Pei-Yu Wang

Incidence and mortality of testicular and prostatic cancers in relation to world dietary practices

The incidence and mortality rates of testicular and prostatic cancers in 42 countries were correlated with the dietary practices in these countries using the cancer rates (1988–92) provided by the International Agency for Research on Cancer (IARC) and the food supply data (1961–90) provided by the Food and Agriculture Organization (FAO). Among the food items we examined, cheese was most closely correlated with the incidence of testicular cancer at ages 20–39, followed by animal fats and milk. The correlation coefficient (r) was highest (r = 0.804) when calculated for cheese consumed during the period 1961–65 (maternal or prepubertal consumption). Stepwise‐multiple‐regression analysis revealed that milk + cheese (1961–65) made a significant contribution to the incidence of testicular cancer (standardized regression coefficient [R] = 0.654). Concerning prostatic cancer, milk (1961–90) was most closely correlated (r = 0.711) with its incidence, followed by meat and coffee. Stepwise‐multiple‐regression analysis identified milk + cheese as a factor contributing to the incidence of prostatic cancer (R = 0.525). The food that was most closely correlated with the mortality rate of prostatic cancer was milk (r = 0.766), followed by coffee, cheese and animal fats. Stepwise‐multiple‐regression analysis revealed that milk + cheese was a factor contributing to mortality from prostatic cancer (R = 0.580). The results of our study suggest a role of milk and dairy products in the development and growth of testicular and prostatic cancers. The close correlation between cheese and testicular cancer and between milk and prostatic cancer suggests that further mechanistic studies should be undertaken concerning the development of male genital organ cancers.

Milk Consumption Is a Risk Factor for Prostate Cancer: Meta-Analysis of Case-Control Studies

Prostate cancer has become the most common cancer among men in the United States. Although milk consumption is considered to be a risk factor in some epidemiological studies, the results are inconsistent. A meta-analysis method was conducted to estimate the combined odds ratio (OR) between milk consumption and prostate cancer from case-control studies published between 1984 and 2003 using commercial software (comprehensive meta-analysis). The combined OR was 1.68 (95% confidence interval = 1.34-2.12) in the 11 published case-control studies. The combined OR varied little by study stratification. Additionally, we evaluated the possible risk factors in milk for prostate cancer. In conclusion, we found a positive association between milk consumption and prostate cancer. The underlying mechanisms, including fat, calcium, hormones, and other factors, should be investigated further.

Estrogen: one of the risk factors in milk for prostate cancer.

Studies to elucidate the cause of prostate cancer have met with little success to date. Epidemiological studies suggested that milk consumption is probably as one of the risk factors for prostate cancer. The studies thus focused on the fat and calcium in milk, but reached no definitive conclusion. According to the measurements of estrogen levels in milk by different studies, it was suggested that estrogen in milk was a possible risk to cause prostate cancer. One reason supporting this hypothesis is that Western diet (characterized by milk/dairy products and meat) causes a trend of increasing levels of estrogens, and Western males show a higher incidence rate of prostate cancer than Asia males. Estrogen levels in prostate fluid are also correlated very well with the prostate cancer. During several decades, estrogens, together with testosterone, was commonly used to induce the rodent model of prostate cancer. Our hypothesis also was supported by the presence of estrogen receptors in the prostate gland and the genotoxic role of estrogens on the prostate gland, as possible mechanisms. Therefore, if modern milk consumption does expose consumers to high levels of estrogen and plays an adverse role in prostate cancer, action should be taken to produce the noncontaminant milk.

Time courses of hepatic injuries induced by chloroform and by carbon tetrachloride: comparison of biochemical and histopathological changes

The relationship was investigated between biochemical and morphological changes in chloroform (CHCl3)- and carbon tetrachloride (CCl4)-induced liver damage. The time courses of hepatic microsomal cytochrome P450 (CYP) content, hepatic microsomal CYP2E1 activity, hepatic reduced glutathione (GSH) content, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were examined in relation to the liver morphology in rats orally treated with CHCl3 or CCl4 (3.35 mmol/kg). The CYP content and the activity of CYP2E1 markedly decreased in the CCl4-treated rats 3 h after treatment compared to much lower decreases in the CHCl3-treated rats. The hepatic GSH content was decreased to a similar extent in both groups of rats at 3 h after treatment; in the CCl4-treated rats, the GSH content continued to decrease, reaching a minimum at 24 h and without attaining the normal level at 72 h after treatment. By contrast, hepatic GSH content in the CHCl3-treated rats began to increase from 6 h, attaining complete recovery 48 h after treatment. Plasma ALT and AST activities were significantly elevated by CCl4 as early as 3 h after treatment, while the activities in the CHCl3-treated rats did not increase until 6 h after treatment. In both groups of rats, ALT and AST activities reached a maximum at 24 h, and gradually decreased, remaining at abnormal levels at 72 h. Hepatic cells in the CCl4-treated rats were found to be necrotic as early as 3 h post-treatment, whereas few or no morphological changes appeared in the liver of CHCl3-treated rats. The extent of necrosis was at a maximum 24 h after treatment in both CHCl3- and CCl4-treated rats. In addition, some necrotic cells remained in the liver of CCl4-treated rats 72 h after treatment, while the necrosis in the CHCl3-treated rats was almost negligible. The present results indicate that almost the same time-courses of biochemical and morphological changes were followed in rats of both the CHCl3- and CCl4-treated groups.

LOW-FAT MILK PROMOTES THE DEVELOPMENT OF 7,12-DIMETHYLBENZ(A)ANTHRACENE (DMBA)-INDUCED MAMMARY TUMORS IN RATS

Commercial cow milk contains considerable amounts of estrogens. Our study assessed the effect of commercial low‐fat milk on the development of 7,12‐dimethylbenz(a)anthracene (DMBA)‐induced mammary tumors in rats. Eighty 6‐week‐old female Sprague‐Dawley rats received a single oral dose of 5 mg DMBA. Twenty‐four hours later, the animals were divided into 4 groups of 20 animals each and given 1 of 4 test solutions for 20 weeks as their drinking liquid: low‐fat (1%) milk (M), artificial milk (A), estrone sulfate solution (0.1 μg/ml, E), or tap water (W). The artificial milk was formulated to supply essentially the same calories as the milk. The low‐fat milk contained 378 pg/ml estrone sulfate. Tumor incidence, the cumulative number of tumors and the sum of tumor diameters were higher in the M and E groups than in the A or W groups. Overall, the development of mammary tumors was in the order: M = E > A = W. Whereas the plasma 17β‐estradiol concentration in the M group was the 2nd highest after the E group, the plasma level of insulin‐like growth factor (IGF‐I) was significantly higher in the M group than in the other 3 groups. In conclusion, commercially available low‐fat milk promotes the development of DMBA‐induced mammary tumors in rats. The degree of the promotion is almost comparable to that of 0.1 μg/ml estrone sulfate. The high estrogen content in the milk may be responsible for the promotional effects, acting in concert with other hormones such as IGF‐I.

Troglitazone enhances the hepatotoxicity of acetaminophen by inducing CYP3A in rats

Troglitazone (TRZ) is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is proven to lower plasma glucose levels in patients with type 2 diabetes mellitus. However, the concern has been raised because of several reports, in which severe hepatic dysfunction leading to hepatic failure was demonstrated in a few patients receiving the drug. We studied the effects of TRZ on the hepatotoxicity of carbon tetrachloride (CCl(4)) and acetaminophen (APAP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 3A (CYP3A) and 2E1 (CYP2E1). Male standard (Wistar/ST) and type 2 diabetic model (GK/Jal) rats were kept on a powdered chow diet containing 0, 100, 500 mg/kg/rat of TRZ. Three weeks later, the rats were either sacrificed for an in vitro metabolism study or challenged with 0.50 g/kg CCl(4) p.o. or 0.75 g/kg APAP i.p.TRZ at 100 and 500 mg/kg/rat increased the CYP3A level as well as the testosterone 6beta-hydroxylation activities in liver microsomes, but did not affect CYP2E1. TRZ also enhanced APAP hepatotoxicity, as evidenced by significantly increased levels of alanine aminotransferase, aspartate aminotransferase and alpha-glutathione S-transferase in the plasma of rats, and by significantly low hepatic glutathione concentration. Our study demonstrated that high doses of TRZ can enhance hepatotoxicity of APAP in Wistar/ST and GK/Jal by inducing hepatic CYP3A.

The experience of Japan as a clue to the etiology of testicular and prostatic cancers

In Japan dramatic lifestyle changes occurred after World War 2. To examine the experience of Japan as a clue to the etiology, trends in the mortality rates of testicular and prostatic cancers from 1947 to 1998 were related to changes in dietary practices. The male population born before 1945 had a peak in death from testicular cancer in their thirties or forties, whereas those born after 1946 had a peak in their twenties. The death rate of prostatic cancer increased 25-fold almost linearly after the war. The intake of milk, meat, and eggs increased 20-, 9-, and 7-fold, respectively, after the war. In connection with the development and growth of testicular and prostatic cancers in Japan, particular attention should be paid to milk, because the increase in its consumption in this country is a recent occurrence and because milk contains considerable amounts of estrogens plus saturated fats.

Glucose Intolerance Induced by a High-Fat/ Low-Carbohydrate Diet in Rats

We examined the time course of effects of a high-fat/low-carbohydrate (HF/LC) diet on the impairment of glucose tolerance in rats, clarified whether insulin secretion and sensitivity were impaired by the HF/LC diet, and investigated the relationship between the increased nonesterified fatty acids (NEFA) after HF/LC diet feeding and insulin secretion and sensitivity. We found that glucose tolerance and the postglucose-loading insulin secretion were impaired after 3 and 7 d on the HF/LC diet. The glucose intolerance was accompanied by a rise in the fasting plasma NEFA level. When stimulated with 15 mmol/L of glucose, the insulin secretion was impaired in pancreatic islets from rats fed the HF/LC diet. Rats fed the HF/LC diet showed insulin resistance in vivo. The glucose-stimulated insulin secretion was inhibited in the islets following 24-h culture with palmitic acid. The 24-h infusion of palmitic acid decreased whole-body insulin sensitivity. In summary, at least 3 d on a HF/LC diet is needed to induce glucose intolerance in rats, and the impairment may be induced by decreased insulin secretion and sensitivity, which is related to the increase in the plasma NEFA level.

The development of diabetes mellitus in Wistar rats kept on a high-fat/low-carbohydrate diet for long periods.

The present study was performed to determine the effect of long-term feeding with a high-fat/low-carbohydrate (HF/LC) diet on the onset of type-2 diabetes mellitus in normal rats. Male Wistar Imamichi rats were kept on a Control (carbohydrate 60%, fat 15%) or HF/LC (carbohydrate 10%, fat 65%) diet for 16 mo. An intraperitoneal glucose tolerance test was performed once every 2 mo. Glucose tolerance was impaired 2 mo after the start of HF/LC diet feeding, accompanied by a decrease in the insulinogenic index. Along with time of HF/LC diet feeding, the glucose tolerance was further deteriorated with more serious impairment of insulin secretion and sensitivity. At the end of the experiment, 15 of 18 rats in the HF/LC group were diabetic, whereas only 4 of 17 rats in the Control group were diabetic. The present results demonstrate that long-term feeding with a HF/LC diet decreases the secretion and sensitivity of insulin, and induces diabetes mellitus in rats. Furthermore, long-term feeding with such a diet may produce adverse effects on the blood plasma lipid profile, with elevated levels of trigly cerides, non-esterified fatty acids, total cholesterol, and reduced levels of high density protein cholesterol in the plasma.

Dietary carbohydrate intake plays an important role in preventing alcoholic fatty liver in the rat

BACKGROUND/AIMS Dietary carbohydrate intake during ethanol ingestion augments the induction of hepatic cytochrome P450 2E1 (CYP2E1) by ethanol. This study addresses the role of carbohydrate intake in the development of alcoholic fatty liver in the rat. METHODS Male Sprague-Dawley rats were pair-fed on liquid diets containing ethanol (3.5 g/day, 36% of total calories) with different amounts of carbohydrate and fat for 4 weeks, and the development of fatty liver was observed biochemically and morphologically. RESULTS An ethanol-containing low-carbohydrate diet (protein 17%; fat 36%; carbohydrate 11%; ethanol 36%) had more markedly adverse effects on the liver of rats than did an isocaloric ethanol-containing high-carbohydrate diet (protein 17%; fat 5%; carbohydrate 42%; ethanol 36%). The hepatic triglyceride level in the rats that consumed the low-carbohydrate diet was higher than that in the rats kept on the high-carbohydrate diet, a finding that was confirmed histologically. The ethanol-containing low-carbohydrate diet caused a marked increase in the activity of hepatic CYP2E1. The CYP2E1 protein level, as measured by Western blot analysis, matched the activity of CYP2E1, as measured by the rates of dimethylnitrosamine, p-nitrophenol and ethanol metabolism. The severity of the fatty liver was well correlated with the increased CYP2E1 activity. CONCLUSIONS Dietary carbohydrate intake plays an important role in the development of alcoholic fatty liver by affecting CYP2E1 activity in the liver. A liquid diet containing ethanol in which the ethanol is included at the expense of fat is more acceptable to rats than a diet in which the ethanol replaces carbohydrate.