Prenatal window of susceptibility to perfluorooctane sulfonate-induced neonatal mortality in the Sprague-Dawley rat

The critical period for increased neonatal mortality induced by perfluorooctane sulfonate (PFOS) exposure was evaluated in the rat. Timed-pregnant Sprague-Dawley rats were treated by oral gavage with 25 mg/kg/d PFOS/K(+) on four consecutive days (gestation days (GD) 2-5, 6-9, 10-13, 14-17, or 17-20) or with 0, 25, or 50 mg/kg/d PFOS/K(+) on GD 19-20. Controls received vehicle (10 ml/kg 0.5% Tween-20) on these days. Maternal weight gain was reduced in treated animals during dosing, as were food and water consumption. Following a 4-day treatment, litter size at birth was unaffected while pup weight was similarly reduced in the three earliest PFOS groups. All PFOS groups experienced decreases in survival while controls remained near 100%. Neonatal survival decreased in groups dosed later during gestation, approaching 100% with dosing on GD 17-20. Most deaths occurred before postnatal day (PND) 4, with the majority in the first 24 hours. Maternal serum PFOS levels on GD 21 were higher in groups exhibiting higher mortality. Following a 2-day treatment, PFOS groups experienced significant pup mortality by PND 1. Neonatal mortality continued through PND 5, when survival was 98, 66, and 3% for the 0, 25, and 50 mg/kg groups, respectively. Pup weight was reduced in treated groups with surviving litters. Gross dissection and histological examination of lungs revealed differences in maturation between control and treated animals on PND 0. We conclude that exposure to PFOS late in gestation is sufficient to induce 100% pup mortality and that inhibition of lung maturation may be involved.     

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.     

Development in the cynomolgus macaque following administration of ustekinumab,a human anti‐il‐12/23p40 monoclonal antibody,during pregnancy and lactation

BACKGROUND: Ustekinumab is a human monoclonal antibody that binds to the p40 subunit of interleukin (IL) 12 and IL‐23 and inhibits their pharmacological activity. To evaluate potential effects of ustekinumab treatment during pregnancy, developmental studies were conducted in cynomolgus macaques. METHODS: Ustekinumab was tested in two embryo/fetal development (EFD) studies and in a combined EFD/pre and postnatal development (PPND) study. In the EFD studies, pregnant macaques (12/group) were dosed with saline or ustekinumab (9 mg/kg IV, 22.5 mg/kg SC, or 45 mg/kg IV or SC during the period of major organogenesis, gestation day [GD] 20–50). Fetuses were harvested on GD100–102 and examined for any effects on development. In the EFD/PPND study, pregnant macaques were injected with saline or ustekinumab (22.5 or 45 mg/kg SC) from GD20 through lactation day 33. Infants were examined from birth through 6 months of age for morphological and functional development. Potential effects on the immune system were evaluated by immunophenotyping of peripheral blood lymphocytes and immunohistopathology of lymphoid tissues in fetuses and infants and by T‐dependent antibody response (TDAR) to KLH and TTX and by DTH response in infants. Ustekinumab concentrations were measured in serum from dams, fetus, and infants and in breast milk. RESULTS: Ustekinumab treatment produced no maternal toxicity and no toxicity in the fetuses or infants, including no effects on the TDAR or DTH responses. Ustekinumab was present in serum from GD100 fetuses and was present in infant serum through day 120 post‐birth. Low levels of ustekinumab were present in breast milk. CONCLUSIONS: Exposure of macaque fetuses and infants to ustekinumab had no adverse effects on pre‐ and postnatal development. Birth Defects Res (Part B) 89:351–363, 2010. © 2010 Wiley‐Liss, Inc.     

Mouse placental prostaglandins are associated with uterine activation and the timing of birth

We explored a potential mechanism linking placental prostaglandins (PGs) with a fall in plasma progesterone and increased expression of uterine activation proteins in the mouse. PG endoperoxide H synthase 2 (PGHS-2) mRNA expression increased in placenta in late gestation in association with an 8-fold increase in PGF(2alpha) concentration, reaching a peak on Gestational Day (GD) 18. This peak coincided with the final descent in plasma progesterone and birth on GD 19.3 +/- 0.2. Implantation of a progesterone-releasing pellet in intact pregnant dams on GD 16 delayed birth at term until GD 20.9 +/- 0.4 and inhibited the GD 18 increase in placental PGF(2alpha) levels in conjunction with a delayed fall in plasma progesterone that reached its lowest level 1 day after term birth. The mRNA levels of uterine activation proteins, connexin-43 (CX-43), oxytocin receptor, PGF(2alpha) receptor (FP), and PGHS-2, and the concentration of uterine PGF(2alpha) all increased at normal term birth. At progesterone-delayed term birth on GD 19.3, even though tissue PGF(2alpha) concentrations were at the same high levels observed at normal term birth, CX-43 and FP mRNA levels were lower than those at normal term birth, thereby possibly contributing to the delay of birth. These data are consistent with the hypotheses that fetal placental PGs affect the timing of birth by hastening luteolysis, that uterine activation initiates labor, and that birth may be delayed by blocking or decreasing the expression of two of the uterine activation proteins.     

Non-invasive faecal steroid monitoring of ovarian and adrenal activity in farmed blue fox (Alopex lagopus) females during late pregnancy, parturition and lactation onset

In the semi-domesticated blue fox, handling stress may influence reproductive performance and increase perinatal pup loss. Ovarian and adrenal steroids were analysed in faecal samples collected from mid-gestation through the first week of lactation in 40 female blue foxes to characterize hormone patterns during this important reproductive period. Daily faecal samples were collected from 40 foxes during 30 pregnancies, one late abortion and nine bred-matched non-pregnancies. Mean concentrations of faecal progestagens over the 10 days before birth were significantly higher in pregnant compared to non-pregnant females (51+/-1.50 microg/g versus 36+/-3.72 microg/g, respectively; P < 0.01). From 10 to 3 days before whelping, total faecal oestrogen concentrations also were higher (P < 0.01) in pregnant (1082+/-41.69 ng/g) than non-pregnant (628+/-72.43 ng/g) foxes, before declining to non-pregnant values (402+/-24.88 ng/g) after parturition. Overall mean faecal corticoid concentrations from 3 to 20 days before whelping differed between pregnant and non-pregnant foxes (128+/-3.11 ng/g versus 103+/-5.86 ng/g, respectively; P < 0.01). Furthermore, in pregnant foxes, corticoid excretion increased further from 2 days before to 3 days after whelping (216+/-13.71 ng/g; P < 0.01). Thereafter, corticoid concentrations were similar between pregnant and non-pregnant females (P > 0.05). In sum, the faecal steroid hormone patterns for oestrogens and progestagens were similar to those previously obtained by analyses of fox serum hormones, with both steroids being higher in pregnant than non-pregnant foxes at the end of gestation. The elevation in corticoid concentrations in pregnant females suggests that adrenal activation is involved in the initiation of parturition in the blue fox. Thus, faecal steroid analyses can be used to monitor ovarian activity during pregnancy and pseudopregnancy in farmed blue fox females.     

Investigation of alkaline phosphatase activity in the serum of pregnant rats

An investigation was undertaken to determine if the placental alkaline phosphatase of the rat enters the maternal circulation and to study some of its characteristics. Unlike human, rat placental alkaline phosphatase was found to be heat labile and the alkaline phosphatase activity in the serum of both pregnant and non-pregnant rats was also found to be heat labile. Also unlike the human, the alkaline phosphatase activity in rat serum does not increase as pregnancy progresses to term. In an endeavour to establish if the rat placental enzyme is present in the serum of the pregnant rat, the characteristics of the enzyme in both placental extracts and serum of non-pregnant and 1-, 2- and 3-week pregnant rats were studied using the techniques of heat stability at 56°, gel filtration through Sephadex columns, disc gel electrophoresis, and L-phenylalanine inhibition. The presence of rat placental alkaline phosphatase in maternal serum could not be positively demonstrated by any of these procedures, suggesting that rat placental alkaline phosphatase does not enter the maternal serum.     

Ontogeny of hematological cell and biochemical profiles in maternal and fetal baboons (Papio species)

The normal ranges of hematological cell profiles and biochemistry are documented in adult non-pregnant, pregnant, juvenile, and neonatal baboons. Despite the extensive use of the baboon as a model for the study of various aspects of pregnancy, there is no data from paired mothers and their fetuses at different stages of gestation. Hematologic and biochemical profile data were obtained from eight non-pregnant female baboons, 37 mothers and 38 fetal baboons at 30 +/- 2, 90 +/- 2, 125 +/- 2, and 175 +/- 2 days of gestation (mean +/- range; dGA; term, 180 dGA). Changes observed in fetal and maternal blood during normal baboon pregnancy were similar to those reported in human pregnancy. The level of alkaline phosphatase was two times higher in fetal blood circulation than that reported in human pregnancy.     

ACTH/MSH(4-10) peptide increases postnatal metabolic activity of EDL muscle following early prenatal administration

ACTH/MSH(4-10) (10 micrograms/kg/b.i.d.; IP), administered to pregnant Sprague-Dawley rats during gestational days (GD) 3 to 12, significantly increased the metabolic activity of extensor digitorum longus (EDL) muscle at postnatal day 14. ACTH/MSH peptide, administered from day of birth to postnatal day 13, had no effect on EDL muscle metabolic activity using the 2,3,5-triphenyltetrazolium chloride indicator. By postnatal day 30, no differences were seen between the early prenatally treated group and saline controls. These results confirm our previous electrophysiological studies that showed that early prenatal ACTH/MSH(4-10) administration accelerates EDL muscle maturation.     

Gestational stage sensitivity to ultrasound effect on postnatal growth and development of mice

BACKGROUND: An experiment was conducted to find out whether ultrasound exposure leads to changes in postnatal growth and development in the mouse. METHODS: A total of 15 pregnant Swiss albino mice were exposed to diagnostic levels of ultrasound (3.5 MHz, 65 mW/cm2, I(SPTP) = 1 mW/cm2 Intensity(Spatial Peak-Temporal Peak), I(SATA) = 240 mW/cm2 Intensity(Spatial Average-Temporal Average)) for 30 min for a single day between days 10 and 18 of gestation (GD 10-18). Virgin female mice were placed with same age group males for mating in the ratio 2 females : 1 male and examined the next morning for the presence of vaginal plug, a sign of successful copulation. The females with vaginal plugs were separated and labeled as 0-day pregnant. Maternal vaginal temperature was also measured. A sham exposed control group of 15 pregnant mice was maintained for comparison. All exposed as well as control animals were left to complete gestation and parturition. Their offspring were used in our further studies. They were monitored during early postnatal life for standard developmental markers, postnatal mortality, body weight, body length, head length, and head width, and growth restriction was recorded up to 6 weeks of age. RESULTS: An exposure to ultrasound induced nonsignificant deviations in the maternal vaginal temperature or developmental markers. Significant low birth weight was observed in the present study, after exposure at GD 11, 12, 14, and 16. However, 14 and 16 days postcoitus during the fetal period appears to be the most sensitive to the ultrasound effect, in view of the number of different effects as well as severity of most of the observed effects when exposed on these gestation days. CONCLUSIONS: The results indicate that diagnostic ultrasound can induce harmful effects on mouse growth and development when given at certain critical periods of gestation.     

Postnatal oxytocin alleviates adverse effects in adult rat offspring caused by maternal malnutrition

Repeated oxytocin administration to adult rats causes a long-term decrease of plasma levels of corticosterone and blood pressure and stimulates growth and fat retention. Maternal undernutrition increases blood pressure and plasma corticosterone in adult offspring. We hypothesized that oxytocin treatment early in life would alleviate adverse effects of intrauterine food restriction. Male pups from ad libitum-fed and food-restricted (fed 60% of ad libitum intake) dams were injected with oxytocin or saline in days 1-14 after birth. At 4 mo, blood pressure, plasma levels of corticosterone, and adiposity were assessed. Oxytocin treatment decreased blood pressure independently of nutrition, whereas the increased plasma levels of corticosterone were lowered to normal levels in food-restricted offspring. Blood pressure and adiposity were not affected by in utero food restriction, whereas birth and adult weight were. In conclusion, postnatal events may alleviate adverse effects caused by in utero food restriction. In contrast to more severe food restriction, a moderate general food restriction during gestation had no effect on blood pressure in the offspring.     

Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR)

Background

Exposure of pregnant mothers to elevated concentrations of circulating testosterone levels is associated with fetal growth restriction and delivery of small-for-gestational-age babies. We examined whether maternal testosterone crosses the placenta to directly suppress fetal growth or if it modifies placental function to reduce the capacity for transport of nutrients to the fetus.

Methods

Pregnant rats were exposed to testosterone propionate (TP; 0.5 mg/kg) by daily subcutaneous injection from gestational days (GD) 15-19. Maternal and fetal testosterone levels, placental nutrient transport activity and expression of transporters and birth weight of pups and their anogenital distances were determined.

Results

This dose of TP doubled maternal testosterone levels but had no effect on fetal testosterone levels. Maternal daily weight gain was significantly lower only on GD 19 in TP treated dams compared to controls. Placental weight and birth weight of pups were significantly reduced, but the anogenital distance of pups were unaffected by TP treatment. Maternal plasma amino acids concentrations were altered following testosterone exposure, with decreases in glutamine, glycine, tyrosine, serine, proline, and hydroxyproline and increases in asparagine, isoleucine, leucine, lysine, histidine and arginine. In the TP dams, placental system A amino acid transport activity was significantly reduced while placental glucose transport capacity was unaffected. Decreased expression of mRNA and protein levels of slc38a2/Snat2, an amino acid transporter, suggests that reduced transporter proteins may be responsible for the decrease in amino acid transport activity.

Conclusions

Taken together, these data suggest that increased maternal testosterone concentrations do not cross the placenta to directly suppress fetal growth but affects amino acid nutrient delivery to the fetus by downregulating specific amino acid transporter activity.     

Maternal Obesity during the Preconception and Early Life Periods Alters Pancreatic Development in Early and Adult Life in Male Mouse Offspring

Maternal obesity induced by a high fat (HF) diet may program susceptibility in offspring, altering pancreatic development and causing later development of chronic degenerative diseases, such as obesity and diabetes. Female mice were fed standard chow (SC) or an HF diet for 8 weeks prior to mating and during the gestational and lactational periods. The male offspring were assessed at birth, at 10 days, and at 3 months of age. The body mass (BM) gain was 50% greater before pregnancy and 80% greater during pregnancy in HF dams than SC dams. Dams fed an HF diet showed higher oral glucose tolerance test (OGTT), blood pressure, serum corticosterone, and insulin levels than dams fed SC. At 10 days of age and at 3 mo old the HF offspring showed greater BM and higher blood glucose levels than the SC offspring. The mean diameter of the islets had increased by 37% in the SC offspring and by 155% in the HF offspring at 10 days of age. The islet mass ratio (IM/PM) was 88% greater in the HF offspring at 10 days of age, and 107% greater at 3 mo of age, compared to the values obtained at birth. The HF offspring had a beta cell mass (BCM)/PM ratio 54% lower than SC offspring at birth. However, HF offspring displayed a 146% increase in the BCM/PM ratio at 10 days of age, and 112% increase at 3 months of age than values at birth. A 3 mo of age, the HF offspring showed a greater OGTT and higher levels of than SC offspring. In conclusion, a maternal HF diet consumed during the preconceptional period and throughout the gestational and lactational periods in mice results in dramatic alterations in the pancreata of the offspring.     

Thyroid hormone levels in rats exposed to alcohol during development

Maternal ingestion of alcohol appears to cause a pattern of congenital anomalies with a reduction of pre- and postnatal growth in the offspring. In order to study the possible implication of thyroid function in the effects of pre- and/or postnatal exposure to alcohol, we have studied serum thyroxine (T4) and triiodothyronine (T3) levels in rats from alcohol-fed mothers during the postnatal period (0-50 days). Blood alcohol levels of ethanol-treated pregnant rats were approximately equal to 20-25 mM and their serum T4 levels were decreased, compared with the pair-fed controls, at 15 and 21 days of gestation. No significant changes were observed in T3 levels. Prenatal alcohol exposure was associated with a decrease in both T4 and T3 levels in pups at birth. Although T4 levels continued reduced in the 40-50 days of the postnatal period, no clear effects were observed on T3 levels during this time. Moreover, the more marked alterations were obtained when the offspring were postnatally and pre + postnatally exposed to alcohol. Significant decreases were found in both T4 and T3 levels following postnatal exposure, except at the 20-25th day when a marked but transient increase in T4 levels was observed. These results indicate that alcohol exposure disturbs the hypothalamo-pituitary-thyroid axis, as measured by T3 and T4 hormone levels, mainly when the rats are exposed during the postnatal period.     

Postnatal development in cynomolgus monkeys following prenatal exposure to natalizumab,an α4 integrin inhibitor

BACKGROUND : Natalizumab is a humanized monoclonal IgG4 antibody to human α4 integrin that blocks the interaction of α4β1 and α4β7 integrins with their ligands, including fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1. Because α4 integrins and their ligands are widely involved in mammalian development, lymphopoeisis, and hematopoiesis, natalizumab may interfere with these processes. METHODS : The effects of prenatal exposure to natalizumab on postnatal development were assessed in cynomolgus monkeys at doses of 0 and 30 mg/kg administered intravenously every other day from gestational day (GD) 20 to 70 or GD 20 to term. Infants were delivered by natural birth and evaluated for general health, survival, development, and immunological structure and function at 12 or 18 months. RESULTS : An increase in abortions was seen in the first cohort of natalizumab-treated dams (39.3 vs. 7.1% in the controls) but not in the second cohort (33.3, 37.5%). Infants in the term treatment group had elevated lymphocyte (∼150%) and nucleated red blood cell counts (∼400%), consistent with the pharmacological effect of natalizumab, and reductions in platelet counts (∼28%), which were reversible following clearance of natalizumab. No anemia was observed. Infants in the term treatment group had significantly increased spleen weights at 12 months but not at 18 months. All other experimental observations in infants from natalizumab-treated dams were comparable with those of controls. CONCLUSION : Natalizumab had no adverse effects on the general health, survival, development, or immunological structure and function of infants born to dams treated with natalizumab during pregnancy. Birth Defects Res (Part B) 86: 144-156, 2009. © 2009 Wiley-Liss, Inc.     

Metallothionein synthesis in foetal, neonatal and maternal rat liver

The synthesis of hepatic metallothionein relative to other cytosol proteins was measured by [35S]cysteine incorporation in foetal, neonatal and pregnant rats. The relative rate of hepatic metallothionein synthesis reached a maximum in foetal liver on days 18-21 of gestation. Metallothionein synthesis then declined until weaning, when adult levels were established. The rate of metallothionein synthesis was greater in pregnant rats at term than in nulliparous rats. To determine if circulating inducing agents could play a role in the regulation of metallothionein synthesis in foetal liver we treated pregnant rats with inducers at a time prior to the normal rise in foetal liver metallothionein synthesis. Injections of copper, cadmium or hydrocortisone to 17-day-pregnant dams failed to induce foetal metallothionein synthesis. In contrast, zinc injection to the dam was an effective inducer in the foetuses. Maternal laparotomy (performed to expose the foetus for direct injection of inducers) induced foetal metallothionein synthesis. Metallothionein synthesis in the livers of 17-day-gestation dams was induced by all metal injections and laparotomy but, surprisingly, not by hydrocortisone injection. Maternal adrenalectomy did not influence the subsequent normal elevation in foetal or maternal metallothionein synthesis. These results, in conjunction with previous reports, suggest that mobilization of zinc in serum during late gestation may regulate foetal and maternal changes in metallothionein synthesis.     

Pharmacology and placental transfer of a human αv integrin monoclonal antibody in rabbits

BACKGROUND: Intetumumab is a human IgG1 anti‐αv‐integrin monoclonal antibody that inhibits angiogenesis. Integrin binding and angiogenesis are important in reproduction including fertilization, implantation, and embryofetal development. These studies were designed to determine the pharmacological relevance of the rabbit for the evaluation of potential effects on embryofetal development and to evaluate the placental transfer of intetumumab in rabbits. METHODS: In vitro pharmacology studies evaluated the binding of intetumumab to rabbit cells and the inhibition of vessel sprouting from rabbit aorta. For the evaluation of placental transfer, pregnant rabbits (8/group) were injected intravenously with intetumumab 50 or 100 mg/kg every 2 days from Gestation Day (GD)7 to GD19. Maternal sera, fetal homogenates/sera, and amniotic fluid were collected at necropsy on GD19 or GD28 for evaluation of intetumumab concentrations. Clinical condition of the dams was monitored and fetuses were screened for abnormalities. RESULTS: Intetumumab (5–40 µg/mL) inhibited aortic cell adhesion to vitronectin and vessel sprouting from rabbit aortic rings. Immunohistochemical staining of rabbit tissues demonstrated binding of intetumumab to placenta. Administration of intetumumab to pregnant rabbits was well tolerated by the dams and the fetuses did not show major abnormalities. Fetal exposure to intetumumab relative to maternal exposure was <0.1% on GD19 and 100–130% on GD29. CONCLUSIONS: The rabbit is a pharmacologically relevant species for evaluation of potential developmental effects of intetumumab. Intetumumab crosses the rabbit placenta during the fetal period (GD 19–28). Birth Defects Res (Part B) 89:116–123, 2010. © 2010 Wiley‐Liss, Inc.     

Effects of growth hormone and hypophysectomy of pregnant rats on serum concentrations of pregnancy-associated murine protein-1

Continuous infusion of bovine GH to hypophysectomized non-pregnant rats increased serum concentrations of pregnancy-associated murine protein-1 (PAMP-1) to the levels of adult female rats and pregnant rats. Serum concentrations of PAMP-1 were followed from Day 16 of gestation until 3 days after parturition in hypophysectomized (on Day 14 of gestation) and intact pregnant rats. In the intact pregnant rat there was a decrease in PAMP-1 values from Day 16 until delivery. The serum concentrations of PAMP-1 in hypophysectomized pregnant rats were similar to those in intact pregnant rats before parturition, but PAMP-1 concentrations decreased markedly after parturition in the hypophysectomized rats. We suggest that the serum concentrations of PAMP-1 can be maintained without pituitary GH in late pregnancy, while serum values of PAMP-1 in non-pregnant rats is dependent upon a continuous secretion of pituitary GH.     

The effects of maternal undernutrition on maternal and fetal serum insulin-like growth factors, thyroid hormones and cortisol in the guinea pig.

The insulin-like growth factors (IGF-I and -II) are potential mediators of the effects of maternal undernutrition on fetal growth and muscle development. The effects of a 40% reduction in maternal feed intake on serum levels of the IGFs, the thyroid hormones and cortisol, were investigated for the last two trimesters (day 25 to birth). This level of undernutrition is known to cause a 35% reduction in fetal and placental weights, and a 20-25% reduction in muscle fibre number. Maternal IGF-I level was greater than non-pregnant levels on day 25 gestation, in both control and restricted dams, and declined with gestational age. The increase in IGF-I level in the 40% restricted group was approximately two-thirds that of control animals. Fetal serum IGF-I was also reduced in undernourished fetuses throughout gestation. Maternal IGF-II did not change with gestational age and was unaffected by undernutrition. Fetal IGF-II reached a peak at day 55 of gestation, this peak was greatly diminished by maternal feed restriction. Both IGF-I and IGF-II tended to be related to fetal, placental and muscle weights at day 65 of gestation. Thyroid hormone concentration declined in maternal serum and increased in fetal serum with increasing gestational age. Levels were not significantly affected by undernutrition. Both triiodothyronine (T3) and thyroxine (T4) were correlated with IGF-I in maternal serum (P < 0.05), but not in fetal serum. Cortisol levels were elevated by undernutrition in both maternal and fetal serum, and increased with gestational age. Cortisol was inversely correlated with serum IGF-I in both maternal and fetal serum. Maternal serum IGF-I may mediate the effects of undernutrition on fetal growth by affecting the growth and establishment of the feto-placental unit in mid-gestation. Fetal IGF-I may mediate the effects on muscle growth, whereas IGF-II seems to be related to hepatic glycogen deposition. Cortisol may play a role via its effect on the IGFs, but the thyroid hormones are unlikely to be important until the late gestation/early postnatal period.     

Characteristics of ceruloplasmin synthesis in embryogenesis and in the early postnatal period of laboratory white rats

The dynamics of ceruloplasmin content was studied by immunochemical methods in the postimplantation rat embryos and postnatal animals. Ten to twenty two day old embryos contained ceruloplasmin (CP) in yolk sac, serum, and amniotic fluid. The highest CP levels were found in yolk sac. CP concentration profiles were almost identical in the serum and amniotic fluid being the highest on the 12th day (0.26 mg%) and the lowest (0.04) on the 16th day of gestation. CP concentration in the serum increased rapidly up to 3.5 mg% from the 17th day of gestation till the term (22nd day) while remaining at a constant and rather low level in the amniotic fluid. Within 16-18 days after birth, CP concentration in the serum remained at the level of 11 +/- 0.3 mg%. Later on it gradually increased and attained plateau (46-48 mg%) by the time of sex maturity. The maternal serum CP does not penetrate, in the embryo, as can be inferred from the experiments with 125I-CP injected into pregnant rats. Differences in the CP degradation rate and modes were found between the embryos and postnatal rats. It is suggested that CP is initially synthesized by the yolk sac endoderm during organogenesis (10-16 days of gestation) and predominantly by the liver during the foetal period (17-22 days).