Oxytocin-induced parturition in copper-deficient guinea pigs.

Dietary copper-deficient guinea pig dams (0.8 microgram Cu/g diet) were administered oxytocin to induce delivery of pups, whereas dietary copper-sufficient guinea pig dams (5.8 micrograms Cu/g diet) had uneventful deliveries with 79% surviving pups. The copper-deficient dams carried the fully-formed fetuses to term but did not go into labor unless 0.5 to 6.2 U oxytocin was administered (i.m.). Birth of live pups from copper-deficient dams increased from 28% overall, to 50% if oxytocin was administered in a timely manner. Many pups died of internal hemorrhages probably the result of defective connective tissue crosslinks requiring copper as a co-factor for lysyl oxidase activity. Dietary copper deficiency may be a factor in depressed parturition in the copper-deficient guinea pig dam that responds to administration of exogenous oxytocin for delivery of pups.     

Possible role for prostacyclin in human parturition.

Human amnion, chorion, decidua and placenta produced 6-oxo-PGF1alpha when superfused in vitro. Furthermore amnion, an avascular tissue, produced more 6-oxo-PGF1alpha after labour than all other tissues investigated and its production of 6-oxo-PGF1alpha was significantly greater after labour than before the onset of labour. These findings suggest that prostacyclin production by foetal membranes may have a role in the mechanisms controlling human parturition. Moreover, this is the first evidence for the production of prostacyclin by an avascular tissue.     

Ability of nifedipine to prolong parturition in rats.

Rats were randomly assigned to treatments: (i) no surgery control; (ii) saline control; (iii) 0.25, 0.5, 1.0 or 2.0 micrograms nifedipine kg-1 min-1; or (iv) 5.0 micrograms ritodrine kg-1 min-1. All drug treatments increased the interval between pup deliveries compared with the no surgery and saline controls. Apparent complete tocolysis was observed in 20, 60, 80 and 80% of the animals receiving 0.5, 1.0 or 2.0 micrograms nifedipine kg-1 min-1 or 5.0 micrograms ritodrine kg-1 min-1, respectively. A positive pharmacodynamic relationship was observed for the nifedipine doses. Analysis of pup viability showed no statistically significant difference among treatments. Treatment with 2.0 micrograms nifedipine kg-1 min-1 gave a delay in pup delivery comparable to that with ritodrine.     

Diethylstilbestrol-induced perinatal lethality in the rat. II. Perturbation of parturition

Evidence is presented suggesting that the fetolethal properties of diethylstilbestrol (DES) are indirect, mediated maternally through a perturbation of the normal mechanisms of parturition. Oral administration of the compound to Sprague-Dawley rats near Day 18 of pregnancy was shown to delay the onset of parturition, prolong labor, and induce dystocia, with a concomitant large increase in perinatal mortality. Exposure during Days 8-16 was without effect, whereas treatment in the Day 18-20 interval resulted in preterm delivery. Inability to initiate labor at term, accompanied by fetal death, also resulted from the administration of hCG on Days 16-18. The relative incidence of stillbirths in DES-exposed pups was markedly decreased by Caesarean delivery. The average weight of the maternal pituitary gland was not affected by treatment, whereas maternal adrenal glands were 30% larger. Maternal blood levels of corticosterone were not significantly elevated, however. The average number of follicles on Day 21 was significantly reduced by DES, and a histological analysis failed to demonstrate a luteotropic effect of the compound. In dams treated on Days 8-18, serum progesterone was reduced by as much as 60%, and total estrogens were 32% lower than in controls. We conclude that DES acts in the rat to depress the preterm levels of steroid hormones, which leads to a failure of uterine contraction accompanied by placental detachment and fetal death.     

Initiation of adenovirus DNA replication.

In an attempt to study the mechanism of initiation of adenovirus DNA replication, an assay was developed to investigate the pattern of DNA synthesis in early replicative intermediates of adenovirus DNA. By using wild-type virus-infected cells, it was possible to place the origin of adenovirus type 2 DNA replication within the terminal 350 to 500 base pairs from either of the two molecular termini. In addition, a variety of parameters characteristic of adenovirus DNA replication were compared with those obtained in a soluble nuclear extract competent for viral DNA replication. It was observed that in vitro DNA replication, which is dependent on the exogenously added viral DNA-protein complex as its optimal template, occurs in a manner apparently indistinguishable from the situation in virus-infected cells. This includes the presence of proteinaceous material on the molecular termini of newly initiated viral DNA.     

Lactogenesis in the rat. Changes in metabolic parameters at parturition

1. Tissue concentrations of nucleic acids, protein, fat, water, metabolites and lactose, and the activities of seven enzymes concerned in milk biosynthesis, were measured in the rat mammary gland at closely spaced times before, at and after parturition. 2. Changes are seen in the tissue concentrations of most substances, and several changes are initiated at least during the day preceding parturition. 3. Lactose, which is absent 1 day before parturition, is found in amounts of 12μmoles/g. fresh wt. of tissue at parturition. 4. From the tissue activities before parturition of three enzymes on the biosynthetic pathway of lactose, and, from the small changes observed in their activities at parturition itself, it is concluded that the factors responsible for the appearance of lactose at parturition remain to be demonstrated.     

Initiation of methyl-directed mismatch repair.

Escherichia coli MutH possesses an extremely weak d(GATC) endonuclease that responds to the state of methylation of the sequence (Welsh, K. M., Lu, A.-L., Clark, S., and Modrich, P. (1987) J. Biol. Chem. 262, 15624-15629). MutH endonuclease is activated in a reaction that requires MutS, MutL, ATP, and Mg2+ and depends upon the presence of a mismatch within the DNA. The degree of activation correlates with the efficiency with which a particular mismatch is subject to methyl-directed repair (G-T greater than G-G greater than A-C greater than C-C), and activated MutH responds to the state of DNA adenine methylation. Incision of an unmethylated strand occurs immediately 5' to a d(GATC) sequence, leaving 5' phosphate and 3' hydroxy termini (pN decreases pGpAp-TpC). Unmethylated d(GATC) sites are subject to double strand cleavage by activated MutH, an effect that may account for the killing of dam- mutants by 2-aminopurine. The mechanism of activation apparently requires ATP hydrolysis since adenosine-5'-O-(3-thiotriphosphate) not only fails to support the reaction but also inhibits activation promoted by ATP. The process has no obligate polarity as d(GATC) site incision by the activated nuclease can occur either 3' or 5' to the mismatch on an unmethylated strand. However, activation is sensitive to DNA topology. Circular heteroduplexes are better substrates than linear molecules, and activity of DNAs of the latter class depends on placement of the mismatch and d(GATC) site within the molecule. MutH activation is supported by a 6-kilobase linear heteroduplex in which the mismatch and d(GATC) site are centrally located and separated by 1 kilobase, but a related molecule, in which the two sites are located near opposite ends of the DNA, is essentially inactive as substrate. We conclude that MutH activation represents the initiation stage of methyl-directed repair and suggest that interaction of a mismatch and a d(GATC) site is provoked by MutS binding to a mispair, with subsequent ATP-dependent translocation of one or more Mut proteins along the helix leading to cleavage at a d(GATC) sequence on either side of the mismatch.     

Studies on the role of zinc in parturition in the rat.

1. Pregnant rats were fed either low (less than 1 p.p.m.) Zn or control (40 p.p.m. Zn) diets from day 10 of gestation. They were killed at intervals during the last 96 h preceding the normal time for onset of parturition, and differences in plasma progesterone, oestradiol-17 beta and ovarian 20 alpha-hydroxysteroid dehydrogenase were assessed. 2. Gestation was prolonged in Zn-deficient rats. 3. Although the preparturient decline in plasma progesterone began at the same time in all groups, at term, plasma progesterone concentration in Zn-deficient rats remained significantly higher than in normal females. 4. Induction of ovarian 20 alpha-hydroxysteroid dehydrogenase activity was delayed by about 8 h by Zn deficiency. This delay was not observed if prostaglandin F2 alpha was injected previously. 5. The results suggest a Zn-dependent step(s) in uterine synthesis and/or release of prostanoids.     

Selective induction of parturition in cattle

Sixty pregnant beef cows 2 to 10 yrs of age were assigned to a control or treated group. Treated cows received 3.5 mg of flumethasone at 1600 hrs on each consecutive Monday, beginning 20 to 2 days prior to expected term and continuing until parturition occurred. Cows were successfully induced with 1, 2 or 3 treatments of flumethasone. Cows requiring 2 or more treatments (7 days apart) to induce parturition had parturition limited to only 2 days a week. Induction treatments resulted in: shorter gestations (P=.001); no reduction in birth weights; no increase in calving difficulty; improved calf vigor (P=.058) and increased incidence of retained placenta (P=.024).     

Genetic influences on premature parturition in an Australian twin sample.

We investigated possible genetic influences on women's liability to preterm birth, using data from a large sample of Australian female twin pairs. In a 1988-90 questionnaire survey, both members of 905 parous twin pairs (579 monozygotic and 326 dizygotic) reported on whether deliveries had been more than two weeks preterm. Tetrachoric twin pair correlations for first birth were rMZ = 0.20+/-0.11 and rDZ = -0.03+/-0.14, and for any birth were rMZ = 0.30+/-0.08 and rDZ = 0.03+/-0.11. Best-fitting models to data contained only additive genetic influences and individual environmental effects. Heritability was 17% for preterm delivery in first pregnancy, and 27% for preterm delivery in any pregnancy. In the former case, however, we could not reject a model without genetic influences. Although our data did not allow for differentiation of the varying aetiologies of premature parturition, results from this exploratory analysis suggest that further investigation of genetic influences on specific reasons for preterm birth is warranted.