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J J Heindel

Publications and source records attributed to J J Heindel.

At least 37 records · Page 2Linked to original sources
PubMed1993

The effects of feed restriction on reproductive function in Swiss CD-1 mice.

Many test compounds used in toxicity studies produce a "systemic" toxicity manifested as reduced body weight gain. While it is known that reduced weight gain during juvenile growth reduces or delays reproductive competence, the effects of adult-onset feed restriction (FR) and inhibited weight gain on the reproductive system of mice are poorly known. To gain some information on the effects of graded body weight reduction, or reduced body weight gain, on commonly used reproductive endpoints, the studies reported below were conducted at two laboratories, using adult mice that were maintained at 90, 80, and 70% of concurrent control body weight (CBW) for up to 21 weeks. Estrous cyclicity and fertility in the females were significantly affected. While male fertility was variably affected, there was a significant decrease in the number of epididymal sperm and in the number of testicular spermatids in the 70% CBW groups. Testis weight was conserved in both studies; relative testis weight increased in all FR groups. These data can improve the interpretation of future studies by helping to separate chemically induced changes from those produced by reduced body weight gain.

Animals↗
PubMed1993

Developmental toxicity evaluation of ethylene glycol by gavage in New Zealand white rabbits.

Artificially inseminated New Zealand white (NZW) rabbits were administered ethylene glycol (EG) by gavage on Gestational Days (GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day, with 23-24 inseminated animals per group. Clinical signs were recorded and water consumption was measured daily; does were weighed on GD 0, 6-19, 25, and 30. At necropsy (GD 30), maternal liver, kidney, and gravid uterine weights were recorded. Histopathologic examination was performed on kidneys from 10 does/dose and for all unscheduled deaths. Ovarian corpora lutea were counted and uterine implantation sites (total sites, resorptions, dead and live fetuses) were recorded. All live fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. EG resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology and unaccompanied by any other indicators of maternal toxicity. Renal lesions at 2000 mg/kg/day involved the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis, and tubular dilatation and degeneration. No dose-related maternal toxicity occurred at 100-1000 mg/kg/day. There was no indication of developmental toxicity at any dose tested, including no effects on pre- or postimplantation loss, number of fetuses, fetal body weight, or sex ratio (% male fetuses) per litter, and no evidence of teratogenicity. The "no observable adverse effect level" (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day in this study. The sensitivity of NZW rabbits relative to that of Sprague-Dawley rats and Swiss mice for maternal and developmental toxicity from gavage administration of EG during organogenesis can be determined for maternal toxicity: rabbits > mice > rats, and for developmental toxicity, mice >> rats >> rabbits.

Animals↗
PubMed1993

Specific inhibition of FSH-stimulated cAMP accumulation by delta 9-tetrahydrocannabinol in cultured rat granulosa cells.

delta 9-Tetrahydrocannabinol (THC), the major psychoactive component in marihuana has been shown to affect male and female reproduction in both humans and animals. THC has effects at the level at the pituitary-hypothalamic axis as well as a direct effect on the testis and ovary. A specific gonadal effect of THC is inhibition of steroidogenesis in cultured granulosa cells from immature, estrogen-treated rats that depends in part on a post-cyclic AMP site of action. The effect of THC on cAMP accumulation itself, however, has not yet been examined in this cell type. The aim of the present study was to examine the effect of THC on granulosa cell cAMP accumulation, a process that is important for several granulosa cell functions, including steroidogenesis. THC inhibited FSH-stimulated cAMP accumulation in a dose-dependent manner at concentrations which were not cytotoxic. This inhibition was evident by 2 hr and did not affect the dose of FSH which gave half-maximal stimulation, suggesting that THC does not compete with FSH for binding to its receptor. Detailed investigations regarding the mechanism of THC inhibition were conducted using forskolin and isoproterenol. In contrast to its effect on FSH stimulation, THC did not inhibit forskolin- or isoproterenol-stimulated cAMP accumulation, indicating a specific effect for the FSH receptor. In addition, inhibition of FSH-stimulated cAMP accumulation occurred in the presence of a phosphodiesterase inhibitor, indicating that THC does not decrease cAMP accumulation through an increase in the cAMP degradative pathway. These data indicate that a part of the reproductive toxicity seen with THC may be due to a specific alteration of the hormonal control of granulosa cell function via a specific inhibition of FSH-stimulated cAMP accumulation.

Animals↗
PubMed1993

Fetal thymic atrophy after exposure to T-2 toxin: selectivity for lymphoid progenitor cells.

Treatment of experimental animals with T-2 toxin has been found to markedly decrease thymic cellularity and to suppress cell-mediated immune function. Although T-2 toxin readily crosses the placenta, little is known about its effect on development of immunity following gestational exposure. In the present report, prenatal T-2 toxin resulted in significant fetal thymic atrophy in mice. In vitro exposure to T-2 toxin resulted in decreased thymocyte proliferation, as well as significant but transient increases in thymocyte viability. Cycloheximide increased thymocyte viability parallel to that seen after T-2 toxin, indicating that enhanced viability after T-2 toxin may be the result of inhibited endonuclease synthesis. These findings suggest that direct cytotoxic effects of T-2 toxin make limited contribution to thymic atrophy production. In support of this conclusion, in vivo T-2 toxin exposure resulted in only limited alteration of thymocyte development, as evidenced by expression of CD4, CD8, and alpha beta TCR cell-surface antigens. These data further indicate that antiproliferative effects of T-2 toxin on thymocytes may contribute limitedly to thymic atrophy observed in vivo. In vivo T-2 toxin treatment did not affect total numbers of CD44+, CD45+, or Mac-1+ fetal liver cells. However, such exposure resulted in significant decreases in CD44lo and CD45lo fetal liver prolymphoid cell subpopulations. Subsequent in vitro T-2 toxin exposure of fetal liver cells enriched for lymphoid precursors resulted in both decreased cell viability and highly significant decreased proliferation. Taken together, these data suggest that lymphocyte progenitors, in contrast to thymocytes, represent highly sensitive targets of T-2 toxin exposure, responsible for thymic atrophy.

Animals↗
PubMed1993

Effects of mono(2-ethylhexyl) phthalate, a testicular toxicant, on follicle-stimulating hormone binding to membranes from cultured rat Sertoli cells.

The widely used plasticizer di(2-ethylhexyl) phthalate (DEHP) is a male reproductive toxicant. Its toxicity has been shown to be due primarily to the action of its metabolite mono(2-ethylhexyl) phthalate (MEHP) on Sertoli cells. We have previously shown that at least one of the sites of action of MEHP on the Sertoli cell is the cAMP second messenger system. MEHP inhibits the ability of FSH but not isoproterenol, forskolin, or cholera toxin to stimulate cAMP accumulation in cultured Sertoli cells in a dose- and time-dependent manner. To further characterize this effect of MHP, we prepared a light membrane fraction from control and MEHP-treated Sertoli cells cultured from 18-day-old Fischer 344 rats and measured FSH binding in a radioligand receptor assay using 125I-labeled human FSH (125I-hFSH). MEHP inhibited FSH binding when preincubated with Sertoli cells in culture but not when added simultaneously with 125I-hFSH to the purified membrane preparation. Attenuation of FSH binding was evident after a 3-h preincubation with 100 microM MEHP (18%) and was maximal after 15-24 h of preincubation (70-90%). Preincubation of Sertoli cells for 24 h with 100 microM DEHP had no effect on FSH binding. Half-maximal inhibition occurred at approximately 0.1 microM MEHP. Scatchard analysis indicated a four-fold decrease in FSH affinity with no change in receptor concentration. Exposure of Sertoli cells to MEHP amplified the attenuating effect of guanosine triphosphate (GTP) on FSH binding, suggesting that the action of MEHP may be at the level of the GTP-binding protein that couples the FSH receptor to the adenylate cyclase catalytic subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Exposure to tetrachlorodibenzo-p-dioxin (TCDD) alters fetal thymocyte maturation.

We previously reported that thymic atrophy and reduced thymic cellularity associated with prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice are characterized by quantitative alerations in the number of thymocytes expressing CD4 and CD8 surface antigens. In the present study, these observations have been extended to establish the specific thymocyte maturation processes affected by TCDD through an examination of cell size distributions, alpha beta and gamma delta T cell receptor (TCR) expression, peanut agglutinin (PNA) binding, and J11d marker analysis in murine thymocytes exposed prenatally to TCDD. Pregnant mice were administered vehicle, 1.5 or 3.0 micrograms/kg body wt TCDD by gavage on gestational Days (gd) 6-14. Flow cytometry analysis of gd 18 fetal thymocytes revealed a reduction in the number of small CD4+CD8+ double positive (DP) and PNA+, small thymocytes in the TCDD-exposed groups. The large cell population was reduced by TCDD to approximately 70% of control values. There was also a significant shift in TCR expression of thymocytes with a decrease in alpha beta TCR and a concommitant increase in gamma delta TCR expression from TCDD-exposed fetuses. The CD4-CD8+J11d+ thymocytes were increased in TCDD-treated mice while the more mature CD4-CD8+J11d- thymocyte numbers were similar to controls. Taken together, these data indicate that TCDD inhibits thymocyte maturation at the transition phase between the CD4-CD8+J11d+ phenotype and the DP/J11d+ thymocytes.

Animals↗
PubMed1992

Phthalate ester effects on rat Sertoli cell function in vitro: effects of phthalate side chain and age of animal.

Mono(2-ethylhexyl) phthalate (MEHP), the active metabolite of the testicular toxicant di(2-ethylhexyl) phthalate, inhibits FSH-stimulated rat Sertoli cell cAMP accumulation, stimulates basal lactate production, and decreases intracellular ATP levels in vitro. Dibutyl phthalate and dipentyl phthalate but not diethyldimethyl or dipropyl are also age-dependent testicular toxicants in vivo. We therefore examined the effect of animal age and phthalate monoester on the Sertoli cell FSH-stimulated cAMP accumulation, lactate secretion, and ATP levels in order to determine if these effects are part of the mechanism of action of phthalate esters in vivo. MEHP, monobutyl and monopentyl phthalates but not the monoethyl, monomethyl, or monopropyl phthalates inhibited FSH-stimulated cAMP accumulation, a segregation which matches the in vivo toxicity potential of these agents. MEHP and monopentyl, but not monobutyl phthalates, also stimulated Sertoli cell lactate secretion. The effect of the active phthalates on FSH-stimulated cAMP accumulation and lactate secretion is not dependent on age of animal over a range of 13-80 days, suggesting that the age-related toxicity in vivo may be related to differences in metabolism and disposition rather than tissue sensitivity. Since the ED50 of MEHP inhibition of cAMP accumulation and lactate secretion is similar, these two effects may be related to a common initial effect of the active phthalates. Inhibition of intracellular ATP levels is specific for MEHP and is lost with age (greater than 28 days of age) and thus is not likely to be an essential part of the in vivo mechanism of action of phthalate diesters.

Adenosine Triphosphate↗
PubMed1992

Developmental toxicity of boric acid in mice and rats.

Boric acid (BORA), an ingredient of many cosmetics, pharmaceuticals, and pesticides, was tested for developmental toxicity in timed-pregnant Swiss mice and Sprague-Dawley rats (n = 26-28/group). BORA (0, 0.1, 0.2, or 0.4% in feed) was provided throughout gestation to attain steady-state exposure as early as possible during prenatal development. Average doses (mg/kg/day) were 248, 452, or 1003 in mice, and 78, 163, or 330 in rats. To limit prenatal mortality, BORA (0.8% or 539 mg/kg/day) was provided to an additional group of rats on Gestational Days (GD) 6 to 15 only. On GD 17 (mice) or 20 (rats), fetuses were weighed and examined for malformations (external, visceral, skeletal). Mouse dams exhibited mild renal lesions (greater than or equal to 0.1%), increased water intake and relative kidney weight (0.4%), and decreased weight gain (0.4%) during treatment. There was a reduction of fetal body weight (greater than or equal to 0.2%) and an increased incidence of resorptions and malformed fetuses per litter (0.4%). Morphological changes included an increased incidence of short rib XIII (a malformation) and a decreased incidence of rudimentary or full rib(s) at lumbar I (an anatomical variation). Maternal rats exhibited increased liver and kidney weights at greater than or equal to 0.2%, altered water and/or food intake at greater than 0.2%, and decreased weight gain at greater than 0.4%. Average fetal body weight/litter was reduced at all doses. Prenatal mortality was increased only at 0.8%. The incidence of fetal malformations was significantly increased at greater than or equal to 0.2%. The most frequently observed malformations were enlarged lateral ventricles of the brain and agenesis or shortening of rib XIII. In rats, the no-observable-adverse-effect level (NOAEL) for maternal toxicity was 78 mg/kg (0.1%), while in mice the low dose of 248 mg/kg (0.1%) approached the maternal NOAEL with mild renal lesions in only 2 of 10 females. Embryo/fetal toxicity occurred in all groups of rats at greater than or equal to 78 mg/kg (greater than or equal to 0.1%) while the NOAEL for developmental toxicity in mice was 248 mg/kg (0.1%). Thus developmental toxicity occurred below maternally toxic levels in rats as well as in the presence of maternal toxicity in mice and rats.

Abnormalities, Drug-Induced↗
PubMed1992

Evidence that MEHP inhibits rat granulosa cell function by a protein kinase C-independent mechanism.

We have recently shown that mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of the reproductive toxicant di-(ethylhexyl) phthalate (DEHP), inhibited FSH- but not forskolin-, isoproterenol-, or cholera toxin-stimulated granulosa cell cAMP accumulation in vitro. In addition, MEHP also inhibited FSH-stimulated progesterone production, a cAMP-dependent process. Similar to MEHP, the protein kinase C (PKC) activator, 12-0-tetradecanoyl-phorbol 13-acetate (TPA) has been shown to inhibit rat granulosa cell cAMP accumulation in a FSH-specific manner, and decrease FSH-stimulated progesterone production. Due to the similarity with respect to inhibition of cAMP accumulation, we conducted studies to determine if the inhibitory actions of MEHP on granulosa cell function are mediated via activation of PKC. Treatment of granulosa cells for 48 h with 100 microM MEHP produced no effect on forskolin- or isoproterenol-stimulated progesterone production, indicating that MEHP does not have a post-cyclic AMP site of action with respect to progesterone inhibition. Unlike the FSH-specific effect seen with MEHP, treatment with 10 nM TPA inhibited FSH-, forskolin-, and isoproterenol-stimulated progesterone production. In addition, maximally inhibitory concentrations of TPA and MEHP caused significantly greater inhibition of FSH-stimulated cAMP accumulation than either compound alone. Finally, addition of the progesterone precursor, pregnenolone, reversed the FSH-stimulated progesterone production inhibition by MEHP, but not that by TPA. Taken together, these data indicate that the inhibitory effects of MEHP on granulosa cell function are independent of phorbol ester-sensitive PKC activation.

Animals↗
PubMed1992

Methods for assessing rat sperm motility.

Computer-assisted sperm analysis (CASA) systems are becoming more widely used. With this spread of technology come more data from toxicology studies, designed to determine if treatment with putative toxicants affects sperm motion parameters. While these CASA methods provide us with more ways to evaluate toxicity and thus perhaps increase our chances of successfully protecting human health, there is also a greater likelihood that different laboratories will use different methods of collecting data on sperm motility. Different systems used with different methods in different laboratories will inevitably generate data that are difficult to compare. In a prospective attempt to address this issue of comparability and limit the problems, a group of individuals using CASA systems to analyze rat sperm motility convened to discuss methodologic issues, share data, and try to reach a consensus about methods for performing these studies. This article shares those meetings and data in the hope that common methods will enhance interlaboratory comparisons.

Animals↗
PubMed1992

A novel hypothalamic peptide, pituitary adenylate cyclase activating peptide, modulates Sertoli cell function in vitro.

Pituitary adenylate cyclase-activating peptide (PACAP), a novel hypothalamic peptide that has been shown to exist in several tissues including the testis, was examined for its effects on cultured rat Sertoli cells. PACAP stimulates cAMP accumulation in Sertoli cells cultured from 15-day-old rats in the presence or absence of methylisobutylxanthine, a phosphodiesterase inhibitor, and in the presence of pertussis toxin, a blocker of the adenylate cyclase inhibitory pathway. Maximal stimulation, which is 20-40% of that attainable with FSH, occurs at PACAP concentrations of 10 nM: the ED50 is approximately 100 pM. The ability of PACAP to stimulate Sertoli cell cAMP declines with increasing age of donor animals (15-60 days of age) in a fashion similar to the FSH effect. PACAP stimulation of Sertoli cell cAMP accumulation is additive with submaximal, but not maximal, concentrations of FSH or forskolin. PACAP also stimulates the secretion of lactate, estradiol, and inhibin in a concentration-dependent manner. The stimulation of Sertoli cell cAMP accumulation by PACAP is not altered by a vasoactive intestinal peptide antagonist, and vasoactive intestinal peptide alone does not stimulate cAMP accumulation, indicating that PACAP is not acting via vasoactive intestinal peptide receptors. Further experiments are needed to determine whether PACAP is synthesized within the testis and if so, in which cell types; however, the present data clearly demonstrate that PACAP can modulate Sertoli cell function in vitro.

Age Factors↗
PubMed1991

The effects of tri-o-cresyl phosphate and metabolites on rat Sertoli cell function in primary culture.

A neurotoxic organophosphate, tri-o-cresyl phosphate (TOCP) is also a testicular toxicant. Histopathologic damage in the testis is first seen in Sertoli cells. TOCP and its activated metabolite saligenin cyclic-o-tolyl phosphate (SCOTP) were evaluated for effects on rat Sertoli cells in primary culture. SCOTP, but not TOCP, caused minor morphologic effects on the cells and increased levels of lactate in the spent medium with no change in pyruvate levels, synthesis of cellular or secreted proteins, or the cyclic AMP response to FSH stimulation. SCOTP was the metabolite of TOCP that produced the largest decrease in nonspecific esterase activity in Sertoli cells (up to 80%), when tested in the concentration range found in vivo. This decrease is consistent with previous in vivo evidence. These in vitro experiments replicate previously observed in vivo biochemical effects and suggest that SCOTP is the metabolite responsible for at least some of the biochemical effects seen in the testis after TOCP exposure.

Adenosine Triphosphate↗
PubMed1991

Reproductive toxicity of boric acid in Swiss (CD-1) mice: assessment using the continuous breeding protocol.

The potential reproductive toxicity of boric acid (BORA) in CD-1 mice (Swiss) was evaluated using the Reproductive Assessment by Continuous Breeding (RACB) Protocol. BORA was administered in the feed for 27 weeks to male and female Swiss (CD-1) mice at concentrations of 0, 1000, 4500, or 9000 ppm. Estimated doses, based on feed consumption and body weight, averaged 152, 636, and 1262 mg/kg body wt during Week 1 for males for 1000, 4500, and 9000 ppm, respectively. During 14 weeks of cohabitation, fertility of F0 mice was partially reduced at 4500 ppm and totally eliminated at 9000 ppm. No litters, dead or alive, were produced by 9000 ppm cohabited pairs. Among the litters born at 4500 ppm, live litter size and body weight were significantly reduced. A crossover mating trial of control and 4500 ppm groups confirmed the male as the affected sex, with fertility rates and the mating index significantly lower in the 4500 male x 0 ppm female group. At necropsy, after 27 weeks of BORA exposure, dose-related changes were present in F0 males for reduced body and reproductive organ weights, increased incidence of abnormal sperm, decreased sperm concentration and motility, and seminiferous tubule degeneration. In the 4500 ppm females, dietary BORA for 27 weeks caused significantly decreased weights of kidney/adrenals and livers; kidney/adrenal weight was also reduced in 4500 ppm males. The last litters of the control and 1000 ppm females, born in the 14-week breeding phase, were reared to 74 days of age and then mated in nonsibling pairs within treatment groups. These F1 mice had normal fertility, but the adjusted mean body weight of F2 pups was decreased. These data establish the reproductive toxicity of BORA in CD-1 mice and demonstrate that the male is the most sensitive sex.

Animals↗
PubMed1990

The interaction of Sertoli and Leydig cells in the testicular toxicity of tri-o-cresyl phosphate.

Previous studies have shown that after dosing with tri-o-cresyl phosphate (TOCP), the testis contains more active intermediate (saligenin cyclic-o-tolyl phosphate; SCOTP) than do other organs or blood. SCOTP is produced by a cytochrome P450-dependent reaction, and the Sertoli cells, although containing little P450, are the testicular cells that show the first signs of damage after TOCP administration. The present studies evaluated (i) whether testicular Leydig cell production of SCOTP might explain the elevated testicular concentration of SCOTP, (ii) if this production affected testosterone secretion, and (iii) if Sertoli cells cocultured over TOCP-exposed Leydig cells would show effects similar to those found after SCOTP exposure of Sertoli cells in vitro, indicating a cell interaction. Previous data showed that a target enzyme for SCOTP in Sertoli cells, nonspecific esterase (NSE), was inhibited by exposure in vitro to SCOTP, but not to TOCP. In the present experiments, HPLC analysis identified SCOTP in media from Leydig cells cultured with radiolabeled TOCP, demonstrating activation. TOCP addition to Leydig cells decreased testosterone output after stimulation with hCG, an effect that was replicated by subsequent in vivo experiments. Addition of various intermediates in the testosterone biosynthesis pathway indicated that both mitochondrial- and microsomal-based steps in the pathway were affected. Collectively, these data indicate that Leydig cells can activate TOCP. To model whether this activation might affect Sertoli cells in vivo, Sertoli cells were plated in culture-well inserts suspended above (cocultured with) isolated Leydig cells in the presence of TOCP. Sertoli NSE activity was diminished, while remaining unchanged when cultured in the presence of TOCP but without Leydig cells, or over Leydig cells alone. These results show that the Leydig cells in the testis are capable of activating TOCP to SCOTP, and that this can produce effects in Sertoli cells. This in situ activation of TOCP to SCOTP may help explain why the testis contains high concentrations of SCOTP after in vivo dosing with TOCP, and why the testis is a target organ for TOCP toxicity.

Androstenedione↗
PubMed1990

Inhibition of FSH-stimulated cAMP accumulation and progesterone production by mono(2-ethylhexyl) phthalate in rat granulosa cell cultures.

Several phthalate esters are male and female reproductive toxicants in vivo. In the male, mono(2-ethylhexyl) phthalate (MEHP), the active metabolite of di(2-ethylhexyl) phthalate (DEHP), inhibits follicle stimulating hormone (FSH)-stimulated cAMP accumulation in the Sertoli cell in vitro. Since granulosa and Sertoli cells share several structural and functional characteristics, the effect of MEHP on granulosa cell intracellular cAMP accumulation was examined to elucidate a possible mechanism for DEHP reproductive toxicity in females. MEHP (100 microM) reduced FSH-stimulated cAMP accumulation in granulosa cells by 40% after a 24-hr preincubation. Significant inhibition of cAMP accumulation by MEHP occurred by 15 hr and MEHP did not affect the dose of FSH which resulted in half-maximal stimulation. Detailed investigations regarding the mechanism of MEHP inhibition were conducted using cholera toxin, forskolin, and isoproterenol. In contrast to FSH, MEHP did not affect the ability of these compounds to stimulate cAMP accumulation. In addition, a functional endpoint of granulosa cell function, progesterone production, was inhibited in a dose-dependent manner by MEHP. Further experiments will be necessary to determine the significance of these findings to in vivo toxicity, but these experiments describe a specific site of action of MEHP in vitro which may be related to the in vivo female reproductive toxicity of phthalate esters.

Adenosine Triphosphate↗
PubMed1990

Assessment of ethylene glycol monobutyl and monophenyl ether reproductive toxicity using a continuous breeding protocol in Swiss CD-1 mice.

A continuous breeding reproduction study design was utilized to examine the reproductive toxicity of ethylene glycol monobutyl ether (EGBE) and ethylene glycol monophenyl ether (EGPE). Swiss CD-1 mice were administered EGBE in drinking water (0, 0.5, 1.0, and 2.0%, i.e., 0.7, 1.3, and 2.1 g/kg body wt/day) and EGPE was administered via the feed (0, 0.25, 1.25, and 2.5%, i.e., 0, 0.4, 2.0, and 4 g/kg body wt/day). Both male and female mice were dosed for 7 days prior to and during a 98-day cohabitation period. EGBE was toxic at the high (2%) and mid dose (1%) to adult F0 female mice: 13 out of 22 females at the high dose and 6 out of 20 at the mid dose died during the cohabitation period. Both the high- and mid-dose animals produced fewer litters/pair, fewer pups/litter, with decreased pup weight. These effects occurred in the presence of decreased body weight, decreased water consumption, and increased kidney weight. A crossover mating trial indicated that the reproductive effects could be attributed primarily to an effect on the female. This was substantiated at necropsy where testes and epididymis weights were normal as were sperm number and motility. Fertility of the offspring of the 0.5% group was normal in the presence of increased liver weights. With respect to EGPE, there was no change in the ability to produce five litters during the continuous breeding period. There was, however, a significant but small (10-15%) decrease in the number of pups/litter and in pup weight in the high-dose group. A crossover mating trial suggested a female component of the reproductive toxicity of EGPE. While fertility was only minimally compromised, severe neonatal toxicity was observed. By Day 21 there were only 8 out of 40 litters in the mid- and high-dose groups which had at least one male and female/litter. Second generation reproductive performance of the mid-dose group (1.25%) was unaffected except for a small decrease in live pup weight. In summary the reproductive toxicity of EGBE and EGPE was only evident in the female and occurred at doses which elicited general toxicity. EGBE was particularly toxic to adult female mice while EGPE was particularly toxic to immature mice of both sexes.

Animals↗
PubMed1989

Specific inhibition of FSH-stimulated cAMP accumulation by delta 9-tetrahydrocannabinol in cultures of rat Sertoli cells.

delta 9-Tetrahydrocannabinol (THC), the major psychoactive component in marihuana, is a reproductive toxicant in both man and animals. THC acts at both the level of the pituitary-hypothalamic axis and the testis, specifically the Leydig cell; an effect on the Sertoli cell has not been shown. Since THC inhibits cAMP accumulation in several cell types, we have examined the effect of THC on Sertoli cell function using altered cAMP accumulation as a marker of toxicity. THC reduced the FSH-induced accumulation of cAMP at concentrations which were neither cytotoxic nor affected cellular ATP levels. This inhibition was evident after 3 hr and did not affect the dose of FSH which gave half-maximal stimulation, suggesting that THC does not compete with FSH for binding to its receptor. The ability of THC to inhibit cAMP accumulation was not affected by incubation in the presence of phosphodiesterase inhibitors, making it unlikely that it acts via stimulation of phosphodiesterase activity. This THC-induced inhibition of Sertoli cell cAMP is specific for FSH; it does not affect the ability of forskolin, cholera toxin, isoproterenol, or prostaglandin E1 to stimulate Sertoli cell cAMP. Furthermore, inhibition occurs in the presence of pertussis toxin, suggesting that this effect of THC is independent of the inhibitory adenylate cyclase pathway. Inhibition of Sertoli cell cAMP also occurs with other cannabinoids which are present in marihuana, but which are not psychoactive. These data indicate that a part of the testicular toxicity of THC may be due to a specific alteration of the hormonal control of Sertoli cell function via an inhibition of FSH-stimulated cAMP accumulation.

Adenosine Triphosphate↗