摘要:

The symmetrical triazine herbicides have been used for the preemergence control of broadleaf weeds for nearly three decades. Recently, certain members of this class, primarily the chlorotriazines (substituted in the 2 position), have been shown to evoke an increased incidence of mammary tumors in female Sprague‐Dawley rats. This response was noted when these chemicals were administered in the diet for 2 yr, and most often at dietary feeding levels at or above the maximum tolerated dose (MTD). At levels exceeding the MTD the health of these animals was compromised, as manifested by toxicity‐related reduced survival that was not associated with the occurrence of mammary tumors. Mammary tumors in rats frequently occur as a result of the influence of endogenous estradiol and prolactin. Those hormones, as well as progesterone, growth‐stimulating, luteinizing, and follicle‐stimulating hormones, were measured after 24 mo of dietary administration of the chlorotriazine, simazine. The plasma hormone pattern seen in aged female Sprague‐Dawley rats administered 1000 ppm simazine in the diet for 24 mo resembled that noted for aged female controls, except that the difference was more pronounced in the simazine‐treated group. These results suggest that prolonged exposure of Sprague‐Dawley females to excessive levels of triazines affects the neuroendocrine system, which in turn alters the pathology of the mammary gland. These changes are comparable to those that occur naturally as the rat ages. Changes in neuroendocrine control could result in the expression of an earlier onset and/or an increased incidence of mammary tumors, which already occur at a high spontaneous rate in aging Sprague‐Dawley female rats.

ISSN:0098-4108    

DOI:10.1080/15287399409531911

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

Atrazine or simazine (s‐chlorotriazines) was administered by gavage daily for 2 wk to female Sprague‐Dawley and Fischer 344 rats at oral doses of 100 or 300 mg/kg to evaluate effects on body, ovary, uterus, and adrenal weights, estrous cycle stages, vaginal cytology, and plasma hormone (estradiol, progesterone, prolactin, and corticosterone) levels. Significant reductions in body weights of both Sprague‐Dawley and Fischer 344 female rats at both dose levels were accompanied by a significant reduction in ovarian and uterine weights, and a decrease in circulating estradiol levels. The magnitudes of the effects were less in Fischer 344 rats than in Sprague‐Dawley rats, and the effects of simazine were less pronounced than those of atrazine at the same dose. A maximum tolerated dose (MTD: ≥10% body weight reduction) was estimated to be 100 mg/kg for atrazine and 300 mg/kg for simazine for both stains. The Sprague‐Dawley female rats exhibited a treatment‐related lengthening of the estrous cycle and an increased number of days characterized by cornified epithelial cells. This resulted in a greater percent of the cycle days spent in estrus and reduction in the percent of the cycle days spent in diestrus. Atrazine‐dosed Fischer 344 females also exhibited a significant trend toward cycle lengthening, but this was due to reduction in the percent of cycle spent in estrus and a concomitant increase in diestrual days. These findings suggest that treatment with doses of triazine at or above the MTD may result in prolonged exposure to endogenous estrogen in the Sprague‐Dawley but not the Fischer 344 rat. These changes may account for the observed earlier onset and/or increased incidence of mammary tumors in chlorotriazine‐treated female Sprague‐Dawley rats. This strain of rat is already known to be prone to a substantial development of mammary tumors with advancing age, while the Fischer 344 strain is not as likely to exhibit this response.

ISSN:0098-4108    

DOI:10.1080/15287399409531912

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

The chronic effects of dietary administration of atrazine at levels as high as 400 ppm on selected endocrine and tumor profiles were evaluated in Fischer 344 and Sprague‐Dawley female rats. The study showed that lifetime dietary administration of atrazine at a maximum tolerated dose (MTD) to Sprague‐Dawley female rats caused (1) lengthening of the estrous cycle, (2) increased number of days in estrus or under the influence of exposure to estrogen, (3) earlier onset of galactocele formation, and (4) earlier onset of mammary and pituitary tumor formation but not an increased incidence of mammary and pituitary tumors when compared to concurrent control rats. Fischer 344 female rats fed atrazine at an MTD exhibited slightly lengthened estrous cycles, but no effects were observed on estradiol or progesterone levels, or on the onset or incidence of mammary tumors. These results support a hypothesis that high‐dose atrazine administration in Sprague‐Dawley females is related to an acceleration of age‐related endocrine changes leading to an earlier onset and/or increased incidence of mammary tumors. This endocrine‐mediated response, which appears to be unique to the Sprague‐Dawley female rat, occurs only at or above a threshold dose (the MTD) that interferes with normal estrous cycling, promoting prolonged exposure to endogenous estrogen.

ISSN:0098-4108    

DOI:10.1080/15287399409531913

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

Several published reports have indicated that certain chloro‐s‐triazine herbicides may alter endocrine function in rats, possibly by androgen receptor binding. In direct tests of estrogenic bioactivity, oral doses of up to 300 mg/kg/d of atrazine, simazine, or the common metabolite diaminochlorotriazine (DACT) did not significantly increase uterine weight of ovariectomized Sprague‐Dawley female rats. The highest dose, which was approximately 10% of the LD50 for these compounds, did cause body weight loss. When administered concomitantly with sc injections of estradiol (2 μg/kg), 300 mg/kg of orally administered chlorotriazines significantly reduced uterine weight in comparison to animals given estrogen alone. Neither atrazine, simazine, nor DACT, at oral doses up to 300 mg/kg/d, stimulated incorporation of [3H]thymidine into uterine DNA of immature Sprague‐Dawley female rats. However, oral treatment at doses of 50 mg/kg and higher significantly reduced thymidine incorporation into uterine DNA extracted from immature rats given a single injection of 0.15 μg estradiol. Oral doses of 300 mg/kg of atrazine, simazine, or DACT significantly reduced expression of progesterone receptor binding in cytosol fractions prepared from uteri of ovariectomized rats injected sc with 1 μg estradiol; 50 mg/kg triazine was not effective in this case. Uterine progesterone receptor levels were not stimulated in rats given oral doses up to 300 mg/kg of these triazines without estradiol injections. These results suggest that atrazine, simazine, and DACT possess no intrinsic estrogenic activity but that they are capable of weak inhibition of estrogen‐stimulated responses in the rat uterus. This inhibition may play a role in the previously observed disruptive actions of chlorotriazines on reproductive endocrine function of female rats.

ISSN:0098-4108    

DOI:10.1080/15287399409531914

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

In an accompanying article (see pp. 183–196), it was reported that administration of very high doses of the chlorotriazine herbicides atrazine, simazine, and diaminochlorotriazine (DACT), a common metabolite, expressed antiestrogenic activity in uteri of female Sprague‐Dawley rats without expressing intrinsic estrogenic activity. In the present article, studies of chlorotriazine interaction with rat uterine estrogen receptors (ER) are reported. Under equilibrium conditions, none of the triazine compounds showed an ability to compete against binding of radiolabeled estradiol to ER. A weak competition was evident only if cytosols were preincubated with triazines at 25°C prior to introduction of tracer. Competition was very weak, with ktestimates of 10–100 μM. A limited Scatchard analysis suggested a competitive type of inhibition. Sucrose gradient analysis of cytosol incubations showed that triazine interaction with the 4S isoform of ER may be greater than with the 85 form. When administered to ovariectomized rats for 2 d at 300 mg/kg/d, atrazine, simazine, or DACT all reduced uterine ER binding capacity by approximately 30%. Results from the receptor binding studies indicated that triazine competition against ER binding occurred to a much lesser degree than inhibition of estrogen‐mediated responses reported in accompanying articles. This suggests that the complete responses to triazines may include inhibition of events other than or in addition to ER binding of estrogen.

ISSN:0098-4108    

DOI:10.1080/15287399409531915

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

Unleaded gasoline (UG), a complex mixture of over 300 hydrocarbons, induced liver tumors selectively in female mice and exhibited liver tumor promoting activity. UG also induced cell proliferation and cytochrome P‐450‐related enzyme activities in mouse liver, properties commonly associated with liver tumor promoters. To determine if the mitogenic and/or cytochrome P‐450‐inducing properties of UG reside in individual fractions of UG, UG was separated into four fractions on the basis of boiling point (BP): fraction 1, BP < 66°C; fraction 2, 66°C < BP < 100°C; fraction 3, 100°C < BP < 132°C; fraction 4, BP > 132°C. Fractions 1 and 2 were combined to form “light UG” (BP < 100°C), and fractions 3 and 4 were combined to form “heavy UG” (BP > 100°C). Female B6C3F1 mice were implanted with osmotic pumps containing 5‐bromo‐2'‐deoxyuridine (BrdU) on d 1, treated by intragastric intubation with corn oil or 3000 mg/kg/d of light, heavy, or whole UG on d 2–4, and euthanized on d 5. Pentoxyresorufin O‐dealkylase (PROD) and ethoxyresorufin O‐deethylase (EROD) activities were assayed in hepatic microsomes, and hepatocyte BrdU labeling index (LI) was determined in liver sections. Whole UG and heavy UG caused comparable increases in hepatic PROD and EROD activities and the hepatocyte LI. Light UG caused relatively small increases in hepatic PROD and EROD activities and did not increase the hepatocyte LI. When fractions 3 and 4 were tested separately in the above treatment protocol, both fractions strongly induced hepatic PROD and weakly induced hepatic EROD activities. However, only fraction 3 increased the hepatocyte LI. To isolate mitogenic components in fraction 3, equimolar doses of individual chemicals in fraction 3 were tested in the above treatment protocol. Toluene did not increase the hepatocyte LI, whereas 2,2,3‐trimethylpentane (TMP), 2,2,4‐TMP, and 2,3,4‐TMP all dramatically increased the hepatocyte LI. Thus, while the hepatic cytochrome P‐450‐inducing activity of UG was concentrated in components of UG with BPs > 100°C, this activity apparently resides in UG components with a wide range of BPs. The mitogenic activity of UG, in contrast, was highly concentrated in components of UG with BPs ranging from ∼100 to 132°C, and quite possibly in specific TMPs.

ISSN:0098-4108    

DOI:10.1080/15287399409531916

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

The possible interaction between intense exercise, known to suppress the immune response, and nutritive factors, such as polyunsaturated fatty acids (PUFA), was examined in inbred female C57BI/6 mice. The animals received for 8 wk either a natural ingredient diet or a diet supplemented with 10 g/100 g linseed oil containing over 50% of 18 : 3 (n‐3) α‐linoleic acid. Other groups received PUFA containing only traces of 18 : 3 (n‐3) fatty acid; beef tallow, containing mostly 18 : 1 (n‐9) saturated fat, safflower oil, an 18 : 2 (n‐6) PUFA, and fish oil, containing longer chain (n‐3) PUFA. Each dietary group was divided into two subgroups: sedentary diet controls and exercised animals. Exercise consisted of continuous swimming at high intensity until exhaustion. It was shown in three separate experiments that (1) the primary humoral response to sheep red blood cells, determined by the plaque‐forming cell (PFC) assay, was affected by PUFA diet in sedentary animals in the order beef tallow > control diet > safflower oil > fish oil > linseed oil, and (2) the PFC response was suppressed by the exhaustive exercise, as compared to sedentary controls, except for animals fed 18 : 3 (n‐3) linseed oil, where the normal response was noted. Phagocytosis of fluorescent microspheres by peritoneal macrophages, determined by flow cytometry, was significantly lower in exercised animals receiving the linseed oil diet, whereas other diets either increased or did not significantly change the macrophage phagocytic activity, compared to the sedentary diet controls. Spleen lymphocyte subsets were unchanged in exercised animals except for a marked shift from the lymphoid peak toward the erythroid peak. Generally, our data showed a marked immunomodulatory effect of 18–3 (n‐3) α‐linoleic acid on the exhaustive exercise‐related immunosuppression, as compared to the effects of other selected PUFA.

ISSN:0098-4108    

DOI:10.1080/15287399409531917

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

摘要:

Free‐radical‐induced oxidative damage has been implicated as an important mechanism responsible for the toxicity of both active and passive smoking. Cigarette smoke contains short‐ and long‐lived radicals and can stimulate cellular production of highly reactive oxygen species. One of the antioxidant enzymes that is protective against reactive oxygen‐induced damage is manganese superoxide dismutase (MnSOD), which is located in the mitochondria of mammalian cells. The present study was conducted to examine the role of oxidative damage in cigarette smoke toxicity. A mouse fibroblast cell line (C3H10T1/2) and its MnSOD‐transfected, enzymatically active clone, R2 cells, which possessed about fivefold greater MnSOD activity, were used to test the cytotoxicity of condensates from mainstream (MS‐CSC) and sidestream (SS‐CSC) cigarette smoke. Growth and respiration studies of the two test cell lines showed that the R2 cells grew to a higher cell density and exhibited greater oxygen uptake than the parent cells under normal growth conditions. Both smoke condensates were cytotoxic to test cells, but SS‐CSC exhibited slightly greater toxicity, and R2 cells were significantly less susceptible to SS‐CSC toxicity than the parent cells. SS‐CSC caused a slightly greater inhibition of respiratory activity in parent cells than in R2 cells. These results suggest a significant contribution of oxidative damage in SS‐CSC cytotoxicity.

ISSN:0098-4108    

DOI:10.1080/15287399409531918

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287399409531910

出版商:Taylor & Francis Group    

年代:1994

数据来源: Taylor