Fetal hormone and metabolite levels in lean and obese pigs

Early development changes in hormone levels were investigated in strains of pigs with genetic propensities for excessive lipid deposition. Fetal serum growth hormone was lowest in the preobese pigs (Ossabaw and high backfat). Fetal serum triiodothyronine was significantly elevated in the fetal pigs from obese strains. Fetal serum cortisol was highest in the high backfat pigs. There were no statistically significant differences in fetal serum glucagon. Ossabaw (obese) sows have higher serum glucose levels during gestation than low backfat or high backfat sows. This hyperglycemia is reflected in higher serum glucose levels in 110 day old Ossabaw fetal pigs. High backfat sows have higher serum triglyceride levels that low backfat or Ossabaw sows. The Ossabaw fetal pig has lower serum triglycerides than either the high backfat or the low backfat fetuses. These studies characterize early changes in serum metabolites and hormones in pigs which have the genetic propensity for obesity. At 110 days of gestation these pigs are similar in body at content (less than 1%). It is proposed that the lower level of growth hormone in the preobese fetal pig promoted a lower rate of lean body growth and a higher rate of lipid deposition postnatally.     

Role of leptin in the regulation of growth and carbohydrate metabolism in the ovine fetus during late gestation

Leptin is an important regulator of appetite and energy expenditure in adulthood, although its role as a nutritional signal in the control of growth and metabolism before birth is poorly understood. This study investigated the effects of leptin on growth, carbohydrate metabolism and insulin signalling in fetal sheep. Crown–rump length-measuring devices and vascular catheters were implanted in 12 sheep fetuses at 105–110 days of gestation (term 145 ± 2 days). The fetuses were infused i.v. either with saline (0.9% NaCl; n = 6) or recombinant ovine leptin (0.5–1.0 mg kg⁻¹ day⁻¹; n = 6) for 5 days from 125 to 130 days when they were humanely killed and tissues collected. Leptin receptor mRNA and protein were expressed in fetal liver, skeletal muscle and perirenal adipose tissue. Throughout infusion, plasma leptin in the leptin-infused fetuses was 3- to 5-fold higher than in the saline-infused fetuses, although plasma concentrations of insulin, glucose, lactate, cortisol, catecholamines and thyroid hormones did not differ between the groups. Leptin infusion did not affect linear skeletal growth or body, placental and organ weights in utero . Hepatic glycogen content and activities of the gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the leptin-infused fetuses were lower than in the saline-infused fetuses by 44, 48 and 36%, respectively; however, there were no differences in hepatic glycogen synthase activity or insulin signalling protein levels. Therefore, before birth, leptin may inhibit endogenous glucose production by the fetal liver when adipose energy stores and transplacental nutrient delivery are sufficient for the metabolic needs of the fetus. These actions of leptin in utero may contribute to the development of neonatal hypoglycaemia in macrosomic babies of diabetic mothers.     

The late gestation fetal cardiovascular response to hypoglycaemia is modified by prior peri-implantation undernutrition in sheep

Undernourished late gestation fetuses display asymmetric growth restriction, suggestive of a redistribution of nutritional resources. The modification of fetal organ blood supply in response to acute hypoxia is well characterized, but it is not known whether similar responses occur in response to acute reductions in nutrition, or if such late gestation responses can be influenced by early gestation nutrition. In pregnant sheep, total nutrient requirements were restricted during the peri-implantation period (PI40, 40%; PI50, 50% of total, days 1–31) or in late gestation (L, 50% total, days 104–postmortem). Control animals were fed 100% nutrient requirements. Fetal organ blood flows were measured at baseline, and during acute fetal hypoglycaemia induced by maternal insulin infusion at 125 dGA. Baseline heart rate was increased in PI40 fetuses. During hypoglycaemia, an initial rise in fetal heart rate was followed by a slower fall. Fetal femoral artery blood flow decreased, and adrenal blood flow and femoral vascular resistance increased in all fetuses during hypoglycaemia. These changes were accompanied by increased fetal plasma adrenaline and cortisol, and reduced plasma insulin levels. The maximum femoral artery blood flow response to hypoglycaemia occurred earlier in PI50 and PI40 compared with control fetuses. The late gestation fetal cardiovascular response to acute hypoglycaemia was consistent with a redistribution of combined ventricular output away from the periphery and towards central organs. One element of the peripheral vascular response was modified by peri-implantation nutrient restriction, indicating that nutritional challenges early in gestation can have an enduring impact on cardiovascular control.     

Effects of fetal decapitation on the structure and function of leydig cells in rhesus monkeys (Macaca mulatta)

Fetal decapitation in utero has enabled us to study the role of fetal pituitary hormones in the development of the fetal testis. Testes from males decapitated near 80 days of gestational life and later delivered at 150 days were smaller than normal and about one-tenth the normal weight. The size of the seminiferous tubules was similar in both groups; however, the number of Leydig cells seemed reduced. In addition, the Leydig cells of the experimental group contained smaller mitochondria with reduced tubular cristae, fewer lipid droplets, and reduced agranular endoplasmic reticulum. Androgen production was inhibited. Measured by radioimmunoassay, the testosterone level in the umbilical vein was 329 ± 82 pg/ml in six decapitated fetuses, 412 ± 62 pg/ml in ten normal fetuses. The level in the umbilical artery was 328 ± 56 pg/ml in five decapitated fetuses, 658 ± 140 pg/ml in normal fetuses. These studies suggest that chronic deprivation of fetal pituitary hormones inhibits the growth and development of the testis in general and of the Leydig cells in particular.     

Recent observations on the regulation of fetal metabolism by glucose

Glucose is the principal energy substrate for the the fetus and is essential for normal fetal metabolism and growth. Fetal glucose metabolism is directly dependent on the fetal plasma glucose concentration. Fetal glucose utilization is augmented by insulin produced by the developing fetal pancreas in increasing amounts as gestation proceeds, which enhances glucose utilization among the insulin-sensitive tissues (skeletal muscle, liver, heart, adipose tissue) that increase in mass and thus glucose need during late gestation. Glucose-stimulated insulin secretion increases over gestation. Both insulin secretion and insulin action are affected by prevailing glucose concentrations and the amount and activity of tissue glucose transporters. In cases of intrauterine growth restriction (IUGR), fetal weight-specific tissue glucose uptake rates and glucose transporters are maintained or increased, while synthesis of amino acids into protein and corresponding insulin–IGF signal transduction proteins are decreased. These observations demonstrate the mixed phenotype of the IUGR fetus that includes enhanced glucose utilization capacity, but diminished protein synthesis and growth. Thus, the fetus has considerable capacity to adapt to changes in glucose supply by relatively common and understandable mechanisms that regulate fetal metabolism and growth and could underlie certain later life metabolic disorders such as insulin resistance, obesity and diabetes mellitus.     

Effect of feeding on the diurnal rhythm of plasma cortisol and adrenocorticotrophic hormone concentrations in the pregnant ewe and sheep fetus.

The effects of two different feeding regimes on the 24 h profiles of maternal and fetal plasma cortisol and adrenocorticotrophic hormone (ACTH) concentrations were studied in eight pregnant ewes between 123 and 144 days of gestation. Once daily-fed ewes (n = 4) received 1 kg of lucerne-chaff at 11.00 h, and multi-fed ewes (n = 4) received 100-200 g of lucerne-chaff at 09.00, 11.00 and 13.00 h and then 150 g until 09.00 h the following day. There were significant differences between the two feeding groups in the 24 h profile of maternal plasma osmolality; once daily feeding at 11.00 h was associated with a peak in maternal plasma osmolality at 15.00 h whereas maternal plasma osmolality reached plateau levels at around 17.00 h in the multi-fed group. There were also differences between the two feeding groups in the 24 h profiles of maternal and fetal plasma glucose. Maternal and fetal plasma glucose reached peak concentrations at 19.00 h in the once daily-fed ewes in contrast to the multi-fed group, where a plateau in maternal and fetal plasma glucose was reached between 19.00 h and 09.00 h the following day. A significant diurnal variation in the plasma concentrations of cortisol was present in the once daily-fed ewes from 123 days gestation and in their fetuses after, but not before, 135 days gestation. Plasma cortisol peaked at 11.00 h in the ewes and at 13.00 h in the fetuses of this group. In the once daily-fed group there was also a significant diurnal variation in maternal and fetal plasma ACTH; plasma ACTH concentrations were highest at 11.00 h in the ewes aged between 123 and 144 days and in fetuses after 135 days gestation. In the multi-fed group, whilst ACTH was highest at 09.00 h in the ewes and at 13.00 h in the fetuses, there was no significant diurnal variation in the plasma concentrations of cortisol in the ewes or fetuses of this group at any stage between 123 and 144 days gestation.     

Does gender affect human pulmonary gas exchange during exercise?

Fetal growth depends on the transplacental nutrient supply, which, in turn, is determined partially by the consumption and production of nutrients by the uteroplacental tissues. In fetal sheep, the rates of growth and umbilical glucose uptake decline coincidently towards term in parallel with the normal prepartum rise in plasma cortisol. While cortisol is known to reduce growth in fetal sheep, its effects on the uteroplacental handling and delivery of nutrients remain unknown. Hence, this study, quantified the rates of umbilical uptake and uteroplacental consumption of nutrients in preterm fetuses infused with cortisol for 5 days to mimic the prepartum cortisol surge. Umbilical uptakes of glucose and lactate, but not oxygen, were significantly lower in cortisol- than saline-infused fetuses, irrespective of whether values were expressed as absolute or weight-specific rates. The rate of uteroplacental consumption of glucose, but not oxygen, was significantly higher in cortisol- than saline-infused animals. Absolute rates of uteroplacental lactate production were lower in cortisol-infused animals. When all data were combined, fetal plasma cortisol levels were positively correlated to uteroplacental glucose consumption and inversely related to umbilical glucose uptake. Cortisol treatment had no apparent effect on placental mRNA expression for the glucose transporters, GLUT-1 and GLUT-3. The results demonstrate that cortisol is physiological regulator of uteroplacental metabolism and nutrient delivery to the sheep fetus. These observations have important implications for fetal growth both in late gestation and during adverse intrauterine conditions, which raise fetal cortisol levels earlier in gestation.     

Nerve endings in the pulmonary trunk, ductus arteriosus and aorta of intact and decapitated pig fetuses

Summary Nerve fibres reactive to acetyl-thiocholine, and tissues showing catecholamine fluorescence were examined in the pulmonary trunk, ductus arteriosus and aorta of 28 pig fetuses between 31 and 113 days of gestation (term=114±1 days). Eight additional fetuses, which had been decapitated in utero at 40–43 days, were also studied at ages between 51 and 114 days of gestation. Spherical micro-networks of nervous tissue reactive to acetyl-thiocholine are present in the adventitia on the cranial aspect of the pulmonary trunk and ductus arteriosus, between the aorta and pulmonary trunk, and on the caudal aspects of the pulmonary trunk and the pulmonary arteries. These fibres invest spherical clusters of catecholamine containing cells which are well supplied with blood vessels. Nerve fibres which fluoresce are also found in association with these cells. Decapitation in utero does not appear to affect the distribution or morphology of these structures. The observations show that structures are present in the major arteries of the fetal pig which may act as sensory receptors, and that these structures are unaffected by chronic vagotomy of the fetus produced by decapitation early in gestation.     

Development of baroreflex function and hind limb vascular reactivity in the horse fetus

This study investigated, in vivo , the mechanisms underlying the development of cardiovascular function in the horse fetus, with particular relevance to baroreflex function and hind limb vascular arterial reactivity to constrictor agonists. Under general anaesthesia, vascular catheters were inserted and a Transonic flow probe was implanted around one of the metatarsal arteries of 13 horse fetuses, either at 0.6 of gestation ( n = 6) or at 0.9 of gestation ( n = 7, term ∼335 days). At least 5 days after surgery, pressor, vasoconstrictor and cardiac chronotropic responses to exogenous bolus doses of phenylephrine, angiotensin II and arginine vasopressin were recorded. Fetal cardiac baroreflex slopes were obtained using the peak pressor and heart rate responses to increasing doses of phenylephrine. Fetal treatment with phenylephrine, angiotensin II and vasopressin produced significant changes in arterial blood pressure, hind limb vascular resistance and heart rate. Pressor and vasopressor responses to all agonists were greater at 0.9 than at 0.6 of gestation; however, fetal cardiac baroreflex sensitivity decreased with advancing gestational age. Correlation analysis revealed that fetal plasma cortisol rather than gestational age was a greater determinant of pressor and vasopressor reactivity. In contrast, gestational age rather than cortisol better determined heart rate and baroreflex responsiveness in the equine fetus. The data show that development of cardiovascular function in the equine fetus occurs via cortisol-dependent and -independent pathways.     

人胎儿垂体生长激素的个体发生

目的：了解胎儿生长激素合成和分泌的个体发生。方法：采用原位杂交化学方法测定２８例１６－３２周胎儿垂体生长激素信使核糖核酸（ＧＨｍＲＮＡ），用放射免疫分析法测定血清生长激素，甲状腺素、皮质醇和胰岛素的浓度。结果：（１）ＧＨｍＲＮＡ的含量随胎龄逐渐增加，到２４－２６周达高峰。（２）血清生长激素的浓度不恒定，有随胎龄增加而上升的趋势。（３）血清甲状腺素浓度和血清皮质醇的浓度与垂体生长激素ＧＨｍＲＮＡ含量     

Fetal and adult bovine interferon production during bovine viral diarrhea virus infection.

Levels of interferon in adult bovine serum and in fetal bovine serum and tissues were examined during the course of transplacental bovine viral diarrhea virus infection. The cows produced circulating interferon between 2 and 9 days after viral inoculation, with mean peak levels in the serum on day 4. Interferon could be routinely detected in fetal tissues (e.g., thymus, spleen, and kidney) between days 4 and 21 after viral inoculation of the cows at 149 to 150 days of gestation (mid-second trimester) and in fetal serum from day 13 through day 21. Interferon was also detectable in the serum and tissues of fetuses from dams infected at day 95 of gestation (the beginning of the second trimester). In general, no differences were found between the ability of the adult and fetus to produce interferon. Fetal lamb kidney cells were more sensitive to the antiviral effects of bovine interferon than were fetal bovine kidney cells. The antiviral substance from the fetal and adult animals was characterized as interferon by standard criteria.     

The effect of chronic hyperinsulinemia on ovine fetal growth

Infusion of exogenous insulin for 18 days to seven ovine twin fetuses caused hyperinsulinemia (31.0 +/- 6.9 microU/ml) when each was compared to its sham-infused twin (6.6 +/- 0.7 microU/ml). The hyperinsulinemic fetuses also had lower arterial serum glucose concentrations (0.77 +/- 0.07 mM) than their sham-infused controls (1.10 +/- 0.04 mM). There were no significant changes in fetal weight or height attributable to insulin infusion. Our methods would have detected a 12% difference in fetal weight; therefore, the lack of effect of insulin on fetal weights was not due to excessive variability of the difference in weights between twins. Hyperinsulinemia increased the myocardial cellular contents of protein and RNA, which suggested that myocardial hypertrophy occurred; however, heart weight itself was not significantly increased. This apparent contradiction may be due to considerable variability in heart weight. From the above data, we conclude that 19 days of documented ovine fetal hyperinsulinemia does not increase the growth rate of the nearterm ovine fetus.     

Increased uncoupling protein-2 mRNA abundance and glucocorticoid action in adipose tissue in the sheep fetus during late gestation is dependent on plasma cortisol and triiodothyronine

The endocrine regulation of uncoupling protein-2 (UCP2), an inner mitochondrial protein, in fetal adipose tissue remains unclear. The present study aimed to determine if fetal plasma cortisol and triiodothyronine (T₃) influenced the mRNA abundance of UCP2, glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and 2 (11βHSD2) in fetal adipose tissue in the sheep during late gestation. Perirenal–abdominal adipose tissue was sampled from ovine fetuses to which either cortisol (2–3 mg kg⁻¹ day⁻¹) or saline was infused for 5 days up to 127–130 days gestation, or near term fetuses (i.e. 142–145 days gestation) that were either adrenalectomised (AX) or remained intact. Fetal plasma cortisol and T₃ concentrations were higher in the cortisol infused animals and lower in AX fetuses compared with their corresponding control group, and increased with gestational age. UCP2 and GR mRNA abundance were significantly lower in AX fetuses compared with age-matched controls, and increased with gestational age and by cortisol infusion. Glucocorticoid action in fetal adipose tissue was augmented by AX and suppressed by cortisol infusion, the latter also preventing the gestational increase in 11βHSD1 mRNA and decrease in 11βHSD2 mRNA. When all treatment groups were combined, both fetal plasma cortisol and T₃ concentrations were positively correlated with UCP2, GR and 11βHSD2 mRNA abundance, but negatively correlated with 11βHSD1 mRNA abundance. In conclusion, plasma cortisol and T₃ are both required for the late gestation rise in UCP2 mRNA and differentially regulate glucocorticoid action in fetal adipose tissue in the sheep during late gestation.     

Developmental regulation of hepatic and renal gluconeogenic enzymes by thyroid hormones in fetal sheep during late gestation

Tissue glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) activities were investigated in sheep fetuses after experimental manipulation of thyroid hormone status. Increments in hepatic and renal G6P and PEPCK activities seen between 127–130 and 140–145 days of gestation (term, 145 ± 2 days) were abolished when the normal prepartum rise in plasma triiodothyronine (T₃), but not cortisol, was prevented by fetal thyroidectomy (TX). At 127–130 days, hepatic and renal G6P, and renal PEPCK, activities were similar in intact and TX fetuses; however, hepatic PEPCK was increased by TX. At 140–145 days, tissue G6P and PEPCK activities in TX fetuses were lower than in intact fetuses. In immature fetuses infused with cortisol (2–3 mg (kg body wt) ⁻¹ day ⁻¹) for five days, hepatic and renal enzyme activities were increased to those seen in mature fetuses near term. After five days of T₃ infusion (8–12 μg (kg body wt) ⁻¹ day ⁻¹), G6P and PEPCK activities in the liver and kidney were greater than in saline-infused fetuses, but only renal G6P and PEPCK increased to the level seen close to term. Therefore, in fetal sheep, thyroid hormones are important for the prepartum rises in G6P and PEPCK activities in the liver and kidney and may mediate, in part, the maturational effects of cortisol.     

Serological response of the bovine fetus to bovine viral diarrhea virus.

Susceptible pregnant heifers were inoculated with bovine viral diarrhea virus at 150 days of gestation and earlier. Fetuses were surgically collected at selected times after inoculation. Serum immunoglobulins were quantitated, and the presence of specific antibodies was determined. In fetuses from heifers inoculated at 150 days, immunoglobulin M (IgM) appeared approximately 2 weeks after inoculation and was followed in 7 days by IgG1. Later IgG2 was detected in the sera of three fetuses. Serum-neutralizing and complement-fixing antibodies were first detected in a fetus taken at 206 days of gestation. Fetuses taken at later times also had specific serum antibodies. Possible explanations for the appearance of serum immunoglobulin substantially before specific bovine viral diarrhea antibodies include the viral alteration of host tissues rendering them antigenic viral activation of polyclonal B cells, and viral modulation of virus-specific lymphocytes causing specific interference with the appearance of antiviral antibodies. In one of the fetuses having IgG2, the serum also contained IgA. Placental leakage of material immunoglobulins was thought to be responsible for the presence of IgA and IgG2 in this fetus. Small quantities of IgM were found in the serum of two fetuses taken from heifers inoculated between 65 and 95 days of gestation, but specific antibodies were found in none.     

Ontogeny of the Bovine Immune Response

The ontogenesis of the bovine immune response was studied in three embryos (<40 days) and 106 fetuses of various ages. In the absence of overt antigenic stimulation, fetuses had lymphoid development of the thymus at 42 days of gestation, the spleen was structurally present at 55 days, and certain peripheral lymph nodes were present at 60 days. Mesenteric lymph nodes were structurally present by 100 days of gestation, and lymphoid tissue of the gastrointestinal tract, particularly the lower ileum, was observed in histologic sections of a 175-day fetus with a bacterial infection. Pyroninophilic cells, plasma cells, and germinal centers were present in lymph node sections of antigenically stimulated fetuses. Lymphoid tissue developed more rapidly in fetuses with bacteria, viral antigens, or apparent maternal red-blood-cell antigens than in the normal fetus. Thymic and splenic indices reached maximal values in the 205- to 220-day fetal age group. Immunoglobulin M (IgM)-containing cells were first observed, by immunofluorescence, in a single fetus at 59 days of gestation. Immunoglobulin G (IgG)-containing cells were observed at 145 days of gestation in one fetus with a bacterial and viral infection. IgM-containing cells were observed in 36 fetuses and IgM and IgG cells were present in seven fetuses. Spleen, lymph nodes, thymus, bone marrow, and liver of one fetus from a dam with lymphosarcoma had immunoglobulin-containing cells. Hemal lymph nodes, blood (buffy coat), Peyer patches, and heart and lung sections from fetuses with immunoglobulin-containing cells in spleen or lymph node did not have immunoglobulin-containing cells.Antigens of the virus of bovine virus diarrhea-mucosal disease (BVD) were detected in one fetus, and antigens of infectious bovine rhinotracheitis (IBR) virus were detected in three fetuses; however, viruses were not isolated in primary bovine embryonic kidney cells. Two of the three fetuses with IBR virus antigens had neutralizing serum antibody titers to IBR virus. Bacteria including Escherichia coli, Lactobacillus sp. and Mima polymorpha var. oxidans were isolated from four fetuses. Antibodies that caused the agglutination of maternal red blood cells were present in 8 of 20 bovine fetal serum samples. The antibodies were 2-mercaptoethanol sensitive and partially heat resistant (56 C for 30 min). The ontogeny of the bovine immune response and human immune response were compared, and it was suggested that the similarities were primarily due to the two species having the same approximate gestation period of 280 days.     

Expression of insulin-like growth factor binding proteins (IGFBPs) before and during the hormone sensitive period of adipose tissue development in the fetal pig

The present study examined the influence of fetal age and thyroxine (T4) and growth hormone (GH) treatment, on the expression of insulin-like growth factor binding proteins (IGFBPs) in fetal pigs. On day 70 of gestation fetuses were either hypophysectomized (hypox), hypox and implanted with T4 pellets, or left intact, and were recovered 5, 10, 15 and 20 days following hypox and T4 pellet placement. Intact fetuses were also recovered from several dams at 50 days of gestation. In additional dams, hypox fetuses (day 70) were implanted with GH loaded Alzet mini-pumps on day 90, and control, untreated, and GH-treated hypox fetuses were recovered on day 105 of development. Subcutaneous adipose tissue, serum and other fetal tissues were collected at the time of recovery and prepared for subsequent ligand blot analysis with 125I -IGF-1 and immunoblot analysis with IGFBP antibodies. The main effect of IGFBP was significant (P <0.01) for age associated changes in serum IGFBP percentages. Between 50 and 75 days of fetal development the levels of 29 kDa IGFBPs in adipose tissue and serum markedly increased. In contrast, IGFBP-2 levels decreased and IGFBP-4 levels increased in adipose tissue while IGFBP-2 levels increased and levels of IGFBP-4 and -3 decreased in serum. Fetal hypox decreased adipose tissue IGFBP levels in a time and IGFBP-dependent manner. For instance, IGFBP-2 and 29 kDa IGFBP levels decreased much faster after fetal hypox than did IGFBP-3 levels whereas IGFBP-4 levels did not decrease. The main effect of IGFBP was significant (P<0.01) for T4-induced changes in adipose tissue IGFBP levels. T4 treatment increased adipose tissue levels of 29 kDa IGFBPs but did not influence IGFBP-2,-3 and -4 levels. GH treatment had no influence on adipose tissue or serum IGFBP levels. These studies indicate that IGFBP-1 (one of the 29 kDa IGFBPs) may be the major IGFBP mediator of the influence of T4 on fetal development.     

Suppression of adernal cortical growth and differentiation in fetal rats exposed to dexamethasone

The effects of maternal dexamethasone (DEXA) administration during the last days of gestation on fetal adrenal growth and differentiation were studied. Timed pregnant rats were divided into three groups: (a) 21d DEXA-3 received DEXA in drinking water (5 μg/ml) from days 18 to 21 of gestation; (b) 21d DEXA-6 received the same dosage of DEXA from days 15 to 21 of gestation; and (c) 21d control received tap water throughout gestation. On gestation day 21, pregnant rats were decapitated and ble into heparinized tubes; their fetuses were excised, weighed, decapitated, and bled. Fetal adrenals were prepared for electron microscopy or weighed and frozen until assayed for corticosterone. Control adrenals were also collected on day 15 of gestation and processed for electron microscopy only. Fetal adrenals were fixed in 2.5% glutaraldehyde in 0.5 M cacodylate buffer, postfixed in 2% osmium tetroxide (OsO₄), dehydrated, and embedded in Epon 812. Twenty-one day (21d) fetal adrenal weights were 44% and 68% lower than control values for DEXA-3 and -6, respectively. Fetal adrenal corticosterone levels were decreased by 70% and 89% for the respective groups. These observations correlated with ultrastructural findings of decreased mitochondrial number and size, altered orientation of the inner mitochondrial membrane, decreased lipid, and dilation of smooth endoplasmic reticulum (SER) in cortical fascicular cells of DEXA-exposed fetuses. Ultrastructural changes in the 21d DEXA fetal adrenals resembled 15d day control fetal adrenals. The results suggest suppressed adrenocortical differentiation probably due to DEXA inhibition of the steroidogenic influence of the fetal pituitary on the developing adrenal gland in DEXA-exposed fetuses.     

Thymidine and somatomedin-like activity of fetal pig sera: effect of fetal decapitation

The effect of fetal decapitation on porcine serum thymidine and somatomedin activity was studied. Fetal decapitation, at 45 d of gestation, did not alter body weight when compared to controls at 110 d of gestation. Thymidine activity, measured as 3H-thymidine incorporation into rat L6 myoblasts in response to test sera, did not differ between decapitated (D) and control (C) fetal pig sera. Thymidine activity of fetal sera was low when compared to a postnatal normal pig serum pool (NPS) and approximately equal to that of a postnatal hypophysectomized pig serum pool (HPS). Somatomedin-like activity, measured as 35S-sulfate uptake into 110 d fetal costal cartilage, was similar in D and C sera and was low when compared to NPS. Postnatal cartilage, but not fetal cartilage, responded greater to NPS than to HPS when measuring somatomedin activity. This indicates that fetal cartilage may be sensitive to different factors than postnatal pig cartilage. Thymidine activity and somatomedin-like activity were also low in maternal sera when compared to NPS. The concentration of insulin-like growth factor-I (IGF-I) was lower in D sera when compared to C sera (0.26 +/- 0.03 vs 0.62 +/- 0.09 U/ml, respectively, p less than 0.05). It is postulated that locally produced growth factors, compared to circulating growth factors, may be more important determinants controlling the rapid growth rate of the fetus.     

Glucocorticoids and hypothyroidism modulate development of fetal lung insulin receptors

We investigated the development of insulin receptors in membranes of fetal rabbit lung during normal ontogeny and the effect of glucocorticoids and hypothyroidism. Specific binding of 125I-insulin to fetal lung membranes increased progressively to a peak at 29 days gestation, declining by 30 days. Scatchard plots were curvilinear and revealed a progressive increase in receptor numbers (X 10(10)/mg protein) from 129 +/- 7 (mean +/- SE) at 22-24 days to 575 +/- 16 at 29 days, declining to 467 +/- 12 at 30 days, term being approximately 31 days. Affinities did not change throughout gestation and were similar to those of adult lung; receptor numbers in adults were significantly lower than in fetuses at 26-30 days. Epinephrine and PGE1 could evoke a doubling of cAMP production in adult and fetal lung membranes until 29 days. Concomitantly with the fall in fetal insulin receptor number at 30 days, cAMP production in response to epinephrine or PGE1 increased fivefold. Induction of fetal hypothyroidism decreased insulin receptor numbers in the lung of the 28-day fetus by 70% from control (P less than 0.001) without a change in receptor affinity. In contrast, betamethasone administration increased fetal lung insulin receptor numbers by 250% (P less than 0.001) but did not alter their affinity; maternal lung insulin receptors were not altered. Thus, normal ontogeny of the fetal lung insulin receptor is characterized by a progressive increase in number followed by decline immediately before parturition associated with a sharp increase of cAMP responsiveness of the membranes. Hypothyroidism and glucocorticoid exposure can modulate the normal development of the fetal lung insulin receptor.