Response of the antral mucosa of the rat stomach to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) produces a striking hypergastrinemia in rats that is thought to mediate the antiatrophy effect of TCDD on the oxyntic gland mucosa of the stomach. However, effects of TCDD on the antral mucosa, which is the origin of most physiologically released gastrin and is not a target for the trophic action of gastrin, has yet to be thoroughly investigated. Also gastrin release from gastrin-containing cells (i.e., G-cells) in the antral mucosa is inhibited by the paracrine secretion of somatostatin from D-cells in the antrum. Our purpose was to determine if the antral mucosa is affected by the trophic influence of TCDD and if alterations in antral mucosa levels of gastrin or somatostatin cause the hypergastrinemia. TCDD (100 micrograms/kg, Day 14 post-treatment) had a trophic effect on the antral mucosa. This was demonstrated histologically and by significant increases in antral wet weight and antral mucosa height. In contrast, pair-fed control rats that lost the same amount of body weight developed antral mucosa atrophy. With respect to serum and antral levels of gastrointestinal hormones, TCDD produced a 7- to 10-fold increase in serum gastrin concentrations that was not detected until Day 14 post-treatment. In contrast, serum gastrin concentrations in pair-fed control rats were comparable to those of control rats. The number of G-cells in the antral mucosa was not affected by either TCDD treatment or paired-feed restriction. These findings demonstrate that hypergastrinemia in TCDD-treated rats is not caused by reduced feed intake or antral G-cell hyperplasia. A major finding was that antral mucosa levels of both gastrin and somatostatin were decreased significantly in TCDD-treated rats. However, the temporal development and dose-dependence of these TCDD effects on antral hormone levels were quite different than those for hypergastrinemia. TCDD-induced decreases in antral levels of gastrin and somatostatin were detected 1 week earlier than hypergastrinemia. Also, the ED50 of TCDD on Day 14 post-treatment for the decrease in antral mucosa content and concentration of gastrin (29 and 22 micrograms/kg, respectively) and somatostatin (24 and 19 micrograms/kg, respectively) was less than that for hypergastrinemia (46 micrograms/kg). These time- and dose-dependent differences demonstrate that hypergastrinemia in TCDD-treated rats is not a consequence of reduced antral levels of gastrin or somatostatin. We conclude that the antral mucosa, an epithelial tissue not responsive to the proliferative effect of gastrin, is nevertheless a target for the trophic influence and gastrointestinal hormone-altering effects of TCDD.

Hypergastrinemia is associated with decreased gastric acid secretion in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) produces a delayed onset hypergastrinemia in rats. The purpose of the present study was to determine if the increased serum gastrin concentrations were caused by decreased gastric acid secretion, decreased plasma clearance of gastrin, and/or decreased gastric emptying. It was found that TCDD treatment decreased gastric acid secretion as determined by decreases in gastric secretory volume, acidity, and total acid output in pylorus-ligated rats. Also, both dose-response and time-course curves for decreased gastric acid secretion in TCDD-treated rats were similar to those for hypergastrinemia. These findings, as well as a significant inverse correlation between serum gastrin concentrations and total gastric acid output in rats treated with graded doses of TCDD (5-100 micrograms/kg), suggest that TCDD-induced decreases in gastric acid production cause elevated serum gastrin concentrations. Neither hypergastrinemia nor decreased gastric acid secretion were observed in pair-fed control rats, demonstrating that neither effect was secondary to undernutrition. The TCDD-induced decrease in gastric acid secretion was not caused by a decrease in the number of acid-secreting parietal cells in the stomach, but rather was associated with a decrease in parietal cell responsiveness to gastrin-elicited acid secretion. This was evidenced by both elevated serum gastrin concentrations and a pharmacological dose of pentagastrin failing to stimulate gastric acid secretion in TCDD-treated rats. The disappearance of iv-administered gastrin-17 from the serum was not affected by TCDD treatment, suggesting that reduced serum gastrin clearance is not responsible for the TCDD-induced hypergastrinemia. Although a marked decrease in gastric emptying of a 51Cr-labeled liquid test meal was also observed in TCDD-treated rats, the lowest dose of TCDD required to produce this effect was greater than that needed to cause hypergastrinemia. This suggests that the hypergastrinemic effect of TCDD is not secondary to a decrease in gastric emptying. We conclude that the most probable cause of hypergastrinemia in TCDD-treated rats is decreased gastric acid secretion.

Androgenic deficiency in male rats treated with perfluorodecanoic acid.

Effects of perfluorodecanoic acid (PFDA, 20-80 mg/kg, ip) on the androgenic status of sexually mature male rats were investigated 7 days after treatment. PFDA decreased plasma androgen concentrations in a dose-dependent fashion with an ED50 of approximately 30 mg/kg. The highest dose of PFDA decreased plasma testosterone and 5 alpha-dihydrotestosterone concentrations to 12 and 18%, respectively, of ad libitum-fed control (ALC) values. Secondary to the decreased plasma androgen concentrations were dose-related decreases in the weights and epithelial heights of accessory sex organs. Results from pair-fed control (PFC) rats show that hypophagia in PFDA-treated rats was not a major cause of the low plasma androgen concentrations. When rats were castrated and implanted with testosterone-containing capsules, PFDA-treated and ALC rats had similar plasma testosterone concentrations and secondary sex organ weights. Therefore, the androgenic deficiency in intact PFDA-treated rats does not result from increased plasma clearance of androgens. Rather, PFDA must cause the androgenic deficiency by decreasing the secretion of testosterone from the testis. The decrease in testosterone secretion does not appear to result from a decrease in plasma luteinizing hormone (LH) concentrations, because plasma LH concentrations were not significantly altered by PFDA treatment. This finding suggests that PFDA treatment decreases testicular responsiveness to LH stimulation. The observation that PFDA treatment reduced the secretion of testosterone by testes stimulated in vitro with the LH analog human chorionic gonadotropin demonstrates that this is the case. In addition, since plasma LH concentrations did not increase in response to the low plasma androgen concentrations in PFDA-treated rats, we suggest that PFDA disrupts the normal feedback relationship which exists between plasma androgen and LH concentrations.

Role of hypergastrinemia in the antiatrophy effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on oxyntic gland mucosa of the rat stomach.

Atrophy of the gastrointestinal mucosa that occurs in pair-fed control rats is not observed in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats (1). Our objective was to determine if the gastrointestinal trophic hormone, gastrin, is involved in the antiatrophy effect of TCDD on the gut mucosa. Adult male Sprague-Dawley rats treated with 100 micrograms/kg of TCDD were slightly hypergastrinemic 7 days after dosing and markedly hypergastrinemic 14 days after treatment whereas pair-fed control rats were normogastrinemic. After 14 days of feed restriction, atrophy of the oxyntic gland and ileum mucosa occurred in pair-fed control rats but only atrophy of the ileum mucosa developed in TCDD-treated animals. The oxyntic gland mucosa of TCDD-treated rats was protected from mucosa atrophy as well as from mucosa erosions. The protection against feed restriction-induced atrophy was demonstrated by measurements of oxyntic gland mucosal height and DNA and protein content. Since hypergastrinemia stimulates growth of oxyntic gland mucosa, but not ileum mucosa, the antiatrophy effect of TCDD on mucosa of the oxyntic gland might in part be due to hypergastrinemia. In support of this interpretation, TCDD treatment exerted an antiatrophy effect on the oxyntic gland mucosa only when TCDD-treated animals were hypergastrinemic. For example, hypergastrinemia does not develop within the first 48 hr after TCDD administration, and TCDD treatment affords no protection against fasting-induced atrophy of the oxyntic gland mucosa during this time. On the other hand, the ability of TCDD treatment to protect against feed restriction-induced erosions of the oxyntic gland mucosa might be mediated by hypergastrinemia since these events occur at a later time.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of tolerance to the prolongation of hexobarbitone sleeping time caused by cannabidiol.

1 The effects of acute and subacute cannabidiol (CBD) administration on hexobarbitone sleeping time and on some constituents of the hepatic microsomal drug-metabolizing system were assessed in the mouse.2 Acutely administered CBD prolonged sleeping time; but with subacute treatment, tolerance to the effect rapidly developed.3 Brain hexobarbitone concentration upon awakening was unchanged by either acute or subacute CBD treatment, which suggests that neither the prolongation of sleeping time nor the tolerance is the result of a change in sensitivity of the central nervous system to the barbiturate.4 Acute CBD treatment increased the half-time of hexobarbitone in the brain, which returned toward normal with the development of tolerance.5 Acutely, CBD caused a 30% decrease in hepatic cytochrome P-450 level; with tolerance, the cytochrome concentration returned to normal.6 The evidence suggests that the CBD-induced prolongation of barbiturate sleeping time and the tolerance to this effect are the result of changes in the rate of drug metabolism, which are related to changes in the amount of cytochrome P-450.7 The effects of CBD on the hepatic microsomal drug-metabolizing enzyme system are different from those attributed to SKF 525-A and piperonyl butoxide because the cannabinoid does not decrease cytochrome P-450 quantitatively by complex formation, it does not produce a recovery overshoot in the cytochrome concentration and, finally, it does not cause an induction of the hexobarbitone-metabolizing enzymes.