Reproductive Sciences

To better understand the science linking environmental contaminants exposures with adverse pregnancy outcomes, we reviewed the relevant epidemiologic literature. We searched PubMed (primarily 1995-2006) using the key word combinations for select environmental exposures and pregnancy outcomes. Environmental tobacco smoke is a risk factor for reduced birth weight and preterm delivery. Outdoor air pollution is associated with reduced term birth weight and preterm delivery. Suggestive evidence associates pesticides and polychlorinated biphenyls with decreased fetal growth and length of gestation. Stronger evidence, primarily occupational, links certain birth defects with exposure to organic solvents and chlorophenoxy herbicides. Evidence suggests dichlorodiphenyltrichloroethane and bisphenol-A could be associated with pregnancy loss. Exposures in utero can also increase the risk of developmental delays (ie, impaired neurological function), adult chronic illnesses (ie, heart disease, diabetes, cancer), and next generation effects (ie, reduced reproductive capacity). Further research, education, and improved public health policy are needed to reduce potentially adverse exposures.

Large conductance K ⁺ channels (BK_Ca) are expressed in uterine artery (UA) smooth muscle from nonpregnant and pregnant sheep and contribute to the regulation of basal vascular tone and responses to estrogen and vasoconstrictors. To determine if BK_Ca are expressed in women and contribute to UA function, we collected UA from nonpregnant women (n = 31) at elective hysterectomy and analyzed for subunit protein, localization with immunohistochemistry, and function using endothelium-denuded rings. UA expresses BK_Ca α -, β1- and β2-subunit protein. KCl and phenylephrine (PE, an α ₁-agonist) caused dose-dependent vasoconstriction (P < .001), and UA precontracted with PE dose-dependently relaxed with sodium nitroprusside (SNP; P < .001).Tetraethylammonium chloride (TEA, 0.2-1.0 mM), a BK_Ca inhibitor, dose-dependently increased resting tone (P = .004; 28% ± 5.3% with 1.0 mM), enhanced PE-induced (10 ^{− 6} M) vasoconstriction (P < .04), and attenuated SNP-induced relaxation at 1.0 mM (P = .02). BK _Ca are expressed in human UA and modulate vascular function by attenuating vasoconstrictor responses and contributing to nitric oxide-induced vasorelaxation.

The dynamics of the subcellular distribution of PLCβ1 was investigated during meiosis competence acquisition and meiosis resumption in relation to oocyte diameter and to nonsurrounded-nucleolus or surrounded-nucleolus chromatin configurations. Oocytes collected after both in vivo and in vitro folliculogenesis were studied. In both conditions, at the beginning of the process, most oocytes exhibited a nuclear PLCβ 1 associated with a nonsurrounded-nucleolus chromatin configuration. Then at the final stage of the process, the factors shifted mainly toward a cytoplasmic PLCβ1 and a surrounded-nucleolus chromatin configuration, typical of a preovulatory fertilizable oocyte. Additionally, only germinal vesicle oocytes with a diameter > 75 μm, and exhibiting cytoplasmic PLC β1 distribution and surrounded-nucleolus chromatin configuration, resumed meiosis. Our findings demonstrate a strong correlation between oocyte diameter, chromatin configuration, and PLCβ1 localization. Thus, PLCβ1 localization appears to be a key factor determining the progressive acquisition of meiotic competence and final resumption of meiosis.

Objective. This study aimed at evaluating the expression of tyrosine kinase receptors c-kit, (platelet-derived growth factor receptor-α (PDGFR-α), and PDGFR-β in ovarian granulosa cell tumors (GCTs). Study design. Primary ovarian GCT specimens were obtained for immunohistochemical staining.The expressions of c-kit, PDGFR-α, and PDGFR-β were analyzed and scored by a semiquantitative (SQ) method. Normal ovarian tissue from the same patients' specimens served as internal controls. Results. A total of 21 specimens were available for evaluation. C-kit was expressed in only 2 samples, whereas both PDGFR-α and PDGFR-β stained positive in 100% of tumors. PDGFR targets demonstrated strong positive expression in intensity and amount of tissue stained. Normal ovarian tissue demonstrated complete absence of staining for all 3 antibodies evaluated. Conclusions. The data demonstrated significant expression of PDGFR targets of imatinib mesylate in GCTs, whereas normal ovarian tissues had a complete absence of staining.This expression profile provides the rationale to investigate the role of imatinib mesylate in PDGFR-positive GCTs.

The uterine expressions of epidermal growth factor(EGF) family are examined to elucidate their exact role(s) in rat pregnancy. EGF and its receptors' (EGF-R) mRNA levels increased significantly at implantation after which their expression gradually decreased. Heparin-binding EGF (HB-EGF) and transforming growth factor-α (TGF-α) showed a modest expression at gestation day (GD), GD4 and GD3, respectively, but were much strongly expressed at mid-pregnancy.Amphiregulin (Areg) was strongly expressed around implantation (GD4) and at mid-pregnancy (GD12).Treatment of pregnant rats with RU486 at GD5 or GD8 blocked the expression of all the genes, and administration of immature rats with progesterone (P4) induced the uterine expression of all the genes except HB-EGF. In addition, HB-EGF,TGF-α, and Areg proteins in the uterine and glandular epitheliums may participate in mid-pregnancy. Taken together, all of these activities are likely to be controlled by P4 in the uterus of pregnant rats.

The feto-maternal safety of sodium nitroprusside (SNP) administration in the cervix of pregnant sheep is evaluated. Chronically catheterized pregnant sheep at ∼0.9 gestation were divided into 2 groups that received 0.1 mg/kg maternal body weight of SNP gel (2%) or placebo into the internal cervical os. SNP or placebo gel was administered at 9 AM with both maternal and fetal blood gas/pH, and cardiovascular parameters were monitored for 6 hours. Except for a slight transient decrease of maternal oxygen and meta-hemoglobin content, and fetal oxygen content in the SNP group, no other significant changes were observed. However, such changes are minimal and unlikely to be of any clinical significance. Moreover, nitric oxide metabolites were unchanged in both maternal and fetal circulations.These data demonstrate few, if any, effects of intrauterine SNP administration on both cellular oxygenation and cardiovascular indexes. Thus, SNP treatment, once applied into the cervix, could be considered a safe procedure.

Introduction: Genetic variants of the angiotensinogen gene have been linked to both hypertension and preeclampsia. The M235T polymorphism is more common in hypertension and preeclampsia in some populations. A polymorphism in the angiotensinogen basal promoter region of AGT -217 is more common in African Americans with hypertension. The authors investigated the frequency of M235T and AGT -217 in Caucasian and African American women with and without preeclampsia. Methods: The study was a nested case—control study of primiparous women with singleton pregnancies. Genomic DNA from preeclamptic and control subjects underwent polymerase chain reaction amplification and restriction digestion. Results: The M235T and AGT -217 polymorphisms were both more common in African American women; however, the variants were not more common in preeclampsia. Conclusion: The frequency of angiotensinogen polymorphisms M235T and AGT -217 is different by race; however, these polymorphisms are not associated with an incre ased risk of preeclampsia.

Intrauterine growth restricted (IUGR) offspring exhibit increased appetite and a propensity to adult obesity. Although the rate of newborn catch-up growth may determine the programming of adult obesity, there is little understanding of mechanisms by which orexigenic pathways are modified. Ghrelin is an orexigenic peptide that acts in the hypothalamic arcuate (ARC) and ventromedial (VMH) nuclei. To examine potential programming effects of IUGR,ghrelin's actions onARC and VMH neurons were studied in brain slices of adult offspring previously subjected to maternal food restriction (FR) during pregnancy (FR/AdLib [ad libitum]) and both pregnancy and lactation (FR/FR). FR/FR offspring demonstrated increased baseline neuronal firing frequency in both ARC and VMH when compared with both FR/AdLib and control offspring. Among FR/AdLib pups that exhibit hyperphagia and obesity, ghrelin excited more and inhibited fewerARC neurons when compared with either FR/FR or controls. These results provide evidence of programming of orexigenic/anorexigenic mechanisms depending on the nutrient levels during pregnancy and newbor periods.

Amino acid infusate (Primene) and insulin euglycemic (insulin + 10% dextrose) clamp techniques were used in the ovine fetus near term and the impact on the incidence of low-voltage and high-voltage electrocortical (ECOG) activities was determined. Fetal sheep were studied over a 2-hour control period and a subsequent 6-hour experimental period.With the Primene infusion, the basic and neutral amino acids were increased by 43% and 25%, respectively, whereas the acidic amino acids showed little change. With the insulin/dextrose infusion, the basic and neutral amino acids decreased by 48% and 30%, respectively, whereas the acidic amino acids were again little changed. A small fall in arterial oxygen saturation and an increase in fetal heart rate for both groups can be attributed to an insulin-mediated increase in fetal metabolic rate. Despite the moderate increases and decreases in circulating amino acid levels, there was no significant change in the mean percent time or duration of fetal ECOG activities for either study group.

Disturbances in decidual and placental vascular development may play a role in the pathogenesis of pregnancy complications. This study focused on the role of angiogenic factors in the first trimester in the pathogenesis of preeclampsia (PE) and/or fetal growth restriction (FGR). First-trimester decidua was obtained during chorionic villous sampling.The expression of the angiogenic factors was determined by reverse transcriptase polymerase chain reaction and related to the pregnancy outcome. First-trimester decidua expressed all angiogenic factors.The differential expression of angiogenic factors appeared to be more prominent in FGR than in PE. These first-trimester samples provided a unique opportunity to obtain information regarding the onset of PE and FGR. First-trimester changes in angiogenic factor expression may well occur as a compensatory mechanism. This, in turn, may unintentionally set the stage for increased angiogenesis and altered decidual/placental vascular adaptation, which may be part of the pathogenesis of PE and/or FGR.

Objective. The aim of this study was to investigate the ability of serotonin to increase contractions in human myometrium. Methods. Isometric tension measurements were used to determine the effect of increasing doses of serotonin on strips of human myometrium obtained at the time of cesarean section. Results. Serotonin had little or no effect on the spontaneous activity of myometrium strips in control conditions. In tissue where this activity had been reduced by either forskolin or diazoxide, serotonin caused a dose-dependent increase in contractions and produced up to a 3-fold increase in contractions over basal activity. Conclusions.The ability of serotonin to increase contractions in the uterus appears to depend on the background activity of the tissue and is greatest in quiescent tissue. It is therefore possible that in quiescent, preterm myometrium, aberrant serotonin signaling could contribute to preterm labor. Serotonin may also play a key role in the postpartum prevention of uterine atony and consequent hemorrhage.

This study investigated the expression and methylation profiles of SOX2, a stem cell—related transcription factor, in placentas and gestational trophoblastic disease. The methylation status of SOX2 promoter region in 55 hydatidiform moles, 4 choriocarcinoma, 23 first trimester, and 15 term placentas was evaluated by methylation-specific polymerase chain reaction. The methylated allele was found in 4.4% (1/23) of first trimester placentas, 26.7% (4/15) term placentas, and 56.4% (31/55) of hydatidiform moles and all choriocarcinoma samples and cell lines. A significant reduction in SOX2 messenger RNA expression was found in the hydatidiform moles (P = .027) when compared with that in the placentas. SOX2 messenger RNA expression was significantly correlated with SOX2 hypermethylation (P < .001). SOX2 expression was restored in choriocarcinoma cell lines following treatment to 5-Aza-2 ^' -deoxycytidine and/or Trichostatin A, demethylation and histone deacetylase inhibitors, respectively, and the response was synergistic. Epigenetic mechanisms may play important role on the transcriptional regulation of SOX2 and contribute to pathogenesis of gestational trophoblastic disease.