Ovine placental lactogen stimulation of ornithine decarboxylase activity in brain and liver of neonatal rats

Ovine placental lactogen (oPL), growth hormone (oGH), prolactin (oPRL) and human placental lactogen (hPL) were administered intracisternally (ic) or intraperitoneally (ip) to 17 day old rats and brain and liver ODC activities determined four hours later. When given ic, oPL, oGH and oPRL caused significant increases in brain ODC activity, while hPL had no significant effect. After ip administration, oPL and oGH also caused a significant increase in brain as well as liver ODC activity but oPRL and hPL were without significant effect. The stimulation of polyamine metabolism by oPL together with earlier reports of its potent somatotropic effects and its high concentration in the fetus supports the hypothesis that oPL may be important in the regulation of fetal growth.     

Effects of material methadone administration on ornithine decarboxylase in brain and heart of the offspring: Relationships of enzyme activity to dose and to growth impairment in the rat

Administration of 5 mg/kg of methadone daily to pregnant and nursing rats produced substantial retardation of body, brain and heart growth in the offspring; alterations in biochemical development also were present in the methadone-exposed pups, as evidenced by delays in the maturational declines of brain and heart ornithine decarboxylase (ODC) activity. Lowering the dose of methadone to levels which did not affect growth or brain ODC, still resulted in pro-found abnormalities in the developmental pattern of heart ODC. These studies indicate that downward adjustment of maternal methadone dosage to a point where birthweights and body and organ growth rates are normal, does not eliminate all of the biochemical alterations associated with the perinatal opiate syndrome.     

ODC-polyamine system is involved in morphine analgesia

alpha-Difluoromethylornithine (DFMO) directly infused into a brain-lateral ventricle (12.5, 25 and 50 micrograms/rat) dose- and time-dependently inhibited brain ODC activity. While having no influence per se on pain threshold, DFMO significantly inhibited the analgesic activity of morphine (15 mg/kg i.p.), this effect being obtained when brain ODC activity was reduced by at least 80%. On the other hand, DFMO had no influence on number and affinity of brain opiate binding sites. Morphine per se neither modified whole brain ODC activity nor significantly affected the ODC inhibitory effect of DFMO. In more discrete brain areas (midbrain, brainstem) morphine actually increased ODC activity. The present results indicate that brain ODC/polyamines system may play a role in the analgesic activity of opioids, probably at a post-receptorial level or through a non-opiate receptor-linked mechanism.     

锌对染汞孕鼠胚胎毒性的影响及其机理研究

目的:探讨妊娠期补锌对染汞孕鼠胚胎发育毒性的保护作用.方法:建立孕鼠动物模型,应用不同剂量的氯化甲基汞(0.01、0.05、2.00mg/kg·d)及5.00mg/kg·d硫酸锌于妊娠6～9天连续灌胃.蒸馏水灌胃为对照组,观察孕鼠及胚胎的汞毒性及硫酸锌的影响.应用ICP-MS法测定各组胎鼠脑组织汞含量;Western blot法检测各组胎鼠脑bcl-2蛋白表达情况;TUNEL法检测各组胎鼠脑细胞凋亡情况.结果:各组均未发现死胎、吸收胎及畸形胎;0.01、0.05mg/kg·d氯化甲基汞对孕鼠及胎鼠生长发育没有明显的抑制作用;2.00mg/kg·d氯化甲基汞可以明显抑制孕鼠体重增长及胎鼠身长、体重及尾长的增长(P＜0.05),但对孕鼠产仔数、胎窝总重及胎盘总重没有明显的影响,0.05mg/kg·d、2.00mg/kg·d 氯化甲基汞组胎鼠脑组织汞含量较对照组明显升高(P＜0.05),bcl一2蛋白表达明显下降(P＜0.05),脑细胞凋亡较对照组明显升高(P＜0.05);应用硫酸锌预处理后,氯化甲基汞对孕鼠及胚胎的毒性作用明显降低(P＜0.05),胎鼠脑组织汞含量较染汞组明显降低(P＜0.05),bcl-2蛋白表达明显升高(P＜0.05),胎鼠脑细胞凋亡明显降低(P＜0.05).结论:孕期补锌可以降低氯化甲基汞对孕鼠胚胎的毒性作用,其机制与锌通过升高bel-2蛋白的表达而抑制细胞凋亡有关.     

Dose–Response Effects of Diphenylhydantoin on Pregnant Dams and Embryo‐Fetal Development in Rats

Despite the widespread use of diphenylhydantoin (DPH), there is a lack of reliable information on the teratogenic effects, correlation with maternal and developmental toxicity, and dose–response relationship of DPH. This study investigated the dose–response effects of DPH on pregnant dams and embryo‐fetal development as well as the relationship between maternal and developmental toxicity. DPHwas orally administered to pregnant rats from gestational days 6 through 15 at 0, 50, 150, and 300 mg/kg/day. At 300 mg/kg, maternal toxicity including increased clinical signs, suppressed body weight, decreased food intake, and increased weights of adrenal glands, liver, kidneys, and brain were observed in dams. Developmental toxicity, including a decrease in fetal and placental weights, increased incidence of morphological alterations, and a delay in fetal ossification delay also occurred. At 150 mg/kg, maternal toxicity manifested as an increased incidence of clinical signs, reduced body weight gain and food intake, and increased weights of adrenal glands and brain. Only minimal developmental toxicity, including decreased placental weight and an increased incidence of visceral and skeletal variations, was observed. No treatment‐related maternal or developmental effects were observed at 50 mg/kg. These results show that DPH is minimally embryotoxic at a minimal maternotoxic dose (150 mg/kg/day) but is embryotoxic and teratogenic at an overt maternotoxic dose (300 mg/kg/day). Under these experimental conditions, the no‐observed‐adverse‐effect level of DPH for pregnant dams and embryo‐fetal development is considered to be 50 mg/kg/day. These data indicate that DPH is not a selective developmental toxicant in the rat.     

Differential effects of placental lactogen,growth hormone and prolactin on rat liver ornithine decarboxylase activity in the perinatal period

Ovine placental lactogen, (oPL), ovine growth hormone, (oGH), and ovine prolactin, (oPRL) are present in high concentrations in the fetal circulation late in gestation. To determine if these hormones stimulate the activity of ornithine decarboxylase (ODC), an enzyme widely implicated in the control of cellular growth, rat fetuses were injected $\text{in utero}$ with 100 μg of oPL, oGH, oPRL, rat growth hormone (rGH) or rat prolactin (rPRL) and ODC activity in the livers, hearts, and brains of the fetuses was measured 2, 4, and 6 hours after injection. OPL stimulated fetal liver ODC activity by 282 ± 45% (mean ± SEM) as compared to litter mates injected with buffer alone but oGH, oPRL, rGH and rPRL had no effect on fetal liver ODC activity. However, in neonatal rats 24–48 hours old all five hormones significantly increased liver ODC activity. ODC activities in the hearts and brains of the fetuses and neonates were unaffected by any of the five hormones. In other experiments 50 μg of oPL significantly stimulated fetal liver ODC activity while 250 μg of oGH were without effect. However 25 μg of oGH significantly stimulated liver ODC activity in rat pups 1–2 days after birth. These results suggest that oPL, by its stimulation of ODC activity, has somatotropic effects in the fetus and that rat liver ODC activity becomes responsive to growth hormone and prolactin in the perinatal period.     

Effect of stress and sympathetic activity on rat cardiac and aortic ornithine decarboxylase activity.

Adult male rats were injected either with α- or ß-adrenergic agonists and/ or antagonists and ornithine decarboxylase (ODC) activity in the heart and aorta was measured 4 hours later. At the lower doses, isoproterenol (0.2–0.4 mg/kg) resulted in a 10-fold increase in cardiac ODC activity but caused no significant change in aortic ODC activity. In contrast, phenylephrine (1 mg/kg) caused a 4-fold increase in aorta but no change in cardiac ODC activity levels. Phenoxybenzamine pretreatment completely abolished the PE-induced increase whereas no change was seen in ISop injected animals. Similarly, pretreatment with propranolol blocked the ISop induced response on ODC activity but had no effect on the increases observed after PE. These data suggest that the sympathetic regulation of ODC activity levels is mediated primarily via the ß-receptor in the heart but through the α-receptor in the aorta.     

Teratogenicity of the antiallergic Sm 857 SE in rats versus rabbits

Sm 857 SE is an antiallergic drug chemically described as 11-Oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid that has activity against allergic bronchoconstriction in animal models. The purpose of this study was to investigate the teratogenic potential in pregnant rats and rabbits when administered during the critical period of organogenesis. The drug was suspended in aqueous 0.25% carboxymethylcellulose (CMC) solution. Daily doses of 20, 90, or 400 mg/kg were given orally by gavage to rats on days 7 through 17 of gestation and to rabbits on days 6 through 18. Two additional studies were done in rats dosed with 400 mg/kg, and with 90, 200, or 400 mg/kg, respectively. Doses of 20, 90, and 200 mg/kg had no meaningful effects on maternal animals of either species or on their offspring. A dose of 400 mg/kg was maternally toxic in rats as shown by the effects on body weight and food consumption. Among pregnant rabbits, two deaths and three miscarriages occurred at this dose. In rats, 400 mg/kg caused embryonic death, retarded fetal development, and two specific malformations, namely microphthalmia and vertebral-costal defects. A mild teratogenic action of 400 mg/kg also occurred in the first additional study but not in the second one. There was, however, one anophthalmia in a rat fetus of the 90 mg/kg group. In rabbits, no embryotoxic or teratogenic effects were observed. These species differences were explained by the concentration and protein binding in maternal serum as well as by the relatively high concentration of 14C-Sm 857 SE in the rat fetus.     

Cumulation of active metabolites of levo-alpha-acetylmethadol in the rat fetus and neonate

Levo-alpha-acetylmethadol (LAAM, 0.2 or 2.0 mg/kg/day) was orally administered to female Sprague-Dawley rats for one month prior to and throughout pregnancy. The rats were killed on the 18th day of gestation along with a group of 18-day pregnant females given a single oral 2.0 mg/kg dose of LAAM 24 hours earlier. Although cumulation of LAAM or its active metabolites was not seen in plasma or brain of pregnant rats given drug chronically, significant cumulation was observed in whole fetus and in fetal brain. In addition, a 2–3 fold elevation in the concentrations, and an even greater elevation of total content, was noted in the newborn pup. These data suggest that opiate intoxication soon after birth may be a factor responsible for the increased morbidity and mortality of rat pups prenatally exposed to LAAM.     

Fetal brain serotonin synthesis and catabolism is under control by mother intake of tryptophan.

Previous morphological studies reported that serotonergic neurons appear in rats in the second half of prenatal life. Initially the biochemical differentiation of these neurons before birth was studied. Both serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) was detected in the fetal brain on day 15 of gestation. During prenatal development an increase was detected in the brain levels of 5-HT (200% higher on day 19 than on day 15) and 5-HIAA (700% higher on day 19 than on day 15). Oral administration of tryptophan to pregnant rats induced a dose-related increase of tryptophan concentration in different fetal tissues, including brain. The increase in tryptophan tissue concentration was detected for low doses (50 mg/kg) and remained unsaturated after administration of high doses (1000 mg/kg). This observation suggests that the placental barrier is not effective to block the influx of high levels of tryptophan to the fetus. Tryptophan concentration in the brain is 300% higher than in the carcass and 600% higher than in the placenta. These data suggest a mechanism to assume a role in concentrating of tryptophan in the brain. Finally, it was found that an increase in brain tryptophan induced changes in both serotonin and 5-HIAA brain levels, but did not modify tyrosine, dopamine or norepinephrine levels. Thus, under physiological conditions, tryptophan hydroxylase activity in prenatal brain is probably not saturated by its substrate tryptophan.     

Placental transfer of halogenated benzenes (pentachloro-, pentachloronitro-, and hexabromo-) in rats.

The present study was carried out to provide information on the placental transfer of three organohalogens of environmental concern. Pentachloro-, pentachloronitro-, and hexabromobenzene were administered per os to rats daily on days 6 through 15 of gestation at level of 40, 100, and 200 mg/kg body weight. On day 22, the dams were killed and fetuses removed by caesarean section. Maternal brain, heart, kidney, liver, spleen and adipose tissue as well as whole fetus, fetal liver and fetal brain were analyzed for organohalogen residue by GLC. Pentachlorobenzene accumulated in the fetus to a greater extent than hexabromobenzene. In maternal tissues pentachlorobenzene accumulated to the greatest extent in adipose tissue, followed by liver, spleen, brain, heart and kidney. With hexabromobenzene, the greatest accumulation was observed in adipose tissue, followed by spleen, liver, heart, kidney and brain. Pentachloronitrobenzene was not detected (0.05 p.p.m.) in any maternal or fetal tissue.     

Influence of sire, sex of fetus and type of pregnancy on conceptus development

Estrus was synchronized in 93 crossbred cows 3 to 7 yr old which were then superovulated with 10 mg FSH-P and bred artificially to either a Jersey or Charolais bull. Females pregnant to the Jersey sire were slaughtered at 95, 180 or 250 d of gestation; low pregnancy rate from the Charolais sire resulted in enough dams for slaughter and valid comparisons at 95 d only. Conceptus tissue and organ weights and dam carcass weights and measurements were collected at slaughter. At 95 d of gestation, sire differences were not significant; type of pregnancy (single vs multiple) had significant effects on placentome and membrane weight; fetus sex had highly significant effects on fetus weight and crown-rump length. Fetal brain and heart weights showed little effect of sire, fetus sex or type of pregnancy, indicating these early differentiating tissues are highly competitive for available nutrients for growth. Fetal data at 180 and 250 d of gestation showed highly significant effects of gestation stage on placentome, membrane and fetus weights, crown-rump and metatarsal lengths, and liver, kidney, heart and total brain weights. Type of pregnancy had greater effects on the conceptus traits than did fetus sex at these stages. Nonorthogonal analyses of data from the Jersey-sired pregnancies indicated growth of fetuses in multiple pregnancies was suppressed, and the reduction in fetus weight became more pronounced as gestation progressed. Correlations among conceptus traits and dam carcass data showed different relationships within single and multiple pregnancies. We suggest that the genetic contribution for fetal growth has a positive effect on fetal size throughout gestation while the importance of metabolite availability may change during gestation depending on the genetic growth potential of the fetus and on whether the pregnancy is single or multiple. We speculate that these fetus-dam relationships involve systems controlling fetus growth that arise from the fetus genetic growth potential interacting with positive and negative dam effects that are linked or related to the carcass skeletal-fat-muscle endpoints studied.     

The central effects of morphine on fetal breathing movements in the fetal sheep

The fetal respiratory and electrocortical effects of 0.6 microgram to 600 micrograms of morphine, administered into the lateral cerebral ventricle, have been studied in chronically catheterised, unanaesthetized fetal sheep at 115-135 days gestation. Morphine at 0.6 microgram had no effect on breathing movements or electrocorticographic activity, and at 6 micrograms induced a period of apnoea (43-122 min) but had no effect on electrocortical activity. Intravenous naloxone (2 mg bolus and infusion of 2 mg/kg/h for 2 h) to the fetus had no effect on this apnoea. Morphine at 60 micrograms induced an initial period of apnoea (30-65 min) followed by episodic but significantly deep breathing movements with no effect on electrocortical activity and at 600 micrograms induced an initial period of apnoea (22-95 min) which was followed by deep, irregular and continuous (126-302 min) breathing movements. During the apnoea electrocortical activity initially remained cyclic, but as apnoea progressed there was a gradual reduction in the voltage of the electrocorticogram to a low voltage state. Intravenous naloxone (2 mg bolus and infusion of 2 mg/kg/h for 2 h) reversed both the respiratory and electrocortical effects. The hyperventilation was also inhibited by hypoxia. Naloxone alone had no effect on fetal breathing activity.     

Effects of eflornithine hydrochloride (DFMO) on fetal development in rats and rabbits

Eflornithine hydrochloride (DFMO) is a highly selective, enzyme-activated, irreversible inhibitor of the enzyme L-ornithine decarboxylase (ODC). Because of its role in the biosynthetic pathway of polyamines, ODC is essential for the growth and development of newly implanted embryonic tissue. In order to assess its effect on embryonic growth and fetal development, at various stages of gestation, DFMO was administered in the drinking water to pregnant rats and rabbits at several concentrations (from 0.03% to 3.0%) and times (from days 7, 10, or 11 through days 18 or 19). Rats were killed on day 21 and rabbits on day 29 of pregnancy (day 1 = day of insemination), and the implantations and fetuses were examined. At a concentration of 1.0% (approximately 1,270 mg/kg/day) in rats and 3.0% (approximately 915 mg/kg/day) in rabbits, maternal food and water consumption and body weight gain were significantly reduced during the treatment period, and all implantations were aborted or resorbed. At lower doses (approximately 200-600 mg/kg/day) fetuses survived to term, though in reduced numbers, and a marked reduction in average fetal weight was seen. At levels of 60 mg/kg/day or lower, there were no deleterious effects to the dams or their offspring. Few malformations were detected at any dose level by gross teratologic examination; nor were any considered to have been drug induced because of their sporadic incidence. The embryotoxicity and severe growth retardation demonstrated by these studies verify that adequate polyamine levels are essential for normal embryonic and fetal development.     

Daily ethanol exposure during late ovine pregnancy: physiological effects in the mother and fetus in the apparent absence of overt fetal cerebral dysmorphology

High levels of ethanol (EtOH) consumption during pregnancy adversely affect fetal development; however, the effects of lower levels of exposure are less clear. Our objectives were to assess the effects of daily EtOH exposure (3.8 USA standard drinks) on fetal-maternal physiological variables and the fetal brain, particularly white matter. Pregnant ewes received daily intravenous infusions of EtOH (0.75 g/kg maternal body wt over 1 h, 8 fetuses) or saline (8 fetuses) from 95 to 133 days of gestational age (DGA; term ～145 DGA). Maternal and fetal arterial blood was sampled at 131-133 DGA. At necropsy (134 DGA) fetal brains were collected for analysis. Maternal and fetal plasma EtOH concentrations reached similar maximal concentration (～0.11 g/dl) and declined at the same rate. EtOH infusions produced mild reductions in fetal arterial oxygenation but there were no changes in maternal oxygenation, maternal and fetal Pa(CO(2)), or in fetal mean arterial pressure or heart rate. Following EtOH infusions, plasma lactate levels were elevated in ewes and fetuses, but arterial pH fell only in ewes. Fetal body and brain weights were similar between groups. In three of eight EtOH-exposed fetuses there were small subarachnoid hemorrhages in the cerebrum and cerebellum associated with focal cortical neuronal death and gliosis. Overall, there was no evidence of cystic lesions, inflammation, increased apoptosis, or white matter injury. We conclude that daily EtOH exposure during the third trimester-equivalent of ovine pregnancy has modest physiological effects on the fetus and no gross effects on fetal white matter development.     

Effects of alcohol (ethanol) on the fetus

Alcohol (ethanol) use during pregnancy can produce a wide spectrum of effects in the developing embryo/fetus that are dependent on the maternal drinking pattern. The effects of chronic ethanol exposure on the developing conceptus are reviewed with primary focus on ethanol teratogenesis, manifesting in the human as the fetal alcohol syndrome or fetal alcohol effects. The effects of acute ethanol exposure on the near-term fetus are described, including suppressed fetal breathing movements, electrocorticographic (ECoG) activity and electrooculographic (EOG) activity. The ethanol-induced suppression of fetal breathing movements is a very sensitive index of acute exposure of the near-term fetus to ethanol, and appears to involve a direct mechanism of action rather than an indirect mechanism involving suppression of electrocortical activity. The disposition of ethanol and its pharmacologically active proximate metabolite, acetaldehyde, and the activity of alcohol dehydrogenase and aldehyde dehydrogenase in the near-term maternal-fetal unit are described, and a pharmacokinetic model is proposed. The effects of short-term ethanol exposure on the near-term fetus include the development of tolerance to the ethanol-induced suppression of fetal breathing movements, low-voltage ECoG activity and EOG activity. The development of tolerance occurs more rapidly to the latter two fetal biophysical activities. The mechanism of tolerance development appears to be pharmacodynamic (functional) in nature, as there is no increase in the rate of ethanol elimination from the maternal-fetal unit. The role of prostaglandins (PGs) in the mechanism of the ethanol-induced suppression of fetal breathing movements is described. In the near-term fetus, there is a direct relationship between fetal blood ethanol concentration and fetal plasma PGE2 concentration, and an inverse relationship between the incidence of fetal breathing movements and each of fetal plasma and fetal cerebrospinal fluid (CSF) PGE2 concentrations. Indomethacin, a PG synthetase inhibitor, selectively blocks and reverses the ethanol-induced suppression of fetal breathing movements. These data support the postulates that the ethanol-induced suppression of fetal breathing movements is mediated by increased PGE2 concentration in the near-term fetus and that the ability of indomethacin to antagonize the ethanol-induced suppression of fetal breathing movements is due to its biochemical action to decrease fetal PGE2 concentration.(ABSTRACT TRUNCATED AT 400 WORDS)     

Prenatal alpha-difluoromethylornithine treatment: effects on postnatal renal growth and function in the rat

DFMO (alpha-difluoromethylornithine) is a specific irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines, which in turn control macromolecule synthesis during cell proliferation. The current study was designed to investigate the effects of inhibition of ODC during discrete prenatal periods on renal growth and function. We administered 5 doses of 500 mg/kg DFMO or saline s.c. to timed pregnant Sprague-Dawley rats at 12 hr intervals beginning on gestation days (GD) 11, 14, or 17. Half the dams were killed on GD 20 for fetal morphological analyses and half were allowed to go to term. Renal function was assessed on postnatal days (PD) 3, 6, 10, and 14 by tests of basal renal clearance and urinary concentrating ability, and on PD 42-44 we measured serum chemistries. All three gestational treatment regimens resulted in postnatal deficits in general growth. Only in the GD 11-13 treatment group was there evidence of embryotoxicity and neonatal renal pathophysiology. Fetal weights and urogenital morphology were altered following GD 14-16 treatment and there were persistent deficits of renal growth. GD 17-19 treatment was associated only with transient postnatal deficits of renal growth. Thus, inhibition of ODC during critical prenatal periods induced distinct developmental effects. However, there were no associations between impaired renal growth and function. These data indicate that general tissue growth is not always a predictor of physiological development and support the necessity of multifaceted approaches to the understanding of adverse developmental effects.     

Effect of glutamate intake during gestation on adenosine A(1) receptor/adenylyl cyclase pathway in both maternal and fetal rat brain

Pregnant Wistar rats were orally treated with 1 g/L l -glutamate during the entire gestational period and the status of adenosine A₁ receptor (A₁R)/adenylyl cyclase transduction pathway from maternal and fetal brain was analyzed. Glutamate consumption, estimated from the loss of water from the drinking bottles, was 110 ± 4.6 mg/kg/day. In mother brains glutamate intake did not significantly alter the B _max value, although the K _d value was significantly decreased. However in fetus brain, a significant decrease in B _max was observed, without an alteration of K _d value. Similar results were observed by western blot assays using specific A₁R antibody, suggesting a down-regulation of A₁R in fetal brain. Concerning α subunits of inhibitory G proteins (Gi), αGi₃ protein was slightly but significantly decreased in maternal brain without alterations of either Gi₁ or Gi₂. In contrast, αGi₁ and αGi₂ isoforms were increased in fetal brain. On the other hand, basal, forskolin, and forskolin plus GTPγS-stimulated adenylyl cyclase activity was significantly decreased in both maternal and fetal brain, and this was more prominent in fetal than in maternal brain. Finally, A₁R functionality was significantly decreased in mother brain whereas no significant differences were detected in fetus brain. These results suggest that glutamate administered to pregnant rats modulates A₁R signaling pathways in both tissues, showing an A₁R down-regulation in fetal brain, and desensitization in maternal brain.     

The Response of Ornithine Decarboxylase During Neuronal Degeneration and Regeneration in Olfactory Epithelium

Mature olfactory neurons are continually replaced from a population of progenitor cells. Olfactory nerve section, bulbectomy, or treatment with certain chemicals induces degeneration of olfactory neurons followed in some cases by regeneration. Ornithine decarboxylase (ODC) activity was measured in mouse olfactory tissues as an indicator of cellular regeneration. ODC activity in olfactory tissue (0.2–0.4 nmol/mg protein/h) is 10-30 times higher than in a variety of other cerebral tissues. Within 3 h after unilateral olfactory nerve section, ODC activity in the epithelium declines to 50% of control followed by a slow return to basal activity by 6 days. In the same animals, ODC activity increases severalfold in bulb (1 day) with a gradual decline to normal (9 days). Except for an early transient increase, the effects of unilateral bulbectomy on epithelial ODC activity are similar to those seen after nerve section. The changes in ODC activity following intranasal irrigation with 10 mm -colchicine also closely mimic those seen after nerve section. The effects of intranasal irrigation on ODC activity with 0.5% Triton X-100 or 0.17 m -ZnSO₄ are more complex. Thus, when the mature neuronal population is degenerating after surgery or chemical treatments, ODC activity decreases in the epithelium. The subsequent increase of ODC activity prior to reconstitution of the mature neuronal population probably reflects the regeneration mechanism of the olfactory epithelium. The increase of ODC activity in the olfactory bulb after nerve section is best interpreted as a cellular injury response. These alterations in ODC activity in olfactory tissues after chemical and surgical treatments constitute the earliest biochemical events observed in these tissues in response to cellular damage.     

Ovarian function in the rat following irreversible inhibition of L-ornithine decarboxylase

The possibility that the transient rise in rat ovarian ornithine decarboxylase (ODC) activity and the associated increase in putrescine which occur under luteinizing hormone control late in proestrus have an essential role in ovarian function has been tested using DL-α-difluoromethylornithine (DFMO) an irreversible inhibitor of ODC. Treatment with DFMO, 500 mg/kg s.c. at 12:00 h on the day of proestrus and 200 mg/kg, 6, 12 and 18 h thereafter completely suppressed both the rise in ovarian ODC activity and the associated increase in putrescine concentrations. However, ovulation took place normally under these conditions and the course of the resulting pregnancies was also normal. Similarly, combined treatment with DFMO and an inhibitor of S-adenosyl-L-methionine decarboxylase, 1,1-((methylethanediylidine)-dinitrilo) bis (3-aminoguanidine), 25 mg/kg, given at 10:00 h on the morning of proestrus failed to influence either ovulation or the subsequent period of gestation. These data provide no support for a functional role of the pre-ovulatory rise of ODC in rat ovary in the major peri-ovulatory events of that particular cycle, although they do not exclude effects on systems (e.g. steroidogenesis) not directly examined with our experimental approach. On the other hand, inhibition of ODC resulted in an increase in the number of uterine implantation sites following mating at the next proestrusestrus 4 days later. These data would support the previously expressed view that ODC may be associated with the gonadotrophin-induced initiation of follicular development for ovulation in the succeeding cycle. Moreover, since inhibition of the enzyme resulted in facilitation of the process, the normal physiological function of ODC, and/or the putrescine generated through its action, would appear to be inhibitory.