Co-administration of dextromethorphan during pregnancy and throughout lactation significantly decreases the adverse effects associated with chronic morphine administration in rat offspring.

In this study, we have focused our investigation of the facts whether co-administration of a NMDA antagonist dextromethorphan (DM) with morphine during pregnancy and throughout lactation could prevent the adverse effects associated with chronic morphine administration in rat offspring. Adult female Sprague-Dawley rats were randomly separated into four groups and were received subcutaneous injection of either saline, morphine, morphine + dextromethorphan or dextromethorphan twice a day and progressively increased 1 mg/kg at 7-day intervals from a beginning dose of 2 mg/kg for both morphine and dextromethorphan. The rats were mated between days 7 and 8. Administration of drugs was continued during pregnancy. After rat offspring were born, the doses of morphine or dextromethorphan injected into the maternal rats were increased by 1 mg/kg every two weeks till the offspring were 30 day old. The results showed that mortality of morphine group is much higher than control group. The offspring of morphine group weighed significantly less than control group on postnatal day 14 (p14), p30 or p60. The antinociceptive effect of morphine on p14 rats was reduced in the morphine group and indicated the development of morphine tolerance. The hippocampal NMDA receptor densities have been shown decreased on p14 rats. The precipitated withdrawal symptoms were assessed on p7 rats. Rats in morphine group showed greater frequency of abdominal stretch and wet dog shake in 2 hr than control group. On the other hand, co-administration of DM with morphine effectively prevented all these adverse effects of morphine to the offspring rats. DM co-administered with morphine also partially prevented the development of morphine tolerance in maternal rats. If this effect of dextromethorphan is applied to clinical pregnant patients with morphine addiction or chronic pain, it will have a great value for the benefit of their children.     

Effects of the opioid analgesic oxymorphone hydrochloride on reproductive function in male and female rats

BACKGROUND: Endogenous opioids seem to regulate hypothalamic gonadotropin release in both males and females, as evidenced by the effects of opioid agonists and antagonists on LHRH release and reproductive hormone levels. The effects of long‐term oral administration of opioid analgesics on reproductive function have not been well characterized. METHODS: The reproductive effects of oxymorphone, a potent opioid agonist, were investigated in male and female Crl:CD(SD) IGS BR rats at oral doses of 0, 5, 10, and 25 mg/kg/day (25 animals/sex/group). Males were treated for approximately 9 weeks (mated after 4 weeks of dosing). Females were treated for 14 days before mating, and through Gestation Day (GD) 7. Estrous cycling was evaluated during the premating period. On GD15, pregnancy status and the numbers of corpora lutea, implantation sites, live and dead embryos were determined. Epididymal and testicular sperm counts and epididymal sperm motility and morphology were evaluated in males. RESULTS: Two males given 25 mg/kg/day died. Behavioral changes and deficits in body weight gain occurred at all doses. There were no effects of oxymorphone on reproductive function or sperm parameters in males. The estrous cycle was prolonged in females given 25 mg/kg/day (mean of 5.3 vs. 4.3 days in controls). A small, but consistent decrease in the numbers of corpora lutea (with associated decreases in implantation sites and embryos) occurred in females given ≥10 mg/kg/day. There were no effects on mating or fertility in females. CONCLUSIONS: Oxymorphone seems to partially inhibit ovulation in female rats, with no significant effects on male reproductive outcome. Birth Defects Res (Part B) © 2007 Wiley‐Liss, Inc.     

The Effect of Fetal and Early Postnatal Iron Deficiency on Iron Metabolism in Adult Rats

Undernutrition during pregnancy and/or lactation plays an important role on the overall health of offspring later in life. Using a rodent model, the present study was conducted to examine the effect of fetal and early postnatal iron deficiency on iron metabolism in adult animals. Rats were treated with three stages of low or normal iron diets from gestation until the end of the study. During the first stage (4?weeks prior to 3?weeks after pregnancy, total 7?weeks), two groups of adult females (dams) were fed with either a low-iron (7.4?mg iron/kg, group LD) or control-iron (274?mg/kg, group CD) diet. During the second stage (from 3 to 13?weeks of age, total 10?weeks), all pups from stage 1 (both the LD and CD groups) were placed on a control-iron diet for 10?weeks (groups LD?CCD and CD?CCD, respectively). During the third stage (from 13 to 29?weeks of age, total 16?weeks), both LD?CCD and CD?CCD groups from stage 2 were fed with a low-iron (named LD?CCD?CLD and CD?CCD?CLD groups, respectively). We found that the live birth rate of the offspring of the LD dams (84.7?%) was significantly lower than that of the CD dams (95.4?%). During stage 2, the mean body weight of the LD?CCD male or LD?CCD female rats exceeded the CD?CCD male rats (p?<?0.05). Compared with the CD?CCD?CLD rats, the LD?CCD?CLD rats had significantly increased total iron binding capacity, and higher levels of transferrin, serum erythropoietin (EPO), renal EPO mRNA, duodenal divalent metal transporter-1, and renal transferrin receptors. These findings indicate that rats with an early-life experience of iron deficiency (during pregnancy and the nursing period) can develop stronger iron absorption capabilities in adulthood.     

Sex-and age-dependent effects of prenatal exposure to caffeine on open-field behavior, emergence latency and adrenal weights in rats

Pregnant rats were provided with drinking water containing 0, 0.23 or 0.3 mg/ml of caffeine throughout gestation. These concentrations gave rise to daily doses of 0, 28 and 36 mg/kg. Open-field behavior and latencies to emerge from a darkened chamber were observed in offspring at regular intervals from 1 to 8 months after birth. The main results revealed increases in open-field locomotor and rearing activity with 28 but not 36 mg/kg/day. The opposite pattern characterized emergence latency. These changes were more typical of male rats particularly when older. Combining the present results with those of an earlier study by the authors strengthened the curvilinear trends observed and led to the conclusion that, low doses of prenatal caffeine increase activity and decrease emotionality. Higher doses may have the opposite effects to the point that the significant differences from control subjects reported earlier can occur. When 8 months old, female but not male rats prenatally exposed to 36 mg/kg/day of caffeine had significantly heavier adrenal glands than controls.     

Inducibility of somatic colour and white spots in the mammalian spot test: Examination with,and experience in using,cyclophosphamideR, s.c.

F₁ embryos of the C57BL/6JHan × T-Stock were exposed in utero to 5, 10, 15 and 45 mg/kg b.w. of cyclophophamide (CP) s.c. on the 10th day of pregnancy. 3–5 weeks post-partum the offspring were examined for the appearance of recessive coat-colour mosaics and white midventral spots (WMVS). The frequencies of the coloured spots were 0.93 and 2.59% at 5- and 10-mg/kg doses of CP, res. These frequencies were dose-dependent, but the difference between the doses was not significant. No coloured spots were obtained with CP at 15 and 45 mg/kg. The frequencies of WMVS were much higher than those of coloured spots (1.40, 6.03 and 51.16%, resp.). The differences were highly significant. The reduction in the number of offspring compared with the ratio of the offspring/female of the control (control = 100%) were 16.16, 22.72, 72.48 and 100% at the different doses of CP (5, 10, 15 and 45 mg/kg b.w.).     

Sex-specific effects of prolactin on food intake by rats

While prolactin (PRL) has been reported to increase food intake by virgin female rats, its effects on food intake by male rats are relatively unexplored. The present studies examined the possibility that PRL has sex-specific effects on food intake by rats. In the first study, intact female and male rats were given subcutaneous injections of saline vehicle or ovine (o) PRL (1.0 mg/kg) twice daily at 08:00 and 20:00 h for 10 days. Food intake, body weight, and water intake were measured daily. Results indicate that oPRL administration increased food intake by an average of 4.5 g per day in female subjects, but did not significantly alter body weight or water intake. Male rats treated with oPRL did not significantly alter their food intake, even after an additional five days of treatment. In the second study, a wide range of oPRL doses (vehicle, 0.02, 0.2, 2.0, and 20.0 mg/kg/day) were tested in gonadectomized female and male rats. The results indicate that female rats responded to increasingly larger doses of oPRL with greater increases in food intake, with a maximum increase of approximately 6. 1 g per day at a dose of 20.0 mg/kg. In contrast, male rats maintained baseline levels of intake across all oPRL doses tested. These data suggest that PRL has sex-specific effects on food intake.     

Pre- and postnatal development studies of lasofoxifene, a selective estrogen receptor modulator (SERM), in Sprague-Dawley rats

BACKGROUND: Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) developed for the treatment of postmenopausal osteoporosis. The purpose of these studies was to evaluate the effects of lasofoxifene on the postnatal development, behavior, and reproductive performance of offspring of female rats given lasofoxifene during organogenesis and lactation. METHODS: Two range-finding studies were conducted to determine the effects of lasofoxifene at doses from 0.01-10 mg/kg on parturition and lactation in pregnant rats and on the early postnatal development of the offspring, and to optimize the dosing regimen. Maternal milk and plasma were sampled for concentrations of lasofoxifene on Lactation Days 4, 7, and 14. In the pre- and postnatal development study, lasofoxifene was administered to pregnant and lactating rats by oral gavage at dose levels of 0.01, 0.03, and 0.1 mg/kg on Gestation Days 6-17 and Lactation Days 1-20. Maternal body weight and food consumption were measured throughout pregnancy, and body weight was measured throughout lactation. Parturition was monitored closely. The F1 offspring were measured for viability, body weight, anogenital distance, the appearance of postnatal developmental indices and reflex behaviors, sensory function, in an age-appropriate functional observational battery, motor activity, auditory startle, passive avoidance, and the Cincinnati Water Maze. The F1 generation was assessed for reproductive function, and the F2 offspring were measured for body weight and viability throughout the lactation period. RESULTS: In the range-finding studies, indications of maternal toxicity included decreased body weight and food consumption, increased length of gestation, prolonged parturition, dystocia, and increased offspring mortality at birth. Concentrations of lasofoxifene in maternal plasma were similar to those in milk, increased with increasing dose, and remained consistent over a 10-day period. In the pre- and postnatal development study, maternal body weights and food consumption were decreased in all treated groups during gestation. Length of gestation was increased, parturition was prolonged, and dystocia was noted in the dams in the 0.1 mg/kg group. There was increased pup mortality in the F1 litters in the 0.1 mg/kg group and all treated groups had decreased offspring body weights beginning at 1 week of age, continuing into the postweaning period and, for the F1 males, into adulthood. Female F1 offspring in the 0.03 and 0.1 mg/kg groups had increased body weights as adults. There were delays in the age of appearance of preputial separation in the males in the 0.1 mg/kg group and vaginal opening in the females in all treated groups. Body temperature was decreased by <0.5 degrees C after weaning for male and female offspring in the 0.1 mg/kg group. The sensory, behavioral, and functional measures, including the tests of learning and memory, were unaffected by treatment. Mating success was lower for the F1 animals in the 0.1 mg/kg group, but there were no effects on the reproductive parameters. Mating, reproduction, and maternal behavior of the F1 animals in the 0.01 and 0.03 mg/kg groups and the survival and body weights of the F2 offspring in all treated groups through Postnatal Day 21 were unaffected by treatment. CONCLUSION: The maternal findings in this study were related to the pharmacologic activity of lasofoxifene. Inhibition of growth of the F1 offspring after perinatal exposure to lasofoxifene was observed, but there were no significant effects on the sensory, behavioral, or functional measures, including learning and memory. There were no effects on the F2 generation. The findings are consistent with those reported for at least one other SERM. The findings of this study do not suggest increased risk for the primary indication of use in postmenopausal women.     

Dependence of the cytotoxic effect of guanethidine on the degree of sympathetic activity

Young rats aged 15-29 days received a subcutaneous injection of guanethidine sulphate (5 mg/kg body weight) every day. Owing to damage to the postganglionic sympathetic neurones, on about the 60th day of life we observed a significant decrease in the noradrenaline concentration in these animals' hearts compared with the controls. If every guanethidine injection was followed immediately by intensive physical exercise, there was no drop in the heart noradrenaline concentration. Physical exercise of the same intensity performed a few hours before injecting guanethidine did not prevent the drop in the noradrenaline concentration in the heart. The results show that an exercise-induced increase in sympathetic activity, at a time when guanethidine is circulating in the blood and accumulating in the adrenergic neurones, inhibits the cytotoxic effect of guanethidine. Isolated physical exercise performed between the 15th and 29th day of life leads to an increase in the noradrenaline content of the heart of rats aged 60 days.     

Effects of perinatal polychlorinated biphenyls on adult female rat reproduction: development, reproductive physiology, and second generational effects

Perinatal exposures to endocrine-disrupting chemicals, such as polychlorinated biphenyls (PCBs), can cause latent effects on reproductive function. Here, we tested whether PCBs administered during late pregnancy would compromise reproductive physiology in both the fetally exposed female offspring (F1 generation), as well as in their female offspring (F2 generation). Pregnant Sprague-Dawley rats were treated with the PCB mixture, Aroclor 1221 (A1221; 0, 0.1, 1, or 10 mg/kg), on Embryonic Days 16 and 18. Somatic and reproductive development of F1 and their F2 female offspring were monitored, including ages of eye opening, pubertal landmarks, and serum reproductive hormones. The results showed that low doses of A1221 given during this critical period of neuroendocrine development caused differential effects of A1221 on F1 and F2 female rats. In both generations, litter sex ratio was skewed toward females. In the F1 generation, additional effects were found, including a significant alteration of serum LH in the 1 mg/kg A1221 group. The F2 generation showed more profound alterations, particularly with respect to fluctuations in hormones and reproductive tract tissues across the estrous cycle. On proestrus, the day of the preovulatory GnRH/gonadotropin surge, F2 females whose mothers had been exposed perinatally to A1221 exhibited substantially suppressed LH and progesterone concentrations, and correspondingly smaller uterine and ovarian weights on estrus, compared with F2 descendants of control rats. These latter changes suggest a dysregulation of reproductive physiology. Thus, low levels of exposure to PCBs during late fetal development cause significant effects on the maturation and physiology of two generations of female offspring. These findings have implications for reproductive health and fertility of wildlife and humans.     

高氟低碘对Wistar大鼠大脑组织病理学及DNA损伤的影响

目的研究高氟与低碘对子代大鼠大脑组织病理学及脑细胞DNA损伤的影响。方法断乳Wistar大鼠（雌∶雄=3∶1）32只,随机分为四组：对照组,饲喂大鼠标准饲料,去离子水;高氟组,饲喂大鼠标准饲料,饮100mg/L氟化钠（NaF）去离子水;低碘组,饲喂低碘饲料（定做）,去离子水;高氟低碘组,饲喂低碘饲料,饮100mg/L氟化钠（NaF）去离子水。雌雄大鼠自然交配,待子代大鼠出生后,观察其在10、20天时脑皮质、海马组织病理学变化,及30、60和90天时脑DNA的损伤。结果与对照组相比,高氟组和低碘组大鼠大脑皮质及海马内有较多神经元核固缩、核溶解及细胞轮廓不清晰。高氟低碘组,有大量神经元出现核固缩、核溶解、锥体突明显拉长等现象,并且在大鼠发育期内尤其明显。随着日龄的增加,各实验组子代大鼠脑细胞DNA损伤程度显著增加,以高氟低碘组90日龄大鼠DNA损伤最严重。结论高氟与低碘影响了大鼠大脑皮质及海马组织形态结构与引起了脑细胞的DNA损伤。     

Interactive effects of prenatal cocaine and nicotine exposure on maternal toxicity,postnatal development,and behavior in the rat

Two experiments were performed to investigate the interactive effects of prenatal coadministration of cocaine hydrochloride (C) and nicotine tartrate (N). Experiment I was designed to determine doses of C and N that could be coadministered without altering maternal gestational parameters and/or fetal viability. Exposure of Sprague-Dawley rats to combined high-dose C (20 mg/kg) and high-dose N (5.0 mg/kg) on gestation days 8–21 was not more toxic to dam or fetus than that of exposure to C alone. Experiment II investigated pregnancy outcome, postnatal development, and behavior of the offspring following drug exposure to either high-dose cocaine (20 mg/kg: CS), high-dose nicotine (5.0 mg/kg: NS), or both (NC) on gestation days 8–21. N was administered by osmotic minipump and C by sc injection. Saline-injected dams, fitted with saline-filled pumps (SS), and untreated dams, pair-fed (PF) to NC females, served as controls. Alterations in maternal variables were limited to a 10–15% decrease in food consumption in NC and CS groups. Pregnancy outcome and birth statistics were unaffected by prenatal treatment, as was offspring body weight during the first four postnatal weeks. However, the development of surface righting was delayed in CS pups, and only CS offspring were underresponsive to the stimulatory effects of dopamine agonists on activity and stereotypy. Behavioral responses to N challenge were similar in all groups. In addition, only CS offspring showed altered behavioral responses in a spontaneous alternation task. Treatment effects on dopamine D₁ and D₂ binding in the caudate nucleus were not observed. The combination of N and C did not exacerbate any of the behavioral changes seen in CS offspring. These results support the hypothesis that C is a behavioral teratogen in rodents, and suggest that in the present model, nicotine can mitigate some of the consequences ofin utero exposure to cocaine.     

Induction of rat hepatic drug metabolizing enzymes by dimethylcyclosiloxanes

Low molecular weight dimethylcyclosiloxanes (DMCS) are important precursors in the synthesis of polydimethysiloxane polymers widely used in industry, and in medical and personal care products. The objective of this study was to characterize the ability of two DMCS, octamethylcyclosiloxane (D4) and decamethylcyclopentasiloxane (D5) to induce drug metabolizing enzymes in rats. Male and female Sprague-Dawley rats were administered 1, 5, 20, or 100 mg/kg D4 or D5 in corn oil daily by gavage for 4 days. Changes in the levels of activity and/or immunoreactivity of CYP1A1/2, CYP2B1/2, CYP3A1/2 and NADPH cytochrome P450 reductase in liver microsomes were examined. Significant increases were observed in the liver to body weight ratio in female rats administered either D4 or D5 at doses > or = 20 mg/kg. Increases in the liver to body weight ratio were observed in male rats treated with > or = 100 mg/kg D5 but not with D4. Relatively large increases in CYP2B1/2 enzymatic activity and immunoreactive protein were observed with increasing concentrations of both D4 and D5. Significant increases in 7-pentoxyresorufin O-depentylase (PROD) activity were also detected in male and female rats given D4 at doses > or = 5 mg/kg. D5 increased PROD activity in male rats at doses > or = 20 mg/kg and in female rats at doses > or = 5 mg/kg. 7-Ethoxyresorufin O-deethylase (EROD) activity was increased in both male and female rats receiving > or = 20 mg/kg D4 or > or = 5 mg/kg D5; however, no changes were detected in CYP1A1/2 immunoreactive protein in rats of either sex. D4 and D5 caused significant increases in CYP3A1/2 immunoreactive protein in only male rats treated with 100 mg/kg of either compound. However, significant increases were detected in CYP3A1/2 immunoreactive protein in female rats at D4 doses > or = 20 mg/kg and D5 doses > or = 5 mg/kg. Induction of NADPH cytochrome P-450 reductase immunoreactive protein was observed with D4 in female rats and in both male and female rats with D5. Induction of CYP2B/1/2, CYP3A1/2 and NADPH cytochrome P450 reductase was observed in rats treated with 50 mg/kg phenobarbital by intraperitoneal injection. Maximal CYP2B induction detected with D4 was approximately 50% of the increase observed with phenobarbital. In summary, D4 and D5 induced CYP2B1/2 in adult rat liver in a manner similar to that observed with phenobarbital; however, differences were observed between D4 and D5 in their ability to induce CYP3A1/2 and NADPH cytochrome P450 reductase. Female rats were more sensitive to the inductive properties of low doses of both DMCS than male rats whereas male rats were more responsive to phenobarbital induction.     

Excess Manganese-Induced Apoptosis in Chicken Cerebrums and Embryonic Neurocytes

Methyl mercury (MeHg) is a developmental neurotoxin that causes irreversible cognitive damage in offspring of gestationally exposed mothers. Currently, no preventive drugs are established against MeHg developmental neurotoxicity. The neuroprotective effect of gestational administration of a flavanoid against in utero toxicity of MeHg is not explored much. Hence, the present study validated the effect of a bioactive flavanoid, fisetin, on MeHg developmental neurotoxicity outcomes in rat offspring at postnatal weaning age. Pregnant Wistar rats were simultaneously given MeHg (1.5 mg/kg b.w.) and two doses of fisetin (10 and 50 mg/kg b.w. in two separate groups) orally from gestational day (GD) 5 till parturition. Accordingly, after parturition, on postnatal day (PND) 24, weaning F₁ generation rats were studied for motor and cognitive behavioural changes. Biochemical and histopathological changes were also studied in the cerebral cortex, cerebellum and hippocampus on PND 25. Administration of fisetin during pregnancy prevented behavioural impairment due to transplacental MeHg exposure in weaning rats. Fisetin decreased the levels of oxidative stress markers, increased enzymatic and non-enzymatic antioxidant levels and increased the activity of membrane-bound ATPases and cholinergic function in F₁ generation rats. In light microscopic studies, fisetin treatment protected the specific offspring brain regions from significant morphological aberrations. Between the two doses of fisetin studied, 10 mg/kg b.w. was found to be more satisfactory and effective than 50 mg/kg b.w. The present study shows that intake of fisetin during pregnancy in rats ameliorated in utero MeHg exposure-induced neurotoxicity outcomes in postnatal weaning F₁ generation rats.     

The male genital tract and the nipples of male and female offspring of rats given the non-steroidal antiandrogens DIMP and Sch 13521, during pregnancy.

Male and female offspring of rats given antiandrogens, the steroidal BOMT or the non steroids DIMP or Sch 13521, daily during the last third of pregnancy were studied. Detailed examinations were made of the genital tract of male, and of the nipples of male and female offspring. A) Male offspring. 1) Genital tract of newborn and 31-91 day old males : Modifications of the development of accessory sexual tissues were found in all treatment groups. As indicated by the severity of deviations from normal (morphology and weight of sex accessories), the antiandrogenic effect of the preparations, in the doses given to the mother rats, increased from BOMT (50 or 75 mg/day) via Sch 13521 (30 mg/day) and DIMP (50 or 60 mg/day) to Sch 13521 (60 mg/day). 2) Nipples of 10-60 day old males : Whole mount preparations were made unilaterally of the row of 6 mammary glands with nipples. The number of intact and abnormal nipples, respectively, was recorded. The relation between intact and abnormal nipples served as indicator of the efficiency of the antiandrogenic substances studied. The result showed that the antiandrogenic effect increased from BOMT to Sch 13521, 60 mg, in the same order as that arrived at from studies of the genital tract. The combined results obtained from the male offspring indicated that the tissues of the genital region, the growth and differentiation of which was most readily impaired by antiandrogens, were the same as those known from other work to be stimulated most easily in female rat fetuses by testosterone. B) Female offspring. Nipples of 31-60 day old females were judged from whole mount preparations and recorded as in the males. The nipples of adult virginal females were examined macroscopically. The same procedure was applied to lactating females, but the results were controlled in consecutive lactational periods and at autopsy. The 3 groups of females showed uniformly that 1) offspring of rats given BOMT during pregnancy had many (about 50 per cent) malformed nipples and 2) the treatment of mother rats with DIMP or Sch 13521 did not influence the development of nipples in female offspring. The result was assumed to be due to an androgenic effect of the steroidal antiandrogen, BOMT, on the nipple anlage.     

Teratogenic and postnatal developmental studies of morphine in Sprague-Dawley rats

The teratogenic and postnatal developmental effects of morphine exposure during pregnancy were studied in Sprague-Dawley rats in three separate experiments using chronically implanted osmotic minipumps in order to avoid respiratory depression. In the first experiment, the teratogenic effects of three different morphine dosages were studied: a low dose (10 mg/kg/day), an intermediate dose (35 mg/kg/day), and a high dose (70 mg/kg/day). On day 5 of gestation, osmotic minipumps that deliver their contents at a constant rate for 15 days were implanted subcutaneously on the back of the rats. On day 20 of gestation, cesarean sections were performed, reproductive indices were determined, and fetuses were examined externally and then preserved for subsequent visceral and skeletal examinations. The pregnancy rate was significantly reduced at the intermediate and high doses to 57% and 6%, respectively (control, 83%). No teratogenic effects were observed at any dosage, but growth retardation was present in the intermediate-dose group. In the second experiment, postnatal survival of the offspring of dams treated with either normal saline, morphine (35 mg/kg/day), or the synthetic opioid, fentanyl (500 micrograms/kg/day) were studied. Offspring of morphine-treated dams had a significantly higher mortality rate, which peaked at 56% within 2 days. No effect was seen after fentanyl treatment. In the third experiment, pups of morphine-treated dams were cross-fostered by saline-treated dams; the postnatal mortality in offspring of morphine-treated dams remained high (62%). Our results indicate that doses of morphine up to 35 mg/kg/day delivered by osmotic minipumps are not teratogenic in rats but cause other adverse fetal effects that result in increased postnatal mortality.     

Effect of serotonin deficit at different stages of prenatal ontogenesis on behavior of adult male and female rats

Effects of maternal parachlorophenilalanine (PCPA) administration on the offspring behavior were studied in the open field, Porsolt forced swimming, and Morris water maze tests. PCPA was administered in two different gestational periods: on gestational days (GD) 8-11 or GD 14-17, at doses 200/100/100/50 mg/kg. It was found that prenatal exposure to PCPA results in fetal serotonin (5-HT) depletion and changes in both open field activity and depression-related behavior, as well as impairments in spatial learning in the adult offspring. The most pronounced effects on behavior were observed in the male and female offspring whose mothers were depleted of serotonin by PCPA during the third trimester of pregnancy. These results provide further evidence that adverse factors have the most severe effects on the development of rat brain function when exposed during the final trimester of pregnancy than during the second trimester.     

The neuroteratogenicity of procarbazine in the rat: behavioral, morphological, and neurochemical aspects

Pregnant female Sprague-Dawley rats were treated from day 12 through day 15 of gestation with procarbazine, an antineoplastic drug, and their offspring were subjected to tests of locomotor development and behavior. Treatment levels ranged from 0.5 mg/kg/day, a dose that produced no abnormalities, to 10 mg/kg/day, a dose that caused a marked micrencephaly in the absence of other teratological changes. Despite marked morphological brain changes, preweaning locomotor development, as assessed by open-field swimming activity and vertical grid climbing, was normal in all offspring. Post-weaning passive avoidance learning and retention were also normal. Groups that had been treated prenatally with teratogenic doses (5.0 and 10.0 mg/kg/day) displayed less rearing behavior in the open field, while ambulation in the periphery of the open field arena was unaffected. Groups treated with subteratogenic doses (0.5 and 1.0 mg/kg/day) did not differ from control. In addition to the behavioral studies, sodium-dependent high-affinity choline uptake and choline acetyltransferase activity (CAT) were measured (per mg protein) in the cortex and hippocampus of animals that had been exposed prenatally to either teratogenic or subteratogenic doses of procarbazine. In spite of a substantial reduction in size of both brain structures in the group receiving a teratogenic dose, choline uptake and CAT did not differ from control.     

二月桂酸二丁基锡对大鼠妊娠及对子代毒性作用

目的通过染毒观察二月桂酸二丁基锡（Dibulytin Dilaurate,简称DBTD）对子代胎鼠形态、体重、性别及骨骼发育状的影响。方法按随机分组的原则,将大鼠分为对照组和染毒组,对照组用玉米油,染毒组用DBTD玉米油溶液,浓度分别是2.5 mg/kg体重（1/72 LD50）、10 mg/kg体重（1/18 LD50）和20 mg/kg体重（1/9 LD50）,采用灌胃的方式进行染毒,6 d/周,每天同一时间进行染毒,共计染毒48 d。染毒第五周后,各组大鼠与正常雄性大鼠以1：1的比例合笼,合笼期间不染毒,每只雌鼠查到阴栓为妊娠第0天,继续染毒,于妊娠第18天处死取胎鼠。结果1/18 LD50及1/9LD50剂量组中活胎及胎儿的体重明显下降,1/18 LD50剂量组胎儿的性别开始发生明显的变化（P〈0.05）。结论DBTD染毒对大鼠每胎存活数、胎重、胎儿的形态及性别有影响,有一定的生殖毒性。     

Contraceptive activity of combinations of steroids and antiadrenergic preparations]

Experiments were conducted on mature female rats. Simultaneous administration through a tube for 14 days, daily, of mestranol (0.04 mg/kg) and megestrol acetate (0.8 mg/kg) gave no significant contraceptive effect, whereas the use of steroid preparations in the same doses in combination with antiadrenergic substances--dopegit (100 mg/kg) or pyrroxan (10 mg/kg) prevented pregnancy effectively.     

Metabolism and toxicity of anacrotine, a pyrrolizidine alkaloid, in rats

The effects of anacrotine, a pyrrolizidine alkaloid (PA) which has the structure of senecionine with an additional 6-hydroxy group, have been investigated in weanling male rats. When anacrotine was given i.p. (100 mg/kg), pyrrolic metabolites reached a peak level in the liver during the first 0.5 h, then fell rapidly to a lower level which subsequently declined more slowly. Pyrrolic metabolites accumulated in the lungs during the first hour to a level which then remained relatively steady for at least 4 h. The lung level of pyrrolic metabolites after 2 h was about 39% of the liver level, compared with 16% in rats given senecionine. Anacrotine caused acute centrilobular necrosis and congestion of the liver when 125 mg/kg or more was given i.p., but oral doses (up to 180 mg/kg) caused relatively little liver necrosis. Enlarged hepatocytes developed during ensuing weeks, but these were moderate compared with the bizarre giant cells often associated with pyrrolizidine intoxication. In contrast, anacrotine produced much more severe lung damage than most other pyrrolizidine alkaloids. The lungs were affected by i.p. or oral doses well below those needed to produce acute liver damage. Pulmonary congestion and oedema, extensive necrosis of the pulmonary endothelium, and thickening of alveolar septae, developed within 2 days after dosing. After single i.p. doses of 60 mg/kg or more progressive consolidation of lung tissue often led to death after 2-5 weeks. Hearts showed myocardial necrosis of the right ventricular wall. Dehydroanacrotine, the putative reactive pyrrolic metabolite of anacrotine, given i.v. to rats, caused dose-related chronic lung and heart damage identical to that produced by anacrotine, but after lower doses (6-27 mg/kg); larger amounts caused acute lung damage. It is suggested that the severe lung damage in animals given anacrotine is due to dehydroanacrotine, formed in the liver. This metabolite is more stable than the pyrrolic derivatives of most other pyrrolizidine alkaloids, and it is thus able to reach the lungs in relatively large amounts.