Maternal L-proline supplementation enhances fetal survival, placental development, and nutrient transport in mice†.

L-Proline (proline) in amniotic fluid was markedly increased during pregnancy in both pigs and sheep. However, in vivo data to support a beneficial effect of proline on fetal survival are not available. In this study, pregnant C57BL/6J mice were fed a purified diet supplemented with or without 0.50% proline from embryonic day 0.5 (E0.5) to E12.5 or term. Results indicated that dietary supplementation with proline to gestating mice enhanced fetal survival, reproductive performance, the concentrations of proline, arginine, aspartic acid, and tryptophan in plasma and amniotic fluid, while decreasing the concentrations of ammonia and urea in plasma and amniotic fluid. Placental mRNA levels for amino acid transporters, including Slc36a4, Slc38a2, Slc38a4, Slc6a14, and Na+/K+ ATPase subunit-1α (Atp1a1), fatty acid transporter Slc27a4, and glucose transporters Slc2a1 and Slc2a3, were augmented in proline-supplemented mice, compared with the control group. Histological analysis showed that proline supplementation enhanced labyrinth zone in the placenta of mice at E12.5, mRNA levels for Vegf, Vegfr, Nos2, and Nos3, compared with the controls. Western blot analysis showed that proline supplementation increased protein abundances of phosphorylated (p)-mTORC1, p-ribosomal protein S6 kinase (p70S6K), and p-eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), as well as the protein level of GCN2 (a negative regulator of mTORC1 signaling). Collectively, our results indicate a novel functional role of proline in improving placental development and fetal survival by enhancing placental nutrient transport, angiogenesis, and protein synthesis.

Effects of intravenous infusion of E. coli lipopolysaccharide in early pregnant cows.

The objective was to characterize effects of Escherichia coli LPS (given i.v.) on corpus luteum (CL) and embryonic viability in early pregnant cattle. Eight non-lactating German Holstein cows were given 0.5 µg/kg LPS on 35 ± 3 day (mean ± s.e.m.) of pregnancy, whereas seven heifers, 41 ± 6 day pregnant, were given 10 mL saline (control group). Transrectal B-mode examinations of the CL were done at -1, 3, 6, 12, 24, 48, 72 and 96 h relative to treatment. Blood samples were collected at -1, 0.5, 1, 2, 3, 4, 6, 9, 12, 24, 48, 72 and 96 h. At 12 and 48 h, the CL was biopsied. None of the cows still in the experiment 10 day after LPS (n = 7) had embryonic loss. In LPS-treated cows, luteal area decreased (from 4.1 to 3.1 cm2; P ≤ 0.05) within 6 h and until 48 h. Luteal blood flow decreased by 39% (P ≤ 0.05) within the first 6 h after LPS, but returned to pre-treatment values by 48 h. Plasma P4 decreased by 62% (P ≤ 0.05), reached a nadir (2.7 ± 0.6 ng/mL) at 12 h after LPS and was not restored to pre-treatment (P ≤ 0.05). In luteal tissue, mRNAs for STAR and for FGF1 were lower (P ≤ 0.05) in LPS than in saline-treated cattle at 12 h, with no difference between groups at 48 h. Levels of mRNAs for CASP3 and FGF2 were not different between groups (P > 0.05) at 12 or 48 h after treatment. In conclusion, LPS transiently suppressed CL function, but did not induce embryonic mortality.

Dysregulation of solute carrier transporters in malaria-infected pregnant mice.

AIMS: Malaria in pregnancy (MiP) alters the expression of ATP-binding cassette efflux transporters in maternal and foetal tissues, as well as the placenta. Malaria induces oxidative stress, and pregnancy is associated with arginine deficiency. We hypothesized that reducing oxidative stress during MiP by supplementation with L-arginine, a NO precursor, would attenuate transcriptional changes in a second superfamily of transporters, solute carrier (SLC) transporters, and improve pregnancy outcomes. METHODS AND RESULTS: Pregnant BALB/c mice receiving L-arginine (1.2%) in water, or water alone, were infected with Plasmodium berghei ANKA on gestational day 13 and sacrificed on gestational day 19. Compared to controls, the mRNA of numerous SLC transporters was downregulated in maternal and foetal tissues, as well as in the placentas of infected mice. While supplementation with L-arginine did improve foetal viability, it did not improve the mRNA expression of oxidative stress markers, transporters nor other indices of foetal and maternal health. Moreover, amino acid uptake transporters were downregulated upon infection, which could potentially contribute to decreased foetal birthweight. CONCLUSIONS: Malaria in pregnancy significantly alters the expression of SLC transporters in maternal and foetal tissues as well as the placenta, regardless of L-arginine supplementation. Further studies to investigate methods of reducing oxidative stress in MiP are warranted.

Arsenic trioxide exposure impairs testicular morphology in adult male mice and consequent fetus viability.

The acute promyelocytic leukemia (APL) is a rare disease, affecting 0.1/100,000 individuals globally. Despite significant advances in APL therapy, some patients still experience relapsed disease. Currently, arsenic trioxide (As2O3) was found to be effective in relapsed APL treatment and considered as standard treatment for these cases. However, it has been shown that exposure to As2O3 may exert adverse effects on the male reproductive system since this substance might also induce apoptosis of other important cell types including stem cells. Studies demonstrated that treatment with this metallic substance decreased plasma levels of testosterone and interfered with sperm parameters such as concentration, motility, and viability. In addition, As2O3 was found to produce significant damage to spermatocytes, which may be associated with testicular toxicity and consequent inhibition of spermatogenesis. The aim of this study was to determine sub-chronic treatment effects of As2O3 on sperm and testicular morphology, androgen receptor (AR) immunoreactivity in testes and epididymis, in addition to evaluation of fertility parameters in adult male mice. Thirty adult Swiss mice were divided into three experimental groups: control; received distilled water (vehicle) while treated received 0.3 or 3 mg/kg/day As2O3 subcutaneously, for 5 days per week, followed by 2 days of interruption, for 5 weeks. Results showed that As2O3 (1) decreased spermatozoa number, (2) produced seminiferous epithelium degeneration and exfoliation of germ cells tubule lumen (3) altered nucleus/cytoplasm proportion of Leydig cells and (4) reduced AR immunoreactivity in both Leydig and epithelial epididymal cells. Further, fetal viability tests demonstrated an increase in post-implantation loss in females that were mated with As2O3-treated males. Data indicate that As2O3 exposure altered the spermatogenic process and subsequently fetal viability.

The inhibitory effect of progesterone on lactogenesis during pregnancy is already evident by mid- to late gestation in rodents.

Lactogenesis is a very complex process highly dependent on hormonal regulation. In the present study the time-course of the inhibitory actions of progesterone on prolactin secretion, mammary gland morphology and lactogenesis from mid- to late gestation in rodents was investigated. Groups of pregnant rats were luteectomised or administered with mifepristone on Day 10, 13, 15 or 17 of gestation and decapitated 28 or 48h later. Whole-blood samples and the inguinal mammary glands were taken for determinations of hormone levels and for measurement of mammary content of casein and lactose and for tissue morphology analyses, respectively. Luteectomy or mifepristone evoked prolactin increases only after Day 17 of gestation. Mammary content of casein was increased by both treatments regardless of timing or duration. Mifepristone was less effective than luteectomy in inducing lactose production and the effect was only observed after Day 15 of gestation. Analysis of mammary gland morphology confirmed the observed effect of progesterone on lactogenesis. Both treatments triggered remarkable secretory activity in the mammary gland, even without a parallel epithelial proliferation, demonstrating that the mammary epithelium is able to synthesise milk compounds long before its full lobulo-alveolar development is achieved, provided that progesterone action is abolished. Thus, the present study demonstrates that progesterone is a potent hormonal switch for the prolactin and prolactin-like effects on mammary gland development and its milk-synthesising capacity during pregnancy, and that its inhibitory action is already evident by mid-pregnancy in rodents.

Efficacy of Ginkgo biloba on vaginal estrous and ovarian histological alterations for evaluating anti-implantation and abortifacient potentials in albino female mice.

Ginkgo extract, EGb 761 is known as a vasoregulatory variable for the conventional reproduction therapy. EGb 761 was orally administered in 0 (control), 3.7, 7.4, and 14.8 mg/kg bw/day for 28 days (thereafter mated with normal fertile male), from day 1 to day 7 of pregnancy or from the 10th to 18th day of pregnancy, respectively. Vaginal smears were performed daily. On 20th day of pregnancy, the females were killed by cervical dislocation and their kidneys, liver, brain, placenta, spleen and ovaries were removed and weighed. The ovaries were prepared for histological examinations, and then ovarian follicles were counted. Maternal toxicity, estrous cycle, reproductive hormones, ovarian follicle counts, resorption index, implantation index, fetal viability and fetuses, and placenta mean weights were evaluated. There was a dose-dependent ovarian toxic effect of EGb 761. Ovarian follicle counts, resorption index, implantation index, fetal viability were significantly reduced in 14.8 mg/kg bw/day dose. Treatment with 14.8 mg/kg bw/day EGb 761 induced disruption of estrous cycle and caused maternal toxicity, in addition to fetal toxicity. Therefore, the data obtained indicate that Ginkgo biloba extract at 14.8 mg/kg bw/day dose level exhibit toxic effect on reproductive cyclicity and could have anti-implantation and abotifacient properties in female mice.

[The influence of calcium N-(5-hydroxynicotinoyl)-L-glutamate on reproductive function, prenatal and postnatal development of rats].

The safety of a new nootrope and neuroprotector--calcium N-(5-hydroxynicotinoyl)-L-glutamate (ampasse)--has been evaluated. It is shown that ampasse at a dose of 6.7 mg/kg (10 times the maximum therapeutic dose for humans) did not affect the reproductive function in experimental animals and did not produced any embryotoxic and teratogenic effects.

[Influence of hemicellulose based anticoagulant on male rat reproductive function].

Results of estimation of the effect of a new hemicellulose-based anticoagulant drug on the reproductive function of white male rats are presented. No negative impact on the fertility and breed was observed for the drug administered in doses of 5 and 25 mg/kg. However, in a dose of 50 mg/kg, the new drug negatively affected spermatogenesis and decrease the reproductive function of male rats.

Hazardous apoptotic effects of 2-bromopropane on maturation of mouse oocytes, fertilization, and fetal development.

2-Bromopropane (2-BP) is used as an alternative to ozone-depleting cleaning solvents. Previously, we reported that 2-BP has cytotoxic effects on mouse blastocysts and is associated with defects in subsequent development. Here, we further investigate the effects of 2-BP on oocyte maturation and subsequent pre- and post-implantation development, both in vitro and in vivo. Notably, 2-BP induced a significant reduction in the rates of oocyte maturation, fertilization, and in vitro embryonic development. Treatment of oocytes with 2-BP during in vitro maturation (IVM) resulted in increased resorption of postimplantation embryos and decreased fetal weights. Experiments with a mouse model disclosed that consumption of drinking water containing 20 µM 2-BP led to decreased oocyte maturation in vivo and fertilization in vitro, as well as impairment of early embryonic development. Interestingly, pretreatment with a caspase-3-specific inhibitor effectively prevented 2-BP-triggered hazardous effects, suggesting that embryonic impairment by 2-BP occurs via a caspase-dependent apoptotic process. A study using embryonic stem cells as the assay model conclusively demonstrated that 2-BP induces cell death processes through apoptosis and not necrosis, and inhibits early embryo development in mouse embryonic stem cells. These results collectively confirm the hazardous effects of 2-BP on embryos derived from pretreated oocytes.

Preeclampsia before fetal viability in women with primary antiphospholipid syndrome- materno-fetal outcomes in a series of 7 cases.

INTRODUCTION: Preeclampsia complicates about 10-17 % of pregnancies with antiphospholipid syndrome (APS). It is often severe and might occur sometimes at early gestation. The development of preeclampsia before fetal viability is a huge challenge for obstetricians and demands an intensive discussion regarding the therapeutical options. PATIENTS AND METHODS: We retrospectively reviewed the data of 7 women with primary APS who developed preeclampsia before 24 weeks of gestation. Plasma exchange had been performed in four of the cases and two women received corticosteroids. One of the women had received 20 mg of pravastatin daily, starting at 18 weeks of gestation. Neonatal outcome was: live birth in four cases and IUFD in three cases. The main pediatric complications were noted in a 28-week-old premature born boy, who developed severe IRDS and thrombocytopenia. At the present time, the boy continues to have a retarded status. DISCUSSION: This retrospective analysis revealed that women with APS can develop severe preeclampsia even before 20 weeks of gestation. Several management options for prolongation of pregnancy such as plasma exchange, pravastatin, LMHW, hydroxychloroquine/HCQ, or TNF-alpha blocker should be discussed with the patients. Optimal management of preeclampsia before 24 weeks of gestation usually depends on weighing the maternal and fetal complications from expectant management with prolongation of pregnancy versus the predominant fetal and neonatal risks of extreme prematurity from "aggressive" management with immediate delivery.

Effects of cadmium on the expression of placental lactogens and Pit-1 genes in the rat placental trophoblast cells.

Cadmium is an endocrine disrupter (ED) with detrimental effects on mammalian reproduction. The placenta is a primary target for cadmium toxicity during pregnancy. Very little of this metal crosses the placenta to the fetus, and consequently it accumulates in high concentrations in the placenta. Cadmium affects on steroid synthesis and has estrogen- and androgen-like activities. In this study, we investigated the toxic effects of cadmium on placental trophoblast cells as well as the mRNA levels of placental lactogens (PLs), which are under the control of estrogen and play a pivotal role during pregnancy. Pregnant F344 Fisher rats were injected subcutaneously with 0, 0.2, and 2.0mg/kg BW/day of cadmium (CdCl(2)) dissolved in saline from days 11 to 19 of pregnancy and were sacrificed on day 20. The mRNA levels of the PL-Iv and -II genes and Pit-1alpha and beta isotype genes, the trans-acting factor of PLs, were analyzed by Northern blot hybridization and reverse transcription-polymerase chain reaction, respectively. The frequency of the placental trophoblast cells was observed histochemically. Developmental data and apoptotic chromosomal DNA fragmentation of placental cells were also observed. The mRNA levels of PL-Iv and -II were reduced in a dose-dependent manner by cadmium. The mRNA levels of the Pit-1alpha and beta isotype genes were also reduced by cadmium. In the uterus-conjugated region of the placental junctional zone, the frequency rates of trophoblast cells were lower in the cadmium-treated groups than in the control group. High-dose cadmium exposure (2.0mg) induced not only the reduction of trophoblast cell frequency but also apoptotic chromosomal DNA fragmentation in the junctional zone of the placenta. Developmental metrics such as placental and fetal weights and a number of live fetuses, decreased, while a numbers of resorptions, dead fetuses, and post-implantation losses increased significantly (p<0.05) in the cadmium-treated groups compared to the control. These data suggested that cadmium inhibits the expression of PL genes and reduces the number of trophoblast cells in the rat placenta via an estrogen-like activity, leading to significant toxic effects on placental growth and physiological function in rats.

Evaluation of the safety and pharmacokinetics of the multi-targeted receptor tyrosine kinase inhibitor sunitinib during embryo-fetal development in rats and rabbits.

BACKGROUND: Angiogenesis plays a key role in embryo-fetal development and, based on nonclinical safety data, the majority of vascular endothelial growth factor (VEGF)-targeted antiangiogenic agents used in cancer therapy are not recommended during pregnancy. We investigated the effects of sunitinib (an oral inhibitor of multiple receptor tyrosine kinases [RTKs] including VEGF-receptors) on embryo-fetal development. METHODS: Presumed-pregnant Sprague-Dawley rats and New Zealand White rabbits received repeated daily oral doses of sunitinib (0-30 mg/kg/day), during the major period of organogenesis. Clinical/physical examinations were performed throughout the gestation phase, and blood samples were collected to determine systemic exposure. Necropsy (including uterine examination) was performed on all animals and fetal morphology was examined. RESULTS: The no-observed-adverse-effect level was 1-5 mg/kg/day for maternal toxicity and 3 mg/kg/day for developmental toxicity in rats; 1 and 0.5 mg/kg/day, respectively, in rabbits. Embryo-fetal toxicity included decreases in the number of live fetuses and increases in the numbers of resorptions and post-implantation/complete litter losses; these were observed at doses of > or =5 mg/kg/day in rats and 5 mg/kg/day in rabbits. Malformations included fetal skeletal malformations (generally thoracic/lumbar vertebral alterations) in rats and cleft lip/palate in rabbits. These developmental effects were observed at approximately 5.5- (rats) and approximately 0.3-times (rabbits) the human systemic exposure at the approved sunitinib dose (50 mg/day). CONCLUSIONS: Similar effects have been reported with the prototype monoclonal antibody bevacizumab. As is typically observed for potent inhibitors of RTKs involved in angiogenesis, sunitinib was associated with embryo-fetal developmental toxicity in rats and rabbits at clinically relevant dose levels.

Critical periods for the teratogenicity of immune-suppressant Leflunomide in mice.

Leflunomide has inhibitory effects on dihydroorotate-dehydrogenase activity and protein tyrosine kinase activity. In the present study, a single dose of 50 mg/kg Leflunomide was administered to pregnant mice on one of gestation days (GD)6-11. Characteristic external malformations were craniofacial defects following dosing on GD7, cleft palate on GD9, cleft palate and limb and tail deformities on GD10, and limb deformities on GD11. Skeletal examination revealed cervical to caudal vertebral malformations after treatment on GD7, GD8, GD9 or GD10. In the viscera, cardiovascular deformities were observed in the GD7 and GD9 Leflunomide-treated groups. These results demonstrate that multiple malformations were seen in various organs and most of the malformations observed appeared to be developmental stage-specific responses to Leflunomide treatment.

Exogenous growth differentiation factor 9 in oocyte maturation media enhances subsequent embryo development and fetal viability in mice.

BACKGROUND: Successful oocyte in vitro maturation (IVM) would eliminate the need for hormonal stimulation used in assisted reproduction techniques. Unfortunately, oocytes matured in vitro have compromised developmental competence possibly due to disrupted oocyte-cumulus communication resulting from inappropriate levels of oocyte-secreted factors such as growth differentiation factor 9 (GDF9). Hence, the aim of this study was to investigate the effects of exogenous GDF9 during IVM of mouse oocytes on development and subsequent fetal viability. METHODS: Cumulus-oocyte complexes from pregnant mare's serum gonadotrophin primed mice were cultured with or without 200 ng/ml exogenous recombinant GDF9, 50 mIU/ml FSH and 10 ng/ml epidermal growth factor (EGF). After 18 h, cumulus expansion was scored and oocytes were fertilized in vitro. Cleavage, blastocyst development, blastocyst total, inner cell mass (ICM) and trophectoderm cell numbers were assessed. Viability of embryos was assessed by transfer to recipient females and pregnancy outcome determined at day 15. RESULTS: Oocytes matured with exogenous GDF9 in the presence of FSH and EGF had higher rates of development, percentage of hatching blastocyst and blastocyst total and ICM cell numbers (all P < 0.05). Although implantation rate and fetal and placental weights were not affected, the number of viable fetuses at day 15 was increased with exogenous GDF9. CONCLUSIONS: Exogenous GDF9 during IVM improved embryo development and fetal viability and provides a promising approach for human IVM.

Effect of captopril on uterine blood flow and prostaglandin E synthesis in the pregnant rabbit.

Captopril, 5 mg/kg, administered to pregnant rabbits caused a reduction in mean arterial pressure (MAP) from 106+/-2 to 87+/-2 mmHg (P<0.01) without change in cardiac output or renal blood flow. Uterine blood flow fell from 31.9+/-2.5 to 21.3+/-3.4 ml/min (P<0.01) as uterine vein prostaglandin E series level (PGE) decreased from 127+/-23 ng/ml to 26+/-8 ng/ml (P<0.01). Saralasin also caused a reduction in MAP from 110+/-5 to 92+/-4.3 (P<0.01), a reduction in uterine blood flow from 28.8+/-1.6 to 21.8+/-1.7 ml/min (P<0.01) as uterine vein PGE decreased from 121.3+/-14.4 to 63.5+/-14.2 ng/ml (P<0.01). Plasma renin activity (PRA) was higher in the uterine vein, 11+/-3 ng/ml per h, than peripheral vein, 6+/-1.6 ng/ml per h, (P<0.05), before Captopril and rose in the uterine vein to 90+/-19 ng/ml per h (P<0.01) as peripheral vein PRA rose to 62+/-15 ng/ml per h (P<0.05) after Captopril. After saralasin uterine vein PRA rose from 4.6+/-1.5 to 14.8+/-6.3 ng/ml per h (P<0.05) and peripheral vein PRA rose from 3.7+/-1 to 6.5+/-2.1 (P<0.05). Reducing MAP with MgSO(4) from 98+/-4 to 70+/-2 (P<0.01) caused a significant fall in cardiac output from 695+/-33 to 588+/-49 (P<0.01) without change in renal or uterine blood flow. Uterine vein PGE concentration also did not change significantly following MgSO(4); 80+/-22 ng/ml before and 60+/-27 ng/ml (NS) during the administration of MgSO(4). Chronic administration of Captopril in doses of either 2.5 or 5.0 mg/kg per d from the 15th d of gestation caused an 86% fetal mortality at the lower and a 92% fetal mortality at the higher dose of the drug. These experiments point to the importance of uterine PGE synthesis in maintenance of uterine blood flow and fetal survival during pregnancy and suggest that uterine PGE synthesis is dependent upon angiotensin II. Synthesis of uterine renin and PGE may be necessary for maintenance of uterine blood flow and fetal survival during pregnancy.

Prenatal exposure to cigarette smoke affects the physiology of pedunculopontine nucleus (PPN) neurons in development.

Prenatal exposure to cigarette smoke is known to produce lasting arousal, attentional and cognitive deficits in humans. The pedunculopontine nucleus (PPN), as the cholinergic arm of the reticular activating system (RAS), is known to modulate arousal, waking and rapid eye movement (REM) sleep. REM sleep decreases between 10 and 30 days postnatally in the rat, especially at 12-21 days. Pregnant dams were exposed to 350 ml of cigarette smoke for 15 min, 3 times per day, from day E14 until birth, and the pups allowed to mature. Intracellularly recorded PPN neurons in 12-21 day rat brainstem slices were tested for intrinsic membrane properties, including the hyperpolarization-activated cation current Ih, which is known to drive oscillatory activity. Type II (A-current) PPN cells from 12-16 day old offspring of treated animals had a 1/2max Ih amplitude of (mean +/- SE) 4.1 +/- 0.9 mV, while 17-21 day cells had a higher 1/2max Ih of 9.9 +/- 1.1 mV (p < 0.0001). Cells from 12-16 day old control brainstems had a 1/2max Ih of 1.3 +/- 0.1 mV, which was lower (p < 0.05) than in cells from prenatally treated offspring; while 17-21 day old cells from controls had a 1/2max Ih of 3.3 +/- 0.3 mV, which was also lower (p < 0.01) than in cells from prenatally treated offspring. In addition, changes in resting membrane potential [control -65. +/- 0.9 mV (n=32); exposed -55.0 +/- 1.4 mV (n = 27) (p < 0.0001)], and action potential (AP) threshold [control -56.5 +/- 0.7 mV (n = 32), exposed -47.0 +/- 1.4 mV (n = 27) (p < 0.0001)], suggest that prenatal exposure to cigarette smoke induced marked changes in cells in the cholinergic arm of the RAS, rendering them more excitable. Such data could partially explain the differences seen in individuals whose parents smoked during pregnancy, especially in terms of their hypervigilance and increased propensity for attentional deficits and cognitive/behavioral disorders.

Vitamin E supplementation in phenytoin induced developmental toxicity in rats: postnatal study.

OBJECTIVES: The aim of this study was to test the effect of supranutritional dosage of the natural antioxidant vitamin E (VitE) on phenytoin (PHT) induced developmental toxicity and possible long-term effects in rat offspring. METHODS: PHT (150 mg/kg) was administered by oral gavage daily from day 7 to 18 of gestation and VitE prior to PHT orally on the same days. RESULTS: PHT administration alone resulted in decreased survival rate and lower body weight of pups on day 21 post partum (PP). Moreover, PHT slightly changed somatic growth and pups failed to present dynamic air righting on days 15-20 PP. VitE supplementation did not alleviate these changes but rather induced persisting body weight reduction on the days 21 PP and 100 PP. We observed also decreased brain wet weight in the PHT and VitE + PHT groups compared to controls. CONCLUSIONS: We concluded that prenatal supplementation with 500 mg/kg of VitE did not ameliorate the developmental toxicity of PHT and failed to protect postnatal development of rat offspring. Further, in the group supplemented with VitE, the occurrence of persistent body weight gain depression up to adulthood indicates its possible interference with somatic growth regulation.

Sodium hydrosulfide prevents hypertension and increases in vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 in hypertensive pregnant rats.

Sodium hydrosulfide (NaHS) has presented antihypertensive and antioxidant effects and may reduce circulating soluble fms-like tyrosine kinase-1 (sFlt-1). We examined whether NaHS prevents maternal and fetal detrimental changes in a model of hypertension in pregnancy induced by N(G)-nitro-L-arginine methyl ester (L-NAME). Forty pregnant rats were divided into four groups (n = 10 per group): Norm-Preg, Preg + NaHS, HTN-Preg, or HTN-Preg + NaHS. Systolic blood pressure (SBP), number of viable fetuses, litter size, pups, and placentae weights were recorded. Circulating plasma sFlt-1, vascular endothelial growth factor (VEGF), myeloperoxidase (MPO), trolox equivalent antioxidant capacity (TEAC) levels, and biochemical determinants of nitric oxide (NO) formation were assessed. SBP values were elevated in the HTN-Preg group on gestational days 16, 18, and 20. However, HTN-Preg + NaHS group presented lower SBP values on days 18 and 20. Lower number of viable fetuses and litter size were found only in HTN-Preg group compared to other. Reductions in placental weight were found in HTN-Preg and HTN-Preg + NaHS groups. Increases in fetal weight were found only in Preg + NaHS group. Increases in circulating sFlt-1 and VEGF levels were observed only in HTN-Preg group compared to other. Higher MPO and lower TEAC plasma levels were found in HTN-Preg + NaHS and HTN-Preg groups. NO was diminished in HTN-Preg animals, and NaHS treatment increased NO levels only in hypertensive pregnant animals. Treatment with NaHS prevents hypertension in pregnancy and concomitantly reduces circulating plasma sFlt-1 and VEGF levels; this correlates with improved litter size with more viable fetuses and increase in NO levels. However, these beneficial effects presented no relation with oxidative stress.

The effect of two new immunosuppressive agents, FK506 and didemnin B, in murine pregnancy.

The purpose of this study was to investigate two promising immunosuppressive agents, didemnin B (DB) and FK506 (FK), during pregnancy to assess potential adverse maternal or fetal effects. Pregnant C3H mice were randomized into control and high- and low-dose treatment groups for each drug. Animals received daily injections from day 1 to day 16, and on day 17 of gestation the maternal condition, litter size, fetal resorption rates, and fetal/placental unit weights were determined. Immunoglobulin (IgG) levels were obtained for DB treatment groups. Delayed type hypersensitivity was assessed in virgin females. Both DB and FK had dose-dependent immunosuppressive activity in the DTH assay, and DB caused elevated IgG concentrations. High doses of DB caused diarrhea and maternal wasting with no fetal survival; with low-dose DB, maternal weight gain was depressed, but pregnancy outcome was not different from control animals. High-dose FK had no obvious detrimental effects on maternal health but caused resorption of all fetuses; administration of low-dose FK resulted in a higher number of resorptions, but fetuses that survived did not appear different from controls. We conclude that these immunosuppressive drugs can have adverse effects on pregnancy, but the maternal and fetal toxicity are dose-dependent.

Relationship between reproductive success and male plasma vitellogenin concentrations in cunner, Tautogolabrus adspersus.

The gene for vitellogenin, an egg yolk protein precursor, is usually silent in male fish but can be induced by estrogen exposure. For this reason, vitellogenin production in male fish has become a widely used indicator of exposure to exogenous estrogens or estrogen mimics in the aquatic environment. The utility of this indicator to predict impacts on fish reproductive success is unclear because information on the relationship between male plasma vitellogenin and reproductive end points in male and female fish is limited. In the research reported in this article, we investigated whether the presence of male plasma vitellogenin is a reliable indicator of decreased reproductive success in mature fish. Adult and sexually mature male and female cunner (Tautogolabrus adspersus) were exposed to 17ss-estradiol, ethynylestradiol, or estrone, three steroidal estrogens that elicit the vitellogenic response. Data were gathered and pooled on egg production, egg viability, egg fertility, sperm motility, and male plasma vitellogenin concentrations. All males, including two with plasma vitellogenin levels exceeding 300 mg/mL, produced motile sperm. Neither percent fertile eggs nor percent viable eggs produced by reproductively active fish demonstrated a significant correlation with male plasma vitellogenin concentrations. Male gonadosomatic index and average daily egg production by females showed significant, but weak, negative correlation with male plasma vitellogenin concentrations. Results suggest that male plasma vitellogenin expression is not a reliable indicator of male reproductive dysfunction in adult cunner exposed to estrogens for 2-8 weeks during their reproductive season, at least in relation to capacity to produce motile sperm or fertilize eggs. Male plasma vitellogenin expression may serve as an indicator of reduced female reproductive function caused by estrogen exposure.