Ablation of calcitonin/calcitonin gene-related peptide-alpha impairs fetal magnesium but not calcium homeostasis

We used the calcitonin/calcitonin gene-related peptide (CGRP)-alpha gene knockout model (Ct/Cgrp null) to determine whether calcitonin and CGRPalpha are required for normal fetal mineral homeostasis and placental calcium transfer. Heterozygous (Ct/Cgrp(+/-)) and Ct/Cgrp null females were mated to Ct/Cgrp(+/-) males. One or two days before term, blood was collected from mothers and fetuses and analyzed for ionized Ca, Mg, P, parathyroid hormone (PTH), and calcitonin. Amniotic fluid was collected for Ca, Mg, and P. To quantify skeletal mineral content, fetuses were reduced to ash, dissolved in nitric acid, and analyzed by atomic absorption spectroscopy for total Ca and Mg. Placental transfer of (45)Ca at 5 min was assessed. Ct/Cgrp null mothers had significantly fewer viable fetuses in utero compared with Ct/Cgrp(+/-) and wild-type mothers. Fetal serum Ca, P, and PTH did not differ by genotype, but serum Mg was significantly reduced in null fetuses. Placental transfer of (45)Ca at 5 min was normal. The calcium content of the fetal skeleton was normal; however, total Mg content was reduced in Ct/Cgrp null skeletons obtained from Ct/Cgrp null mothers. In summary, maternal absence of calcitonin and CGRPalpha reduced the number of viable fetuses. Fetal absence of calcitonin and CGRPalpha selectively reduced serum and skeletal magnesium content but did not alter ionized calcium, placental calcium transfer, and skeletal calcium content. These findings indicate that calcitonin and CGRPalpha are not needed for normal fetal calcium metabolism but may regulate aspects of fetal Mg metabolism.     

Effect of maternal thyroparathyroidectomy before gestation on fetal development in rats.

Female rats were thyroparathyroidectomized (TPTX) at 24 (immature), 40 (pubertal) and 75 (matured) days of age, at least 21 days before mating. Thyroxine (2.5 microgram/kg) or parathyroid hormone (150 USP units/kg x 2) was replaced in two TPTX groups. Thyroxine deficient groups of all ages had reduced body weight, litter size and serum thyroxine and calcium level. Fetal weights at 20 days of gestation in all thyroxine deficient groups were significantly reduced but placental weight was generally increased. Maternal serum thyroxine and fetal weight was positively related when all groups were taken together, but maternal serum calcium and fetal weight was not related. There were no significant differences in gross, visceral or skeletal anomalies in the fetuses in any group.     

Sexually dimorphic effects of maternal alcohol intake and adrenalectomy on left ventricular hypertrophy in rat offspring

In humans, low birth weight and increased placental weight can be associated with cardiovascular disease in adulthood. Low birth weight and increased placental size are known to occur after fetal alcohol exposure or prenatal glucocorticoid administration. Thus the effects of removing the alcohol-induced increase in maternal corticosterone by maternal adrenalectomy on predictors of cardiovascular disease in adulthood were examined in rats. Alcohol exposure of dams during the last 2 wk of gestation resulted in significantly decreased fetal weight and increased placental weight on gestational day 21. Adult female, but not male, offspring of alcohol-consuming mothers exhibited left ventricular hypertrophy. Placental 11beta-hydroxysteroid dehydrogenase-2 (11beta-HSD-2) mRNA levels, measured by Northern blot, were decreased in females but not males. Adrenalectomy of alcohol-consuming dams reversed the increase in placental weight and the decrease in female placental 11beta-HSD-2 expression and eliminated the left ventricular hypertrophy of adult female offspring. These data suggest that alcohol-induced changes in placental 11beta-HSD-2 mRNA levels and left ventricular weight are coupled in female offspring only and depend on maternal adrenal status.     

Leptin concentrations in cord blood in normal newborn infants and offspring of diabetic mothers.

Leptin has been implicated in the regulation of body weight and energy balance; Leptin is produced by adipocytes and placental tissue. Chronic fetal hyperinsulinemia and accelerated fetal growth with increased amounts of body fat are frequent findings in the offspring of diabetic mothers. In this study, we examined whether leptin levels in cord blood of infants of type 1 diabetic mothers (n = 29), gestational diabetic mothers (n = 6 and controls (n = 96) correlated with level of maternal glucose control, maternal leptin level at delivery, gender, fetal and placental size, and C-peptide in cord blood at birth. Leptin was significantly elevated in infants of type 1 diabetic (24.7 ng/ml) and gestational diabetic mothers (29.3 ng/ml) as compared to controls (7.9 ng/ml). C-peptide was also significantly higher in infants of type 1 diabetic (0.91 nmol/l) and gestational diabetic mothers (0.99 nmol/l) vs controls (0.34 nmol/l). Infants of type 1 diabetic mothers with a leptin level in cord blood above the upper normal range, i.e. > 30 ng/ml (n = 13), had an average maternal HbA1c level of 5.4% (normal < 5.5%) that was not different from 5.2% in infants with a leptin level < 30 ng/ml (n = 15). In both neonatal groups of diabetic mothers, leptin in cord blood did not correlate with maternal leptin concentrations, placental weight, birthweight, gender and cord blood C-peptide. In controls, leptin in cord blood was higher in girls than in boys (p = 0.044) and correlated significantly with birthweight (p = 0.41, p < 0.001) and cord blood C-peptide (p = 0.44, p < 0.001) but not with maternal leptin level or placental weight. The 3-4 times higher leptin levels in the offspring of diabetic mothers than normal could reflect increased adipose tissue mass and/or increased contribution from other sources such as placental tissue.     

Effects of calcium and of the Vitamin D system on skeletal and calcium homeostasis: lessons from genetic models

Targeted deletion of genes encoding the 1,25-dihydroxyVitamin D [1,25(OH)(2)D]-synthesizing enzyme, 25 hydroxyVitamin D-1alpha-hydroxylase [1alpha(OH)ase or CYP27B1], and of the nuclear receptor for 1,25(OH)(2)D, the Vitamin D receptor (VDR), have provided useful mouse models of the inherited human diseases, Vitamin D-dependent rickets types I and II. We employed these models and double null mutants to examine the effects of calcium and of the 1,25(OH)(2)D/VDR system on skeletal and calcium homeostasis. Optimal dietary calcium absorption required both 1,25(OH)(2)D and the VDR. Skeletal mineralization was dependent on adequate ambient calcium but did not directly require the 1,25(OH)(2)D/VDR system. Parathyroid hormone (PTH) secretion was also modulated primarily by ambient serum calcium but the enlarged parathyroid glands which the mutants exhibited and the widened cartilaginous growth plates could only be normalized by the combination of calcium and 1,25(OH)(2)D, apparently independently of the VDR. Optimal osteoclastic bone resorption and osteoblastic bone formation both required an intact 1,25(OH)(2)D/VDR apparatus. The results indicate that calcium cannot entirely substitute for Vitamin D in skeletal and mineral homeostasis but that the two agents have discrete and overlapping functions.     

Effects of low-frequency magnetic fields on fetal development in CBA/Ca mice

Effects of alternating magnetic fields (MFs) on the embryonic and fetal development in CBA/Ca mice were studied. Mated females were exposed continuously to a sinusoidal 50 Hz (13 μT or 0.13 mT root mean square) or a sawtooth 20 kHz (15 μT peak-to-peak) MF from day 0 to day 18 of pregnancy for 24 h/day until necropsied on day 18. Control animals were kept under the same conditions without the MF. MFs did not cause maternal toxicity. No adverse effects were seen in maternal hematology and the frequency of micronuclei in maternal bone marrow erythrocytes did not change. The MFs did not increase the number of resorptions or fetuses with major or minor malformations in any exposure group. The mean number of implantations and living fetuses per litter were similar in all groups. The corrected weight gain (weight gain without uterine content) of dams, pregnancy rates, incidences of resorptions and late fetal deaths, and fetal body weights were similar in all groups. There was, however, a statistically significant increase in the incidence of fetuses with at least three skeletal variations in all groups exposed to MFs. In conclusion, the 50 Hz or 20 kHz MFs did not increase incidences of malformations or resorptions in CBA/Ca mice, but increased skeletal variations consistently in all exposure groups. Bioelectromagnetics 19:477–485, 1998. © 1998 Wiley-Liss, Inc.     

Survival and size are differentially regulated by placental and fetal PKBalpha/AKT1 in mice

The importance of placental circulation is exemplified by the correlation of placental size and blood flow with fetal weight and survival during normal and compromised human pregnancies in such conditions as preeclampsia and intrauterine growth restriction (IUGR). Using noninvasive magnetic resonance imaging, we evaluated the role of PKBalpha/AKT1, a major mediator of angiogenesis, on placental vascular function. PKBalpha/AKT1 deficiency reduced maternal blood volume fraction without affecting the integrity of the fetomaternal blood barrier. In addition to angiogenesis, PKBalpha/AKT1 regulates additional processes related to survival and growth. In accordance with reports in adult mice, we demonstrated a role for PKBalpha/AKT1 in regulating chondrocyte organization in fetal long bones. Using tetraploid complementation experiments with PKBalpha/AKT1-expressing placentas, we found that although placental PKBalpha/AKT1 restored fetal survival, fetal PKBalpha/AKT1 regulated fetal size, because tetraploid complementation did not prevent intrauterine growth retardation. Histological examination of rescued fetuses showed reduced liver blood vessel and renal glomeruli capillary density in PKBalpha/Akt1 null fetuses, both of which were restored by tetraploid complementation. However, bone development was still impaired in tetraploid-rescued PKBalpha/Akt1 null fetuses. Although PKBalpha/AKT1-expressing placentas restored chondrocyte cell number in the hypertrophic layer of humeri, fetal PKBalpha/AKT1 was found to be necessary for chondrocyte columnar organization. Remarkably, a dose-dependent phenotype was exhibited for PKBalpha/AKT1 when examining PKBalpha/Akt1 heterozygous fetuses as well as those complemented by tetraploid placentas. The differential role of PKBalpha/AKT1 on mouse fetal survival and growth may shed light on its roles in human IUGR.     

Bone loss is a physiological cost of reproduction in white-footed mice (Peromyscus leucopus)

Investment in offspring production often requires the mobilization of endogenous resources, a strategy that may negatively impact maternal condition. In mammals, skeletal ossification in growing offspring requires a large investment of calcium by mothers, and bone loss has been described in several species as a means of supporting this demand. Although bone loss can have adverse effects on the mother, its potential role in a reproductive trade-off has not been addressed. Using white-footed mice (Peromyscus leucopus), we tested the effect of dietary calcium availability on maternal skeletal condition during reproduction to assess if calcium availability drives a trade-off between maternal skeletal condition and offspring production. We provided mice with a low-calcium or standard diet and monitored reproductive output along with changes in bone mineral density and bone resorption (via serum concentrations of pyridinoline cross-links) throughout reproduction. Reproductive performance was not impaired by low calcium intake. Reproductive females on the low-calcium diet showed a significant reduction in bone mineral density relative to reproductive females consuming the standard diet and non-reproductive mice consuming the low-calcium diet, but no difference in bone resorptive activity. Our results suggest that when dietary calcium is limited white-footed mice reproduce at the expense of their skeletal condition, and may do so by limiting bone mineral accretion relative to resorption.     

Sex-specific responses in placental fatty acid oxidation,esterification and transfer capacity to maternal obesity

Fatty acid metabolism and oxidation capacity in the placenta, which likely affects the rate and composition of lipid delivered to the fetus remains poorly understood. Long chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), are critical for fetal growth and brain development. We determined the impact of maternal obesity on placental fatty acid oxidation, esterification and transport capacity by measuring PhosphatidylCholine (PC) and LysoPhosphatidylCholine (LPC) containing DHA by mass spectrometry in mother-placenta-baby triads as well as placental free carnitine and acylcarnitine metabolites in women with normal and obese pre-pregnancy BMI. Placental protein expression of enzymes involved in beta-oxidation and esterification pathways, MFSD2a (lysophosphatidylcholine transporter) and OCTN2 (carnitine transporter) expression in syncytiotrophoblast microvillous (MVM) and basal (BM) membranes were determined by Western Blot. Maternal obesity was associated with decreased umbilical cord plasma DHA in LPC and PC fractions in male, but not female, fetuses. Basal membrane MFSD2a protein expression was increased in placenta of males of obese mothers. In female placentas, despite an increased MVM OCTN2 expression, maternal obesity was associated with a reduced MUFA-carnitine levels and increased esterification enzymes. We speculate that lower DHA-PL in fetal circulation of male offspring of obese mothers, despite a significant increase in transporter expression for LPC-DHA, may lead to low DHA needed for brain development contributing to neurological consequences that are more prevalent in male children. Female placentas likely have reduced beta-oxidation capacity and appear to store FA through greater placental esterification, suggesting impaired placenta function and lipid transfer in female placentas of obese mothers.     

Role of primary and secondary maternal viremia in transplacental guinea pig cytomegalovirus transfer.

The modulation of the outcome of intrauterine guinea pig cytomegalovirus (GPCMV) infection by maternal viremia was investigated in the guinea pig model. Virus assay and in situ hybridization were used to study GPCMV infection of maternal blood, placentas, and fetuses following inoculation of pregnant guinea pigs by the subcutaneous, intracardiac, or intranasal route. Animals were inoculated in early gestation and were evaluated every 7 to 10 days throughout pregnancy. Although placental and fetal infections occurred in all groups examined, transfer of GPCMV to placentas and fetuses was most efficient in mothers inoculated subcutaneously. Primary viremia was followed by virus clearance from blood and by an episode of secondary viremia in the three groups of mothers examined. Placental and fetal infections in animals infected subcutaneously or intracardially were first detected at the time of primary viremia, persisted throughout gestation, and increased during secondary viremia. In contrast, placental and fetal infections in animals inoculated intranasally were demonstrated primarily during secondary viremia. Fetal infection was detected in all mothers with detectable primary and secondary viremia but in only 33% of mothers that experienced only primary viremia. These results suggest that secondary maternal viremia is associated with increased placental and fetal GPCMV infections.     

Fetal and placental traits at day 35 of pregnancy in relation to the estrogen receptor genotype in pigs

Fetuses from gilts with estrogen receptor (ESR) genotype AA (AA-AA and AA-AB) and BB (BB-AB and BB-BB) were compared at Day 35/36 of pregnancy, to examine whether fetal ESR genotype nested within maternal ESR genotype would affect fetal traits. Furthermore the relation of fetal body weight and fetal heart weight to various placental traits were evaluated relative to ESR genotype. Fetal and placental weight and length, and implantation surface area were not affected by fetal ESR genotype nested within maternal ESR genotype. Fetal weight was related similarly to placental length, placental weight, and implantation surface area: up to a certain threshold value (40 cm, 40 g and 250 cm2, respectively), an increase in the trait was associated with an increase of fetal weight. Thereafter, fetal weight did not change anymore. Thus, at Day 35/36 of pregnancy porcine fetuses seem to have a maximum growth potential. The percentage of AA-AA fetuses that had not reached this maximum growth potential was larger than of the other three genotype combinations studied, and therefore a higher subsequent fetal mortality may be expected in this group. Hearts of AA-AB fetuses were significantly heavier than those of BB-AB and BB-BB fetuses and tended to be heavier than those of AA-AA fetuses. The reason for this hypertrophy is unclear, but might be related to a difference in placental vascularity. Heart weight of fetuses from BB gilts increased with fetal weight, while heart weights of fetuses from AA gilts did not. Heart weight increased with an increase of placental length and implantation surface area up to 51 cm and 437 cm2, respectively, and thereafter decreased again. For BB-AB fetuses a similar relation was found between heart weight and placental weight, while heart weight of the other three genotype combinations remained unaffected as placental weight increased. The fetus and placenta are continuously changing during early pregnancy, therefore different mechanisms may change the demands for cardiac output. However, keeping in mind that placental size and blood volume are relatively large, placental vascularity and vascular development may play a major role. Therefore, further research on heart size, placental size and vascularity, relative to ESR genotype, is recommended.     

Parental Diabetes: The Akita Mouse as a Model of the Effects of Maternal and Paternal Hyperglycemia in Wildtype Offspring

Aim/Hypothesis

Maternal diabetes and high-fat feeding during pregnancy have been linked to later life outcomes in offspring. To investigate the effects of both maternal and paternal hyperglycemia on offspring phenotypes, we utilized an autosomal dominant mouse model of diabetes (hypoinsulinemic hyperglycemia in Akita mice). We determined metabolic and skeletal phenotypes in wildtype offspring of Akita mothers and fathers.

Results

Both maternal and paternal diabetes resulted in phenotypic changes in wildtype offspring. Phenotypic changes were more pronounced in male offspring than in female offspring. Maternal hyperglycemia resulted in metabolic and skeletal phenotypes in male wildtype offspring. Decreased bodyweight and impaired glucose tolerance were observed as were reduced whole body bone mineral density and reduced trabecular bone mass.Phenotypic changes in offspring of diabetic fathers differed in effect size from changes in offspring of diabetic mothers. Male wildtype offspring developed a milder metabolic phenotype, but a more severe skeletal phenotype. Female wildtype offspring of diabetic fathers were least affected.

Conclusions

Both maternal and paternal diabetes led to the development of metabolic and skeletal changes in wildtype offspring, with a greater effect of maternal diabetes on metabolic parameters and of paternal diabetes on skeletal development. The observed changes are unlikely to derive from Mendelian inheritance, since the investigated offspring did not inherit the Akita mutation. While fetal programming may explain the phenotypic changes in offspring exposed to maternal diabetes in-utero, the mechanism underlying the effect of paternal diabetes on wildtype offspring is unclear.     

Teratogenicity of zinc deficiency in the rat: study of the fetal skeleton

Zinc deficiency (ZD) is teratogenic in rats, and fetal skeletal defects are prominent. This study identifies fetal skeletal malformations that affect calcified and non-calcified bone tissue as a result of gestational zinc deficiency in rats, and it assesses the effect of maternal ZD in fetal bone calcification. Pregnant Sprague-Dawley rats (180-250 g) were fed 1) a control diet (76.4 micrograms Zn/g diet) ad libitum (group C), 2) a zinc-deficient diet (0 microgram/g) ad libitum (group ZD), or 3) the control diet pair-fed to the ZD rats (group PF). On day 21 of gestation, laparotomies were performed. Fetuses were weighed, examined for external malformations, and stained in toto with a double-staining technique for the study of skeletal malformations. Maternal and fetal tissues were used for Zn, Mg, Ca, and P determinations. Gross external malformations were present in 97% of the ZD fetuses. No external malformations were found in fetuses from groups C and PF. Ninety-one percent of cleared ZD fetuses had multiple skeletal malformations, whereas only 3% of the fetuses of group PF had skeletal defects; no skeletal malformations were found in fetuses from group C. Some of the skeletal malformations described in the ZD fetuses, mainly affecting non-calcified bone, were not mentioned in previous reports, thus stressing the importance of using double-staining techniques. Examination of stained fetuses and counting of ossification centers revealed important calcification defects in ZD fetuses. These effects were confirmed by lower Ca and P concentrations in fetal bone with alteration of the Ca:P ratio.     

1,25-Dihydroxyvitamin D3 injections into rat fetuses : effects on fetal plasma calcium, plasma phosphate and mineral content

The in vivo effects of 1,25-(OH)2D3 were assessed using fetuses from normal and thyroparathyroidectomized (TPTX) pregnant rats. 21.5-day old decapitated fetuses from TPTX mothers exhibited lowered basal plasma calcium, elevated basal plasma phosphate and an increased percentage of total ash compared to intact littermates. In decapitated fetuses from normal mothers, neither plasma calcium nor plasma phosphate was changed. Subcutaneous injection of 1 micrograms of 1,25-(OH)2D3/kg of body weight to 19.5-day old fetuses (intact or deprived of their parathyroid glands by decapitation) from TPTX mothers induced a marked rise in plasma calcium levels (2.01 and 3.66 mg/dl, respectively) 48 h later. Little change occurred in fetuses from normal mothers (1.06 mg/dl in decapitated and no change in intacts). A decrease in plasma phosphate levels was observed with the same dose in both decapitated and intact fetuses from TPTX mothers (- 1.39 and - 0.65 mg/dl, respectively), while no modification was found in fetuses from normal females. Therefore, the hypersensitivity of fetuses from TPTX mothers to 1,25-(OH)2D3 was unrelated to the development of the fetal hyperparathyroidism secondary to maternal TPTX. The percentage of ash was unchanged in decapitated fetuses from TPTX mothers and was increased in intact littermates after 1,25-(OH)2D3 treatment. However, these values for total ash may represent alterations in bones and/or soft tissues.     

Perturbations in the biochemical composition of fetal fluids are apparent in surviving bovine somatic cell nuclear transfer pregnancies in the first half of gestation

Amniotic and allantoic fluid volumes and composition change dynamically throughout gestation. Cattle that are pregnant with somatic cell nuclear transfer (NT) fetuses show a high incidence of abnormal fluid accumulation (particularly hydrallantois) and fetal mortality from approximately midgestation. To investigate fetal fluid homeostasis in these pregnancies, Na, K, Cl, urea, creatinine, Ca, Mg, total PO(4), glucose, fructose, lactate, total protein, and osmolalities were measured in amniotic and allantoic fluids collected at Days 50, 100, and 150 of gestation from NT pregnancies and those generated by the transfer of in vitro-produced embryos or by artificial insemination. Deviations in fetal fluid composition between NT and control pregnancies were apparent after placental and fetal organ development, even when no gross morphological abnormalities were observed. Individual NT fetuses were affected to varying degrees. Elevated allantoic Na was associated with lower K and increased allantoic fluid volume or edema of the fetal membranes. Total PO(4) levels in NT allantoic and amniotic fluid were elevated at Days 100 and 150. This was not accompanied by hypophosphatemia at Day 150, suggesting that PO(4) acquisition by NT fetuses was adequate but that its readsorption by the kidneys may be impaired. Excessive NT placental weight was associated with low allantoic glucose and fructose as well as high lactate levels. However, the fructogenic ability of the NT placenta appeared to be normal. The osmolality of the fetal fluids was maintained within a narrow range, suggesting that the regulation of fluid composition, but not osmolality, was impaired in NT pregnancies.     

The Effect of Locomotion on the Mobilization of Minerals from the Maternal Skeleton

Bone is a dynamic tissue from which minerals are deposited or withdrawn according to the body’s demand. During late pregnancy and lactation, female mammals mobilize mineral from bone to support the ossification of offspring skeleton(s). Conversely, in response to mechanical loading, minerals are deposited in bone enabling it to develop a stronger architecture. Despite their central importance to reproductive performance and skeletal integrity, the interactions between these potentially opposing forces remains poorly understood. It is possible that inter-individual differences in the loading imposed by different forms of locomotion may alter the amount of mineral mobilized during reproduction. Here, the impact of vertical versus horizontal locomotion on bone mobilization was examined during reproduction in the laboratory mouse. The vertical, or climbing, group had access to a 60-cm tower, increasing strain on their appendicular skeleton. The horizontal, or tunnel, group had access to a 100-cm tunnel, which encouraged movements within the horizontal plane. Form of locomotion did not impact the amount of bone females mobilized during reproduction or the amount of mineral females deposited in the litter, but maternal bone architecture differed between groups. The climbing group displayed more trabeculae than the tunnel group, whereas the tunnel group displayed greater cortical bone mineral density mid-shaft. Interestingly, pups born to mothers in the climbing group had a higher concentration of total body calcium at 16 days than pups of mothers in the tunnel group. As maternal total body calcium composition and the amount of calcium invested in the full litter were not different between groups, the difference in the relative calcium content of pups between groups is not suspected to reflect difference in mineral allocation. Future research should consider the impact of maternal activity on the efficiency of offspring skeletal ossification via hormones and other bioactive factors transferred in utero and in milk.     

Transplacental 45Ca and 32P flux in the guinea pig: effect of maternal hypercalcaemia and hypocalcaemia

Transplacental 45Ca and 32P flux was measured across the in situ perfused guinea-pig placenta under conditions of acute maternal hypocalcaemia and hypercalcaemia. Maternal hypercalcaemia induced acutely by calcium gluconate infusion caused an increase in maternal-to-fetal 45Ca flux which was proportional to the increase in maternal plasma ionized calcium concentration. Acute maternal hypocalcaemia was induced by EGTA infusion and resulted in a decrease in maternal plasma ionized calcium concentration proportional to a corresponding decrease in transplacental 45Ca transfer. A bolus of calcium gluconate caused a transient decrease in 32P flux, whereas EGTA administration was without significant effect on transplacental 32P transfer. Calcium transport across the placenta is not saturated under conditions of maternal normocalcaemia and may be altered according to acute changes in maternal plasma calcium concentration. Thus, control of maternal-to-fetal calcium transfer does not appear to be at the placental level. This suggests that fetal calcium homeostasis may be regulated by the fetus itself.     

Paternal Genetic Contribution Influences Fetal Vulnerability to Maternal Alcohol Consumption in a Rat Model of Fetal Alcohol Spectrum Disorder

Background

Fetal alcohol exposure causes in the offspring a collection of permanent physiological and neuropsychological deficits collectively termed Fetal Alcohol Spectrum Disorder (FASD). The timing and amount of exposure cannot fully explain the substantial variability among affected individuals, pointing to genetic influences that mediate fetal vulnerability. However, the aspects of vulnerability that depend on the mother, the father, or both, are not known.

Methodology/Principal Findings

Using the outbred Sprague-Dawley (SD) and inbred Brown Norway (BN) rat strains as well as their reciprocal crosses, we administered ethanol (E), pair-fed (PF), or control (C) diets to the pregnant dams. The dams'' plasma levels of free thyroxine (fT4), triiodothyronine (T3), free T3 (fT3), and thyroid stimulating hormone (TSH) were measured to elucidate potential differences in maternal thyroid hormonal environment, which affects specific aspects of FASD. We then compared alcohol-exposed, pair fed, and control offspring of each fetal strain on gestational day 21 (G21) to identify maternal and paternal genetic effects on bodyweight and placental weight of male and female fetuses.

Conclusions

SD and BN dams exhibited different baseline hypothalamic-pituitary-thyroid function. Moreover, the thyroid function of SD dams was more severely affected by alcohol consumption while that of BN dams was relatively resistant. This novel finding suggests that genetic differences in maternal thyroid function are one source of maternal genetic effects on fetal vulnerability to FASD. The fetal vulnerability to decreased bodyweight after alcohol exposure depended on the genetic contribution of both parents, not only maternal contribution as previously thought. In contrast, the effect of maternal alcohol consumption on placental weight was consistent and not strain-dependent. Interestingly, placental weight in fetuses with different paternal genetic contributions exhibited opposite responses to caloric restriction (pair feeding). In summary, these novel findings demonstrate both maternal and paternal genetic contributions to in utero vulnerability to alcohol, refining our understanding of the genetically-based heterogeneity seen in human FASD.     

Fetal and placental weight relationships in the albino rat near term.

The relationship of fetal weight to placental weight was examined in 34 albino rats on day 22 of gestation. The influence of maternal weight, fetal position and the number of fetuses in the litter and each uterine horn were assessed also. There was no indication that rats with heavier placentas had heavier or lighter fetuses. However, within each litter, placental weight was weakly correlated (r = 0.297, p less than 0.01) with fetal weight. Maternal weight at mating, although positively related to the number of corpora lutea, was not related to mean fetal or placental weight. The number of fetuses in the litter was negatively related to placental weight but there was no apparent relation to fetal weight. Fetuses and placentas at the ovarian end of the horn were significantly lighter than those at the vaginal end. The strength of the fetal weight:placental weight correlation in the rat is compared to those in other species.