treatment with cadmium chloride

Abstract: The effects of a single sc injection of cadmium chloride (1 or 5 mg) on the reproductive tract and endocrine function were studied in adult male rats. Treatment with 5 mg significantly (p less than .01) reduced the weights of the testis epididymis vas deferens ventral prostate and seminal vesicles 15 days after injection. There was also a marked reduction in the number of sperm in the vas deferens and caput and cauda epididymis. Animals injected with 1 mg did not show any loss of libido or fertility though those receiving 5 mg were affected with some showing sterility. Plasma levels of testosterone and 5alpha-dihydrotestosterone were diminished by treatment while androstenedione concentrations were unaffected. The results suggest that cadmium chloride affects spermatogenesis as well as the production of androgens.

Effects of Cooling Rates and Maturity of the Animal on the Recovery and Fertilization of Frozen-Thawed Rodent Eggs

Abstract: Mouse, rat, golden hamster and Mongolian gerbil eggs were cooled to -75#{176}C in efforts to determine an optimum cooling rate for freezing unfertilized rodent eqs. The best cooling rate for the recovery and in vitro fertilization of mouse and rat eggs was 0.33 C/mm from -4#{176} to -45#{176}C followed by 1#{176}C/mm from -45#{176} to -75#{176}C. Hamster eggs could withstand a wider variation in the rate of cooling, since large numbers of eggs could be recovered at 0.33#{176}, 0.5#{176} or 1#{176} C/mm; and fertilized in vitro. In contrast with the other species gerbil eggs froze poorly at these same rates of cooling. Eggs from mature mice and rats consistently withstood freezing better than those from immature females (P<0.001) when cooled at 0.3 3#{176} C/mm.

Control of Behavior by Noxious Stimuli

Abstract: The control of behavior by noxious stimuli has both historical and contemporary importance in behavioral pharmacology. The development of chlorpro-mazine as a treatment for psychosis stimulated a great deal of interest in the behavioral effects of drugs. The initial pharmacological studies of chlorpromazine included experiments in rats showing that it suppressed a rope-climbing response in the presence of an auditory stimulus previously associated with electric shocks (Courvoisier et al., 1953). Later, Cook and Weidley (1957) showed that chlorpromazine could suppress responses that occurred during a stimulus period preceding the delivery of an electric shock (avoidance responses) at doses that did not affect responses evoked by the shock itself (escape responses). The results obtained with these procedures led to a search for drugs that might be more effective than chlorpromazine in the treatment of psychiatric disorders, and also prompted speculation about how these drugs were acting. It was generally assumed that drugs such as chlorpromazine had selective effects on avoidance responses because they decreased fear and anxiety.

The regulation by fibroblast growth factor of early transport changes in quiescent 3T3 cells

Abstract: This study involves the use of fibroblast growth factor (FGF) as a substitute for exogenous serum to examine the early transport changes which occur when quiescent 3T3 cells re-initiate active growth. FGF, in nanogram amounts, together with insulin and dexamethasone, can induce mitogenesis and mitosis in 3T3 cells GO-arrested by holding in growth medium containing 0.8% calf serum. In terms of quiescent cell transport activity enhancement, FGF is 300,000-fold more effective than fresh serum, on a protein basis. In addition, very short exposure of serum-depleted cells to FGF indicates that a distinct temporal or time sequence exists in the transport system activation process. For example, uptake of alpha-aminoisobutyric acid (AIB) and uridine are stimulated very rapidly, whereas hypoxanthine uptake does not respond until much later. Closer analysis shows that AIB uptake is maximally enhanced within zero to two minutes after FGF addition to cells. Finally, the stimulatory effect of FGF on transport system activities is specific in terms of the proliferative state of the cells to which it is added, and in terms of the uptake systems which respond to it.

Dynamic Aspects of Central Olfactory Processing

Abstract: Perhaps because the sense of smell involves the discrimination of molecules by neural tissue, most neurophysiological studies of vertebrate olfaction have used purified compounds as stimuli and have been directed at relating neural response parameters to the structural and/or physicochemical properties of molecules. In studies of odor responses by individual neurons (single units), a commonly employed paradigm has been one in which individual members from a preselected battery of “odors” (volatile molecules in otherwise highly purified air) are puffed sequentially onto the nasal mucosa and an attempt is made to derive the relevant structural and/or physicochemical parameters of odor from the relative response spectra of the units recorded. When employed in studies of peripheral olfactory neurons (cf. Gesteland, Lettvin and Pitts, 1965), this paradigm is consistent with the assumption that these neurons contain receptor sites for odoriferous molecules and in effect is aimed at a preliminary answer to the two interrelated questions of how specific are the receptor sites and do the peripheral neurons have more than one type of receptor site. This general paradigm also has been used in studies of central olfactory neurons to test hypotheses about the physical dimensions of odors. For example, Higashino, Takeuchi and Amoore (1969) attempted to verify a stereochemical theory of odor quality by using a battery of pure chemical stimuli and comparing the response spectra of single units recorded in the olfactory bulbs with generalization gradients derived from psychophysical studies.