Biomedical subjects

R E Peterson

Publications and source records attributed to R E Peterson.

At least 19 recordsLinked to original sources

PubMed1996

Regulation of peroxisome proliferator-activated receptor-alpha mRNA in rat liver.

Chemical-induced peroxisome proliferation in rodent liver is postulated to occur via activation of members of the steroid hormone receptor superfamily, the peroxisome proliferation-activated receptors (PPARs). In the present study, the expression of the predominant liver subtype PPAR alpha was examined and compared to that of acyl-CoA oxidase (ACO), a marker for peroxisome proliferation and a prototype for genes regulated via PPARs. Despite the induction of both mRNA species in vivo by the peroxisome proliferator perfluorodecanoic acid (PFDA), dose response and time course indicate PPAR alpha and ACO are not controlled similarly. Messenger RNA levels for ACO increased rapidly in rat liver and declined over the subsequent 7 days following PFDA administration, while PPAR alpha mRNA increased slower and remained elevated over this period. In addition, PPAR alpha mRNA accumulation in PFDA-treated rats appears to be due primarily to hypophagia as pair feeding and complete caloric restriction result in a large increase in the concentration of this messenger RNA. Nuclear run-on experiments in vivo suggest that, unlike ACO, PFDA as well as caloric restriction results in accumulation of PPAR alpha mRNA which cannot be explained solely by transcriptional activation. These data indicated that PPAR alpha mRNA accumulation has a very small peroxisome proliferator-dependent component and that other factors may be involved. A rat hepatoma cell line was examined to determine the direct effect on peroxisome proliferators on PPAR alpha mRNA. PPAR alpha and ACO mRNA levels were increased rapidly in the rat hepatoma cell line FaO after treatment with PFDA or the prototypical peroxisome proliferator Wy 14,643. In this cell line, PPAR alpha mRNA levels are not affected by glucagon or insulin and in addition to peroxisome proliferators are induced in this cell line by oleic acid and dexamethasone. The latter treatment had the greatest effect on PPAR alpha mRNA accumulation while having a minimal effect on ACO mRNA. Treatment of FaO cells with actinomycin D prior to Wy 14,643 abolished ACO and PPAR alpha mRNA accumulation, demonstrating that there must be a transcriptional component of the peroxisome proliferator response. Therefore, although PPAR alpha is responsive to peroxisome proliferators and direct effects are observed in cell cultures, mRNA accumulation in vivo is predominantly posttranscriptional, and endogenous regulators such as glucocorticoids may play critical roles in the tissue- and developmentally specific expression of this steroid hormone receptor.

Acyl-CoA Oxidase↗

PubMed1996

In utero and lactational exposure of female Holtzman rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin: modulation of the estrogen signal.

The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) induces severe reproductive defects in male rats when exposure occurs in utero and during lactation. Yet there is currently a paucity of information regarding the effects of this exposure paradigm in females. In the current study, we examine the effects of TCDD during fetal and perinatal development on the estrogen-signaling system in peripubertal female rats. Pregnant Holtzman rats were given 1 microgram/kg TCDD or vehicle control by gavage on gestational Day 15. Body weights were reduced, though not significantly, on postnatal Day 21. While ovarian and uterine wet weights were not increased by TCDD exposure, the percentage of body weight attributed to the ovary was increased significantly. Through use of ribonuclease protection and gel-shift assays, exposed females were compared with nonexposed counterparts for estrogen receptor (ER) mRNA and DNA-binding activity in the following tissues: hypothalamus, pituitary (mRNA only), uterus, and ovary. ER mRNA levels increased in the hypothalamus, uterus, and ovary, and decreased in the pituitary. The results of the DNA-binding assays paralleled the mRNA results in the uterus, while DNA-binding activity was decreased in the hypothalamus and was unchanged in ovarian protein extracts. Circulating concentrations of estrogen were significantly lower in TCDD-exposed rats than in controls. These data suggest that the decrease in serum estrogen may be a cause of the alterations in ER mRNA; the changes in ER DNA-binding activity may indicate alterations in either translation or posttranslational receptor processing. Overall, this study shows that TCDD may act systemically in this model, and these effects should not necessarily be characterized as antiestrogenic.

Animals↗

PubMed1995

Interactions of polychlorinated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners for producing rainbow trout early life stage mortality.

Fish-specific toxic equivalency factors (TEFs), which relate the toxic potency of polyhalogenated aromatic hydrocarbons (PHAHs) to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on the endpoint of early life stage mortality, have been used in assessing the risk to fish early life stage survival of complex mixtures of PHAHs in feral fish eggs. Use of TEFs assumes that PHAH congeners act additively. However, this has not been unequivocally determined. Isobolograms and a probit model were used to assess the validity of the additivity assumption by determining the significance of interactions between pairs of polychlorinated dibenzo-p-dioxin (PCDD), dibenzofuran (PCDF), and biphenyl (PCB) congeners when injected into newly fertilized rainbow trout eggs in ratios bracketing those found in feral lake trout eggs from the Great Lakes. The majority of congener pairs tested acted additively in causing rainbow trout early life stage mortality: [1,2,3,7,8- pentachlorodibenzo-p-dioxin (1,2,3,7,8-PCDD)/TCDD]; [2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PCDF)/1,2,3,7,8-PCDD]; (2,3,4,7,8-PCDF/TCDD), (2,3,7,8-tetrachlorodibenzofuran/2,3,4,7,8-PCDF); [3,3',4,4'-tetrachlorobiphenyl (PCB 77)/3,3',4,4',5-pentachlorobiphenyl (PCB 126)]; [2,3,3',4,4'-pentachlorobiphenyl (PCB 105)/TCDD]; (2,2',4,4',5,5'-hexachlorobiphenyl/TCDD); (PCB 105/PCB 126); and (2,3',4,4',5-pentachlorobiphenyl/PCB 126). The only pairs showing evidence of a statistically significant interaction that deviated from additivity were (TCDD/PCB 77) and (TCDD/PCB 126). Taken together, these results suggest that the use of fish-specific TEFs to determine TCDD equivalents contributed by individual congeners in a fish egg sample and then adding these TCDD equivalents to determine the total amount contributed by all congeners may not exactly predict the mortality risk posed to fish early life stages by the mixture of TCDD-like congeners in the eggs. However, the relatively small deviations from additivity in the rainbow trout sac fry mortality test (1- to 4-fold) are less than traditional uncertainty factors used in noncancer risk assessments (10-fold/factor) and are not sufficient to warrant a change away from the additivity assumption in assessing the risk to fish early life stage mortality posed by TCDD and related compounds in eggs.

Animals↗

PubMed1995

In utero and lactational exposure of the male rat to 2,3,7,8-tetrachlorodibenzo-p-dioxin: impaired prostate growth and development without inhibited androgen production.

To determine whether in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure decreases male rat accessory sex organ weights during postnatal development secondary to decreases in testicular androgen production or changes in peripheral androgen metabolism, pregnant Holtzman rats were administered a single dose of TCDD (1.0 microgram/kg, po) or vehicle on Gestation Day 15 and offspring were exposed via placental and subsequent lactational transfer until weaning on Postnatal Day (PND) 21. Between PNDs 21 and 63, circulating androgen concentrations and intratesticular androgen content tended to be decreased by in utero and lactational TCDD exposure, but in most cases decreases were not statistically significant. In vitro human chorionic gonadotropin-stimulated testosterone production by decapsulated testes from TCDD-exposed animals was not different from control, although 5 alpha-androstane-3 alpha,17 beta-diol production was decreased on PNDs 32 and 49 and increased on PND 63. Taken together, these results imply that in utero and lactational TCDD exposure can cause subtle decreases in testicular androgen production. However, the biological relevance of these reductions is equivocal because they do not correlate temporally with one another or with decreases in androgen-dependent male accessory sex organ weights. Of the male accessory sex organs, ventral prostate (VP) and dorsolateral prostate (DLP) were the most severely affected. Between PNDs 21 and 63, relative VP and DLP weights were decreased to 65-84% and 57-80% of control, respectively, and the magnitude of observed decreases was greatest at early times. In contrast, relative weights of the seminal vesicle and coagulating gland ranged from 80 to 104% of control, and the magnitude of observed decreases was greatest at later times. The sensitivity of the prostate to TCDD could not be explained by tissue-specific decreases in dihydrotestosterone (DHT) concentrations. Although VP DHT concentration was decreased to 63% of control on PND 21, DHT concentration was not decreased in the VP between PNDs 32 and 63 or in the DLP at any time. We conclude that in utero and lactational TCDD exposure selectively impairs rat prostate growth and development without inhibiting testicular androgen production or consistently decreasing prostate DHT concentration.

Androgens↗

PubMed1995

Effects of gestational and lactational exposure to coplanar polychlorinated biphenyl (PCB) congeners or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thyroid hormone concentrations in weanling rats.

Perinatal exposure to polychlorinated biphenyl (PCB) mixtures or to certain ortho-substituted PCB congeners dramatically reduces circulating thyroxine (T4) concentrations. It is not clear whether perinatal exposure to coplanar PCBs or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a similar effect. In this study, time-mated Sprague-Dawley rats were dosed with 2 or 8 mg/kg/day PCB 77 (3,3',4,4'-tetrachlorobiphenyl), 0.25 or 1.00 micrograms/kg/day PCB 126 (3,3',4,4',5-pentachlorobiphenyl), 0.025 or 0.10 microgram/kg/day TCDD, or corn oil vehicle orally on gestation days 10-16. At weaning, plasma total T4 concentrations in PCB 77 and TCDD high-dose female pups were significantly depressed, but the changes were modest (84.4 and 79.6% of control, respectively). T4 concentrations in PCB 126 high-dose females and all high-dose males were also depressed slightly, but the changes were not statistically significant. UDP-Glucuronosyl transferase (UDP-GT) activity towards 4-nitrophenol was increased in all high-dose groups. Thus, the modest decreases in T4 could be due in part to increased T4 glucuronidation by UDP-GT. Triiodothyronine (T3) and thyroid stimulating hormone (TSH) concentrations were unchanged in all groups. In contrast to the minor changes in thyroid hormone status, liver microsomal ethoxyresorufin-O-deethylase (EROD) was markedly induced in all exposure groups and thymus weights were depressed in the high-dose groups. Because doses of coplanar PCBs or TCDD that caused marked induction of EROD activity had only minor effects on T4, we conclude that changes in thyroid hormone status at weaning are not among the more sensitive effects of perinatal exposure to these compounds.

Administration, Oral↗

PubMed1994

Induction of hepatic acyl-CoA-binding protein and liver fatty acid-binding protein by perfluorodecanoic acid in rats. Lack of correlation with hepatic long-chain acyl-CoA levels.

Liver fatty acid-binding protein (L-FABP) and acyl-CoA-binding protein (ACBP) are involved in the intracellular trafficking and compartmentalization of fatty acids and fatty acyl-CoA esters, respectively, in the liver. Both proteins are induced in rat liver by the potent peroxisome proliferator perfluorodecanoic acid (PFDA). While it is believed that the peroxisome proliferator-activated receptor may mediate the responses to peroxisome proliferators by inducing responsive genes, the ligand(s) of this receptor remains unknown. We hypothesized that induction of L-FABP and ACBP in rat liver by PFDA is secondary to accumulation of long-chain acyl-CoA esters. However, neither dose-response nor time-course effects of PFDA on hepatic long-chain acyl-CoA, L-FABP, or ACBP concentrations confirmed this hypothesis. In a dose-response study, PFDA increased hepatic long-chain acyl-CoA concentrations (7 days after treatment) over the dose range of 20-50 mg/kg, whereas it increased ACBP and L-FABP over the wider dose range of 20-65 mg/kg. In the time-course study, PFDA treatment (50 mg/kg) elevated long-chain acyl-CoA esters in the liver beginning on day 3 post-treatment, yet hepatic L-FABP concentrations were increased earlier beginning on day 2 and ACBP was not induced until day 7. To determine if this dissociation of increases in hepatic long-chain acyl-CoA concentrations from increases in hepatic L-FABP and ACBP concentrations could be demonstrated under other conditions, control rats fasted for 24-48 hr were used. Fasting increased hepatic long-chain acyl-CoA levels to a greater extent than PFDA treatment, yet neither L-FABP nor ACBP was induced. We conclude that elevated concentrations of hepatic long-chain acyl-CoAs in PFDA-treated rats are not a major contributor to the induction of L-FABP or ACBP by peroxisome proliferators. A more plausible mechanism is that PFDA induces L-FABP and ACBP by activating the peroxisome proliferator receptor directly rather than indirectly through long-chain acyl-CoA esters.

Acyl Coenzyme A↗

PubMed1994

Reproductive toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male rats: different effects of in utero versus lactational exposure.

The male rat reproductive system is highly sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) when exposure occurs during fetal and neonatal development. Our objective was to determine the relative contributions of in utero versus lactational TCDD exposure to effects on male reproductive function. Pregnant Holtzman rats were treated on Day 15 of gestation with TCDD (1.0 micrograms/kg) or vehicle (control). At birth litters were standardized to five males and five females and fostered to dams of the same treatment or cross-fostered to dams of the opposite treatment. Four treatment groups were assessed: male offspring not exposed to TCDD by either route (control) and male offspring exposed to TCDD in utero (IU), via lactation (L), or in utero and via lactation (IUL). During early postnatal development, two androgen sensitive end points, relative anogenital distance and time to testis descent, were not affected by TCDD. However, end points evaluated later during development were altered. Time to separation of the prepuce from the glans penis (an index of pubertal development) was delayed, plasma testosterone concentrations and accessory sex organ weights were reduced, daily sperm production and epididymal sperm reserves were decreased, and sexual behavior was feminized. Certain responses were only produced by IU exposure whereas other responses only occurred following L exposure. Only IU TCDD exposure delayed pubertal development and decreased daily sperm production, while only L TCDD exposure feminized the sexual behavior of male offspring. For most male reproductive end points both IU and L TCDD exposure produced the same responses. Decreases in plasma testosterone concentrations, reductions in weights, protein, and DNA contents of ventral prostate and seminal vesicles, and decreases in epididymal sperm reserves were caused in young adult rats by either IU or L exposure to TCDD. We conclude that the route and timing of TCDD exposure during fetal and neonatal development of the rat determine the profile of male reproductive effects observed and that all effects in the present study, with the notable exception of feminized sexual behavior, can be caused by low level exposure to TCDD via the IU route alone.

Androgens↗

PubMed1994

Effects of in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on responsiveness of the male rat reproductive system to testosterone stimulation in adulthood.

Previous studies strongly suggested that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may cause incomplete imprinting of the male reproductive system, i.e., that in utero and lactational exposure to TCDD may alter the responsiveness of sex organs to steroids in adulthood. To test this hypothesis, male rats born to dams dosed with 0.7 microgram TCDD/kg or vehicle on Gestation Day 15 were castrated at 63 days of age and implanted with graded lengths of Silastic capsule(s) containing crystalline testosterone. Resultant plasma testosterone concentrations ranged from castrate to about fourfold higher than physiological. Male reproductive organs which are imprinted by exposure to perinatal androgens and which are highly responsive to androgen stimulation in adulthood were assessed 3 weeks later. Ventral prostate weight and protein content in TCDD-exposed rats were significantly less responsive to testosterone regardless of the amount implanted. These decreases were not secondary to alterations in plasma or prostate testosterone or 5 alpha-dihydrotestosterone concentrations in adulthood, none of which was affected by TCDD. In contrast to its effects on ventral prostate weight and protein, TCDD had no effect on responsiveness to testosterone as measured by ventral prostate DNA content; seminal vesicle weight, protein content, or DNA content; penis weight; or plasma LH concentrations. We conclude that in utero and lactational TCDD exposure inhibits imprinting of ventral prostate weight and protein but does not result in a universal inhibition of imprinting. Androgen responsiveness of the prostate is uniquely sensitive to in utero and lactational TCDD exposure and provides a model to study the mechanism by which exposure to TCDD during fetal and early postnatal development modulates hormone-mediated responses in adulthood.

Aging↗

PubMed1994

Partial demasculinization and feminization of sex behavior in male rats by in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin is not associated with alterations in estrogen receptor binding or volumes of sexually differentiated brain nuclei.

In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure partially demasculinizes and feminizes sexual behavior in adult male rats, presumably by causing incomplete sexual differentiation of the central nervous system (CNS). Our objective was to determine if TCDD exposure affects other aspects of sexual differentiation of the CNS. Because sex differences in the estrogen receptor system are thought to play a role in sexually dimorphic estrogen-mediated responses, and because estrogen is an important activator of both male and female sex behavior, the possible effect of TCDD exposure on estrogen binding in specific brain nuclei was examined. In addition, we investigated effects of in utero and lactational TCDD exposure on sex differences in the volumes of brain nuclei which are dependent on steroid hormone stimulation during the period of CNS sexual differentiation. Pregnant Holtzman rats were given TCDD (0.7 microgram/kg, po) or vehicle (control) on gestation Day 15. Offspring were exposed to TCDD in utero and via lactation and then assessed in adulthood. Demasculinized sexual behavior was evidenced in the TCDD-exposed males by increased intromission latencies and a greater number of intromissions prior to ejaculation. These males were then castrated, primed with ovarian steroids, and tested for feminine sexual behavior. In utero and lactational TCDD exposure increased both the frequency and intensity of lordotic behavior, indicating that the males were partially feminized. To determine if TCDD exposure had a generalized effect on estrogen receptor concentrations the arcuate nucleus, cortical and medical amygdala and the bed nucleus of the stria terminalis, previously found to have equivalent numbers of estrogen receptors in males and females, were evaluated in littermates of the rats whose sexual behavior had been assessed. TCDD had no effect in either sex. To determine if TCDD exposure had an effect specific to sexual differentiation of the brain, estrogen receptor concentrations in the medial preoptic nucleus (MPO), ventrolateral aspect of the ventro-medial nucleus, and periventricular preoptic area were assessed. As expected, females had higher estrogen receptor concentrations in these nuclei than did males, but TCDD exposure did not affect estrogen receptor concentrations in any of these sexually dimorphic brain nuclei. The volumes of sexually dimorphic brain nuclei were examined in additional littermates. In control rats, the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) is larger in males than in females whereas the MPO is larger in females than in males. TCDD exposure had no effect on the volume of either the SDN-POA or MPO in either males or females.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Spinal evoked potentials are predictive of neurologic function in a porcine model of aortic occlusion.

The limitations of somatosensory evoked potentials during aortic occlusion stimulated us to evaluate the sensitivity and specificity of spinal (T10 and L4) evoked potentials (SpEPs) in predicting neurologic function after aortic occlusion. Thirty-six swine were assigned randomly to three equal groups (Group 1, control; Group 2, cerebrospinal fluid (CSF) drainage; Group 3, CSF drainage with 20-mg intrathecal papaverine). After induction of anesthesia and initiation of physiologic monitoring, a left-sided thoracotomy was performed to provide access to the descending aorta. SpEPs were generated by stimulating the thoracic spinal cord and recording the conducted response at the T10 and L4 level. After baseline measurements were recorded, the descending aorta was occluded 1 cm distal to the left subclavian artery. SpEPs were recorded every 2.5 min and physiologic variables every 5 min. The aorta was unclamped 10, 15, or 20 min after loss of the L4 SpEP. If the L4 SpEP was not lost, the aortic occlusion interval was terminated at 90 min. Attenuation of the SpEPs occurred earlier at the L4 level. Group 1 experienced the earliest loss of the L4 SpEP (18.3 +/- 7.8 min, P < 0.005). Loss of the L4 SpEP in Group 2 (49.3 +/- 27.8 min) was earlier than in Group 3 (73.7 +/- 26.1 min, P < 0.05). Early postoperative motor function (modified Tarlov scale) correlated with time from loss of the L4 SpEP until reperfusion of the distal aorta (r = 0.93). The sensitivity, specificity, and accuracy of the L4 SpEP in predicting neurologic dysfunction was 92.8% (13 abnormal/14 predicted), 90.9% (20/22), and 91.7% (33/36).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Effect of the peroxisome proliferator perfluorodecanoic acid on the promotion of two-stage hepatocarcinogenesis in rats.

This study was conducted to determine if the peroxisome proliferator perfluorodecanoic acid (PFDA) has promoting activity in two-stage hepatocarcinogenesis. Because PFDA is a non-competitive inhibitor of the peroxisomal bifunctional enzyme and thus inhibits the peroxisomal beta pathway, we hypothesized that PFDA may not have promoting activity as do other peroxisome proliferators, because hydrogen peroxide production is inhibited. Twenty-four hours after partial hepatectomy, female Sprague-Dawley rats were given an initiating dose of 10 mg/kg diethylnitrosamine by gavage. The rats were divided into five groups that received monthly i.p. injections of 0.0, 0.05, 0.50 or 5.0 mg/kg PFDA in corn oil or were placed on diets that contained either 0.01% ciprofibrate or 0.05% phenobarbital for 9 or 18 months. Both ciprofibrate and the highest dose of PFDA increased the activity of the peroxisomal enzyme fatty acyl CoA oxidase. PFDA treatment did not increase the tumor incidence or the number of altered hepatic foci at 9 or 18 months, although the mean volume of foci was increased at 9 months. Ciprofibrate increased the incidence of hepatocellular carcinomas at 18 months but did not increase the number or volume of altered hepatic foci at 9 or 18 months. Phenobarbital increased the number and volume of foci but did not influence the tumor incidence. The results of this investigation indicate that PFDA is not a promoter of hepatocarcinogenesis.

Adenosine Triphosphatases↗

PubMed1993

Coordinate induction of acyl-CoA binding protein, fatty acid binding protein and peroxisomal beta-oxidation by peroxisome proliferators.

Acyl-CoA binding protein (ACBP) and fatty acid binding protein (FABP) are important intracellular lipid binding proteins. The purpose of the present experiments was to test the hypothesis that peroxisome proliferators induce ACBP in rat hepatocytes as has been shown previously for FABP. The effects of two structurally dissimilar peroxisome proliferators perfluorodecanoic acid (PFDA) and clofibric acid (CPIB) were examined in primary rat hepatocyte cultures in a chemically defined media. Both compounds alter lipid metabolism in primary rat hepatocytes in a similar fashion, although PFDA is more potent than CPIB at inducing peroxisomal beta-oxidation. In addition, PFDA and CPIB compete with long-chain fatty acids for binding to FABP but do not compete with long-chain acyl-CoA esters for binding to ACBP. The concentration of ACBP and FABP was increased in peroxisome proliferator-treated hepatocytes relative to vehicle controls within 48 h of treatment. Evidence is given to support increases in ACBP and FABP mRNA being the cause of the increased protein levels by peroxisome proliferators. In addition, the peroxisome proliferators PFDA, perfluorooctanoic acid and ciprofibrate induced hepatic ACBP following in vivo administration to rats indicating that this phenomena is not exclusive to in vitro systems. Therefore, ACBP appears to be a member of the peroxisome proliferator loci, a group of lipid metabolizing proteins, including FABP, which are regulated by peroxisome proliferators such as fibric acids and perfluorinated fatty acids.

Animals↗

PubMed1993

Comparison of the cytotoxicities of Fusarium metabolites and Alternaria metabolite AAL-toxin to cultured mammalian cell lines.

Four water-soluble Fusarium metabolites (fumonisin B1, fusaric acid, butenolide and moniliformin), water-insoluble pigment (8-O-methylbostrycoidin), and an Alternaria metabolite (AAL-toxin) were tested for relative cytotoxicity to five established mammalian cell lines. Butenolide was the most cytotoxic to all five cell lines. LC50s were; 1 microgram/ml to rat hepatoma (RH) (tumors derived from parenchymal cells), 7 micrograms/ml to baby hamster kidney (BHK-21) fibroblast cells, and 15 micrograms/ml to McCoy mouse (MM) fibroblast cells: LC100s were 1 microgram/ml to Chinese hamster ovary (CHO) fibroblast cells, and 5 micrograms/ml to dog kidney (MDCK) fibroblast cells. Fusaric acid was cytotoxic to the MDCK, MM, RH, and CHO cell lines; moniliformin was cytotoxic to the RH, CHO, and MDCK, cell lines. The pigment, however, was cytotoxic only to RH and CHO cell lines. Fumonisin B1 and a related toxin, AAL-toxin, at a high dose level (100 micrograms/ml) were not cytotoxic to the RH, BHK, MM, CHO and MDCK cell lines. T-2 toxin was used as a positive control, and inhibited all cell lines at the nanogram level. The difference in response of these five cell lines to the toxic metabolites, that were noted in this study, was then used to evaluate nine HPLC fractions obtained from a methanol-water extract of an F. moniliforme culture. The results indicated that this type of cytotoxicity assay may be useful in following the isolation of metabolites from extracts of Fusarium culture, especially F. moniliforme.

4-Butyrolactone↗

PubMed1993

2-Hydroxyhexadecanoic and 8,9,13-trihydroxydocosanoic acid accumulation by yeasts treated with fumonisin B1.

Fumonisin B1 is a sphingolipid-like compound that enhances the accumulation of yeast sphingolipids and 2-hydroxy fatty acids. These lipids occur both as freely extractable and cell bound components in yeast fermentations. Both free and bound 2-hydroxy fatty acids produced by Pichia sydowiorum NRRL Y-7130 were increased when fumonisin B1 (50 mg/L) was added to the usual growth medium containing yeast extract/malt extract/peptone/glucose. Fumonisin-treated cultures contained 38 mg/L more 2-hydroxyhexadecanoic and 15 mg/L more 2-hydroxyoctadecanoic acids than did untreated cultures. By contrast, fumonisin inhibited the accumulation of free 8,9,13-trihydroxydocosanoic acid in Rhodotorula sp. YB-2501 cultures, leading to 240 mg/L lower trihydroxy acid production than by untreated cultures.

Carcinogens, Environmental↗

PubMed1993

Physiologic and anesthetic alterations on spinal-sciatic evoked responses in swine.

Spinal-sciatic evoked responses (ScER) have been used successfully to monitor the integrity of the anterior spinal cord during spinal surgery. To evaluate the effects of hypercarbia, hypocarbia, induced hypotension, and hypothermia on the ScER, ten swine anesthetized with ketamine were subjected to varying levels of PaCO2, hypothermia, and induced hypotension. During variation of one physiologic variable, the other variables were closely regulated. There were no significant changes associated with variations in PaCO2. Decreasing temperature provided a consistent increase in latency (r = -0.78, P < 0.001) with no significant alteration in amplitude. Graded hypotension caused little increase in latency (3.2% at 30 mm Hg). The amplitude decrease averaged 23% at 60 mm Hg with a maximal decrease of 50% at 30 mm Hg. To study inhaled anesthetics, 21 swine anesthetized with ketamine were subjected to nitrous oxide (50% and 70%). After termination of the nitrous oxide, one of the potent inhaled anesthetics (n = 7 each) was administered in 0.25 minimum alveolar concentration (MAC) increments. Nitrous oxide caused a significant decrease in amplitude (average 43% and 61% at 50% and 70%) with minimal changes in latency. There was a dose-dependent decrease in amplitude and increase in latency with all inhaled anesthetics. The ScER disappeared at 1.0 MAC with all anesthetics. There were no differences between effects of equipotent concentrations of inhaled anesthetics. These findings may be helpful in the interpretation of the ScER response during anesthesia and surgery.

Anesthesia, Inhalation↗

PubMed1993

Developmental and reproductive toxicity of dioxins and related compounds: cross-species comparisons.

Developmental toxicity to TCDD-like congeners in fish, birds, and mammals, and reproductive toxicity in mammals are reviewed. In fish and bird species, the developmental lesions observed are species dependent, but any given species responds similarly to different TCDD-like congeners. Developmental toxicity in fish resembles "blue sac disease," whereas structural malformations can occur in at least one bird species. In mammals, developmental toxicity includes decreased growth, structural malformations, functional alterations, and prenatal mortality. At relatively low exposure levels, structural malformations are not common in mammalian species. In contrast, functional alterations are the most sensitive signs of developmental toxicity. These include effects on the male reproductive system and male reproductive behavior in rats, and neurobehavioral effects in monkeys. Human infants exposed during the Yusho and Yu-Cheng episodes, and monkeys and mice exposed perinatally to TCDD developed an ectodermal dysplasia syndrome that includes toxicity to the skin and teeth. Toxicity to the central nervous system in monkey and human infants is a potential part of the ectodermal dysplasia syndrome. Decreases in spermatogenesis and the ability to conceive and carry a pregnancy to term are the most sensitive signs of reproductive toxicity in male and female mammals, respectively.

Animals↗

PubMed1993

Intravenous anesthetic alterations on the spinal-sciatic evoked response in swine.

Sciatic evoked responses (ScER) are used to monitor the integrity of the anterior spinal cord during spinal surgery. To evaluate the effects of intravenous anesthetics on the lumbar spinal evoked potential (SpEP) and ScER, 28 swine were anesthetized with halothane and an intravenous infusion of ketamine. After experimental preparation, anesthesia was maintained with ketamine, and the swine were divided into four equal groups (n = 7). The evoked responses were generated by delivering an electrical stimuli to the interspinous ligaments caudal to T1 and T2. The lumbar SpEP was recorded from the interspinous ligaments caudal to L2 and L3. The ScERs were recorded bilaterally from electrodes placed adjacent to the sciatic nerves. In Group 1 the effects of bolus dose administration of ketamine were evaluated. In Groups 2-4 anesthesia was maintained with ketamine by continuous infusion and the effects of fentanyl, sufentanil, and propofol on the L2 SpEP and ScER were evaluated. There was no significant change in either the amplitude or latency of the L2 SpEP with any anesthetic studied. Ketamine administered in bolus doses (2.5, 5, and 10 mg/kg) did not alter the ScER. After bolus doses of fentanyl 10 micrograms/kg or sufentanil 1 micrograms/kg, there was a similar decrement in the amplitude of the ScER (P < 0.05) that recovered at 10 min without changes in latency. There were no changes in the ScER associated with infusion of fentanyl 1-5 micrograms.kg-1 x h-1 or sufentanil 0.1-0.5 microgram.kg-1 x h-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Intravenous↗

PubMed1992

Lack of evidence for perfluorodecanoyl- or perfluorooctanoyl-coenzyme A formation in male and female rats.

Perfluorodecanoic (PFDA) and perfluorooctanoic (PFOA) acids belong to the structurally diverse group of compounds known to cause peroxisomal proliferation. It has been hypothesized that the common mode of action of these compounds is that they act through an activated coenzyme A (CoA) thioester. Using rat liver microsomal and isolated rat hepatocyte incubation conditions that were effective in producing a CoA conjugate of clofibric acid, no corresponding CoA derivative could be found for either PFDA or PFOA.

Acyl Coenzyme A↗