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Biomedical subjects

A Turturro

Publications and source records attributed to A Turturro.

At least 19 recordsLinked to original sources
PubMed1998

Hormesis--implications for risk assessment caloric intake (body weight) as an exemplar.

Hormesis can be considered as a parameter which has a non-monotonic relationship with some endpoint. Since caloric intake is such a parameter, and the impact of this parameter on risk assessment has been fairly well characterized, it can provide clues as to how to integrate the information from a hormetic parameter into risk assessments for toxicants. Based on the work with caloric intake, one could: (a) define a biomarker for hormetic effect; (b) integrate specific information on when in the animals lifespan the parameter is active to influence parameters such as survival; (c) evaluate component effects of the overall hormetic response; and (d) address the consequences of a non-monotonic relationship between the hormetic parameter and endpoints critical for risk assessment. These impacts on risk assessments have been characterized for chronic tests, but are also true for short-term tests. A priority is the characterization of the dose-response curves for hormetic parameters. This quantification will be critical in utilizing them in risk assessment. With this information, one could better quantitatively address the changes one expects to result from the hormetic parameter, and limit the uncertainty and variability which occurs in toxicity testing.

Aging↗
PubMed1998

Upregulation of apoptosis with dietary restriction: implications for carcinogenesis and aging.

The maintenance of cell number homeostasis in normal tissues reflects a highly regulated balance between the rates of cell proliferation and cell death. Under pathologic conditions such as exposure to cytotoxic, genotoxic, or nongenotoxic agents, an imbalance in these rates may indicate subsequent risk of carcinogenesis. Apoptotic cell death, as opposed to necrotic cell death, provides a protective mechanism by selective elimination of senescent, preneoplastic, or superfluous cells that could negatively affect normal function and/or promote cell transformation. The relative efficiency or dysfunction of the cell death program could therefore have a direct impact on the risk of degenerative or neoplastic disease. Dietary restriction of rodents is a noninvasive intervention that has been reproducibly shown to retard tumor development and most physiologic indices of aging relative to ad libitum-fed animals. As such, it provides a powerful model in which to study common mechanistic processes associated with both aging and cancer. In a recent study we established that chronic dietary restriction (DR) induces an increase in spontaneous apoptotic rate and a decrease in cell proliferation rate in hepatocytes of 12-month-old B6C3F1 DR mice relative to ad libitum (AL)-fed mice. This diet-induced shift in cell death/proliferation rates was associated with a marked reduction in subsequent development of spontaneous hepatoma and a marked increase in disease-free life span in DR relative to AL-fed mice. These results suggest that total caloric intake may modulate the rates of cell death and proliferation in a direction consistent with a cancer-protective effect in DR mice and a cancer-promoting effect in AL mice. To determine whether the increase in spontaneous apoptotic rate was maintained over the life span of DR mice, apoptotic rates were quantified in 12-, 18-, 24- and 30-month-old DR and AL mice. The rate of apoptosis was elevated with age in both diet groups; however, the rate of apoptosis was significantly and consistently higher in DR mice regardless of age. In double-labeling experiments, an age-associated increase in the glutathione S-transferase-II expression in putative preneoplastic hepatocytes in AL mice was rapidly reduced by apoptosis upon initiation of DR. Thus, intervention that promote a low-level increase in apoptotic cell death may be expected to protect genotypic and phenotypic stability with age. If during tumor promotion an adaptive increase in apoptosis effectively balances the dysregulated increase proliferation, the risk of permanent genetic error and carcinogenesis would be minimized.

Aging↗
PubMed1997

The physiologic, neurologic, and behavioral effects of caloric restriction related to aging, disease, and environmental factors.

Little is known about the mechanisms by which acute and chronic caloric restriction (CR) modulate disease, longevity, and toxicity. To study these endpoints, behavioral parameters such as food and water consumption and physiologic parameters such as motor activity, body temperature, metabolic output (oxygen use), and respiratory quotient (RQ) were continuously monitored in 26-month-old male B6C3F1 mice and Fischer 344 rats fed either ad libitum (AL) or a CR diet (60% of AL). Different dietary regimens were used: rodents were (1) chronically food-restricted using daily feeding starting at 14 months of age, (2) chronically food-restricted using alternate day feeding, or (3) abruptly switched from CR to AL (acute CR). The physiologic and behavioral changes seen with chronic and acute CR were consistent across strains and species. Average body temperature, the number of meals, and the ratio of food/water consumption were significantly lower in CR rodents than in AL rodents. Also, the daily range of body temperature, oxygen metabolism, RQ, average water consumption, and motor activity was significantly higher in CR rodents. CR caused the onset of altered neurobehavioral functions such as abnormal water consumption; increases in motor activity, serum corticosterone, and stress proteins (HSP); and decreases in the basal setpoint for body temperature and brain metabolism. These changes strongly suggest that many beneficial effects of CR are controlled by the hypothalamic-pituitary-adrenal axis via hormonal regulation. This study supports the assertion that nutritional status may be a primary factor of consideration in development of safety standards and assessment of risk.

Aging↗
PubMed1997

Age and temperature related changes in behavioral and physiological performance in the Peromyscus leucopus mouse.

Age-related and ambient temperature-related changes in motor activity, body temperature, body weight (b.w.), and food consumption were studied in the long-lived Peromyscus leucopus mouse at environmental temperatures of 29 and 21 degrees C. Major changes in physiological performance were observed between the young (6 months) and old (60-72 month) age groups. The number of daily activity episodes, and total activity output was significantly lower in old mice. Maximum, average and minimum daily body temperature was lower in the old mice and a significant ambient temperature-by-age interaction was found. Maximum, minimum, and average daily b.w. was higher in old mice. Motor activity was evenly distributed over the active (night) phase in young mice but in old mice activity was significantly greater in the late night partition of the active cycle than in the early night partition. Both groups were significantly more active at night than during the day. Most of the food consumption in both groups occurred at night, but young mice consumed significantly more during the late night partition than the early night partition, and the consumption rates for old mice were not significantly different between early and late night partitions. The percentage of activity episodes involved with food consumption in both groups was significantly higher during the night partition, but the percentage during the early night partition was significantly higher in old mice than in young mice. Significant episodes of circadian torpor occurred in a high percentage of old mice at 06:00, on consecutive days, at both environmental temperatures, but young mice expressed no evidence of torpor.

Aging↗
PubMed1997

Effect of food restriction on life span and immune functions in long-lived Fischer-344 x Brown Norway F1 rats.

Life-long food restriction is known to slow aging and reduce the rate of occurrence of age-associated disease processes, but the mechanism by which this is accomplished is unknown. In this study we have examined the effect of food restriction on the proliferative response of spleen cells to mitogens and lymphokine production in 6-, 18-, and 30-month-old AL and FR Fischer-344 x Brown Norway (F-344 x BNF1) female rats whose average life span is 137 weeks on an ad libitum (AL) diet and 177 weeks on a food-restricted (FR) diet. In addition, the ability of food restriction to recall antigens was tested in 10-month-old rats by immunizing them with keyhole limpet and hen's egg albumin and measuring proliferative response of draining lymph node cells to these antigens. Our results indicated that the spleen-cell proliferative response to phytohemagglutinin and concanavalin A (Con A) was equal in 6- and 18-month-old rats but declined significantly in 30-month-old AL rats compared to FR rats. Although flow cytometric analyses did not reveal differences for CD4, CD8, and Ig+ cells with age, a significant rise in memory T cells (Ox-22low) in both CD4+ and CD8+ T-cell subset lineage was noted in AL-fed rats at 30 months of age. In FR rats, however, only a minimal shift of naive T cells (Ox-22high) to memory cells was observed. In FR rats, the observed changes in the naive and memory T-cell subsets correlate well with the observed higher levels of the antiinflammatory interleukin-2 (IL-2) and lower levels of the proinflammatory cytokines such as IL-6 and tumor necrosis factor-alpha. The ability of food-restricted animals to recall antigens was lower compared to their age-matched controls, though the proliferative response to T-cell mitogen Con A and superantigen staphylococcal enterotoxin B was higher. These findings indicate that food restriction may selectively act to maintain a lower number of antigen-induced memory T cells with age, thereby maintaining the organism's ability to produce higher levels of IL-2 with age. In summary, the increased cell-mediated immune function noted in aged FR rats appears to be due to the presence of a higher number of naive T cells, which are known to produce elevated levels of the antiinflammatory cytokines, which may in part be responsible for reducing the observed age-related rise in disease.

Aging↗
PubMed1997

Dietary restrictions and cancer.

Dietary restriction (DR) alters a significant environmental factor in carcinogenesis, dietary intake, thus inhibiting both spontaneous and induced tumorigenesis. Potential mechanisms for the inhibition of spontaneous cancer may include the effects of DR to do the following: decrease body weight, which decreases cellular proliferation and increases apoptosis in a number of organs that increase and decrease with body size; decrease body temperature, thereby lowering the amount of endogenous DNA damage temperature generates; decrease oxidative damage, by increasing antioxidant damage defense systems; decrease, generally, cellular proliferation; and protect the fidelity of the genome by decreasing DNA damage, increasing DNA repair, and preventing aberrant gene expression. Potential mechanisms for reducing induced tumor incidence include lowering agent activation, changing agent disposition, decreasing the adducts most associated with agent toxicity, and inhibiting tumor progression through mechanisms similar to those that can effect spontaneous tumorigenesis. As a method to control a major source of environmental cancer, and as the major modulator of the agent induction of this disease, understanding how DR works may significantly contribute to the efforts to explain how diet impacts on development of cancer in the United States, and may suggest methods to reduce the adverse impacts of other environmental agents on the disease.

Animals↗
PubMed1996

Effects of caloric restriction on expression of testicular cytochrome P450 enzymes associated with the metabolic activation of carcinogens.

Previous work demonstrated that microsomal cytochrome P4502A1 (CYP2A1) is expressed in rat testicular Leydig cells. The present study investigates the effects of diet, age, and strain on rat testicular CYP2A1 expression and assesses the potential role of testicular CYP2A1 in the metabolic activation of carcinogens. In ad libitum-fed 18-week-old Fischer 344 rats, testicular CYP2A1 immunoreactive protein and testosterone 7alpha-hydroxylase activity (7alpha-TOHase) exhibited a circadian variation with a daytime maximum and a night-time minimum (82.2 +/- 42.0 and 21.9 +/- 4.5 pmol 7alpha-hydroxytestosterone/min/mg protein, respectively). Caloric restriction (to 60% of ad libitum consumption), which reduces the severity of Leydig cell tumors in rats, decreased expression of both CYP2A1 and testicular 7alpha-TOHase >80% and eliminated their circadian variation. Conversely, caloric restriction induced a circadian rhythm in testicular 7-benzyloxyresorufin-O-dealkylase activity. Testicular microsomes from ad libitum-fed rats having peak diurnal 7alpha-TOHase activity had significantly greater (30%) microsome-mediated aflatoxin B1-DNA binding activity compared to microsomes prepared from nocturnal phase ad libitum-fed or calorically restricted rats which expressed low 7alpha-TOHase activity. In 12-month-old Fischer 344 rats, high CYP2A1 expression was correlated with severe Leydig cell hyperplasia (r = 0.80), whereas CYP2A immunoreactive protein and 7alpha-TOHase were expressed at lower levels in Sprague-Dawley than in Fischer 344 rats and were undetectable in pig, monkey, and human testes. These are strains/species that do not exhibit significant Leydig cell hyperplasia. This suggests that caloric intake, strain, and circadian factors may all mediate testicular CYP2A1 expression in the rat and that CYP2A1 may in turn influence carcinogen activation and pathological status in the testis.

Aflatoxin B1↗
PubMed1996

Anthropometric measures and metabolic rate in association with risk of breast cancer (United States).

To investigate whether cancer risk-reduction seen in calorie-restricted animals also applies to breast cancer in women, we have analyzed data from the first National Health and Nutrition Examination Survey in the United States and subsequent follow-up surveys. During the follow-up of one to 155 months, 182 out of 7,622 women developed breast cancer. Due to biased under-reporting of dietary intake, the analysis did not examine calorie intake as an exposure variable, but rather focused on anthropometric measures and metabolic rate as biomarkers of nutritional balance. Multiple Cox regression analysis showed elevated odds ratios (OR) for height, elbow width, and skinfolds among postmenopausal women. ORs for the fifth quintile were 2.0 (95 percent confidence interval [CI] = 1.0-3.8), 2.3 (CI = 1.2-4.7), and 2.0 (CI = 1.0-4.0), respectively. Weight (OR = 2.5, CI = 1.2-5.1) and resting metabolic rate (OR = 2.0, CI = 1.0-4.0) were significant relative to the second quintile. Bitrochanteric breadth, sitting height, body fat, body mass index, or combination variables were not associated with cancer risk. It was concluded that in the analysis of breast cancer data, skeletal measures ought to be considered as routine potential confounders, and that using measured rather than estimated metabolic rates may improve risk prediction.

Adipose Tissue↗
PubMed1996

Pi-class glutathione-S-transferase-positive hepatocytes in aging B6C3F1 mice undergo apoptosis induced by dietary restriction.

Liver sections from aging ad libitum-fed and diet-restricted B6C3F1 male mice were evaluated immunohistochemically for pi-class glutathione S-transferase (GST-II). GST-II immunostaining of hepatocytes was diffuse and occurred in periportal regions of hepatic acinus, whereas perivenous areas were weakly stained or were stain-free. Expression of GST-II was significantly diminished in diet-restricted mice in all age groups and was associated with a marked decrease in liver tumor development. As most spontaneous liver tumors were GST-II positive, it can be speculated that they developed from GST-II positive initiated hepatocytes. To determine whether dietary restriction induces apoptosis in GST-II-positive hepatocytes, 24-month-old ad libitum-fed mice were introduced to 40% diet restriction. After 1 week of diet restriction, a decrease in GST-II expression was associated with a threefold increase in the frequency of apoptotic bodies as detected by terminal deoxynucleotidyl transferase-mediated d-UTP nick end labeling of DNA fragments. A two-step immunohistochemical procedure revealed that approximately 70% of apoptotic bodies were GST-II positive. These results suggest that spontaneous, potentially preneoplastic hepatocytes in tumor-prone B6C3F1 mice are eliminated by apoptosis with dietary restriction.

Aging↗
PubMed1995

Caloric restriction and toxicity.

The modulatory effects of caloric intake on the rate and extent of both spontaneous and induced disease incidence is well known, but the significance of these effects in the interpretation of testing data has only recently become appreciated. This is especially true relative to the impact of caloric intake on both survival and background incidence for common tumors. In order to enhance the health and survival of animals ongoing chronic toxicity testing it has been suggested that such tests should restrict food consumption. Although this restriction will result in increasing survival of the test animals, it may also effect the expression of toxicity by altering agent metabolism and disease progression. Focus in this symposium is on the necessity to control dietary consumption in toxicity tests (dietary control), and if such a need does exist to what level of consumption should be diet be focused (caloric restriction).

Animals↗
PubMed1995

Spontaneous renal tubular carcinoma in Fischer-344 rat littermates.

Two of 632 Fischer-344 rats in a food restriction study had spontaneous, bilateral, multicentric renal tubular cell carcinomas. Although there were 104 litters represented in this study, both rats that developed this rare neoplasm were from the same litter. The littermates, one male and one female, were in the food-restricted treatment groups (60% of ad libitum intake) and were 550 and 447 days old, respectively, at death. The probability that the two rare bilateral renal neoplasms occurred by a chance event in littermates is approximately 0.8%. The apparent familial predisposition for development of specific types of neoplasms emphasizes the importance of randomization of individuals into treatment groups and consideration of lineage for rare tumors.

Animals↗
PubMed1995

Age-related changes in the intrinsic rate of apoptosis in livers of diet-restricted and ad libitum-fed B6C3F1 mice.

Cancer incidence increases progressively with age. This observation suggests that a mechanistic relationship may exist at the cellular level between these two apparently diverse processes. Indirect evidence for this fundamental relationship is derived from the fact that interventions that retard the rate of aging simultaneously retard the incidence of many forms of cancer. Dietary restriction of rodents is a noninvasive manipulation that reproducibly retards most physiological indices of aging as well as the incidence of spontaneous and chemically induced tumors. As such, it provides a powerful model in which to study common mechanistic processes associated with both aging and cancer. In a recent study, we established that chronic dietary restriction induces an increase in the spontaneous rate of apoptotic cell death in hepatocytes of 12-month-old B6C3F1 mice and is associated with a significant reduction in the subsequent development of spontaneous hepatoma in this genetically susceptible strain. The purpose of the present investigation was to extend and confirm these original observations by determining whether the increased rate of spontaneous apoptosis with chronic dietary restriction is maintained throughout the life span in this strain. We quantified the spontaneous apoptotic rate by histological examination of liver sections from diet-restricted and ad libitum-fed B6C3F1 mice at age intervals of 12, 18, 24, and 30 months. The incidence of apoptotic bodies was enumerated in non-tumor-bearing mice by scoring 50,000 hepatocytes per liver by in situ end-labeling immunohistochemistry and was expressed as the mean incidence per 100 cells. The rate of apoptotic cell death was found to be elevated with age in both diet groups; however, the rate of apoptosis was significantly and consistently higher in the diet-restricted mice, relative to the ad libitum-fed mice, regardless of age. It has been proposed that apoptosis, or physiological cell death, provides a protective mechanism whereby DNA-damaged or potentially neoplastic cells are selectively eliminated. Thus, interventions that increase cellular sensitivity to apoptotic cell death would tend to protect genotypic and phenotypic stability with age; on the other hand, the failure to initiate or respond to appropriate signals for apoptosis would tend to accelerate the accumulation of age-associated genetic lesions and age-related neoplasia. An increase in the intrinsic rate of apoptotic cell death may contribute, in part, to decreased tumor incidence and increased life span potential with dietary restriction.

Aging↗
PubMed1995

Glaucoma in food-restricted and ad libitum-fed DBA/2NNia mice.

We allocated 110 DBA/2NNia mice of either sex to one of two feeding regimens: ad libitum (AL) or food restriction (FR) to 60% of the amount consumed by the AL group. The mice were examined at 3, 6, 9, 12, 18, and 24 months (at 3 months, only AL mice were examined). During the remaining periods approximately equal numbers (n = 10) of mice of both sexes and diet groups were examined. Peripheral anterior synechia was the first glaucoma-associated lesion observed and was present in 8 of 10 AL female mice, 6 of 10 AL males, and 1 FR male at 6 months. At 9 months peripheral anterior synechia was present in all AL females and was accompanied by depletion of retinal ganglion cells and degeneration of the optic nerves and optic tracts. Ninety percent of the eyes in the AL males also had peripheral anterior synechia at 9 months, but ganglion cell depletion and optic nerve degeneration were not observed as frequently. Neovascular membranes in the iridocorneal angle, a component of peripheral anterior synechia, were first observed at 9 months in approximately 55% of the globes of the AL mice and 5% of the FR mice. This was a major difference in the microscopic features of synechia between the diet groups and resulted in increased severity of synechia in the AL mice compared with their FR cohorts. Degeneration of the optic nerves and tracts was characterized by atrophy, astrogliosis, increase in cellularity, fragmentation of axons, and loss of myelin. Glaucoma in the FR mice of both sexes was less severe than in their AL counterparts. The most severely affected were AL females, followed by FR females, AL males, and FR males. Food restriction reduced the incidence and severity of the ocular lesions in females at all periods. The primary benefit of FR in males occurred during the 6- and 9-month periods when the incidence and severity of the glaucoma-related lesions were reduced; in the succeeding months the major benefit was minimal reduction of the severity of the lesions.

Animals↗
PubMed1995

Proliferative lesions of the testis in ad libitum-fed and food-restricted Fischer-344 and FBNF1 rats.

The effect of 40% food restriction on spontaneous proliferative lesions of the testis was evaluated in lifetime and cross-sectional (serial sacrifice) studies of 419 Fischer (F-344) and 304 Fischer x Brown Norway (FBNF1) male rats. Interstitial cell hyperplasia and interstitial cell adenoma (ICA) were the most common proliferative lesions in each genotype; incidence of each was less in the FBNF1. In each genotype, food restriction delayed the onset of both lesions and reduced the incidence of ICA. At 12 months interstitial cell hyperplasia was present in 11 of 12 ad libitum (AL)-fed and 0 of 12 food-restricted (FR) F-344 rats. In FBNF1 rats interstitial cell hyperplasia was observed first at 18 months in AL-fed and at 36 months in FR groups. Interstitial cell adenoma developed in 5 of 12 AL-fed F-344 rats by 18 months and in 2 of 12 FR rats by 24 months; 2 of 12 AL-fed FBNF1 rats had ICA at 30 months, and 1 of 12 FR rats had ICA at 42 months. In these cross-sectional studies approximately half the ICA cases in F-344 rats were bilateral; no FBNF1 rats had bilateral ICA. In lifetime studies the incidence of ICA was reduced from 49% in AL-fed rats to 19% in FR F-344 rats and from 9% in AL to 4% in FR FBNF1 rats. The incidence of mesothelioma was low in both genotypes and was not obviously altered by food restriction. A malignant embryonal neoplasm, an unclassified benign neoplasm, and three seminomas were present in the testes of FBNF1 rats.

Adenoma↗