Reduced body weight at weaning followed by increased post-weaning growth rate interacts with part-per-trillion fetal serum concentrations of bisphenol A (BPA) to impair glucose tolerance in male mice.

There is evidence from longitudinal studies that being light at birth and weaning is associated with subsequent rapid weight gain in infants. This is referred to as "centile crossing", which can lead to increased risk of lifetime obesity, glucose dysregulation and type 2 diabetes. Here, pregnant CD-1 mice were hemi-ovariectomized so that the entire litter was contained in one uterine horn to increase variability in fetal growth rate. Pregnant females were implanted on gestation day (GD) 9 with a Silastic capsule containing 6, 60 or 600 µg bisphenol A (BPA). On GD 18 the mean fetal serum unconjugated BPA concentrations were 17, 177 and 1858 pg/ml, respectively. Capsules were not removed, to avoid maternal stress, and were predicted to release BPA for at least 3 weeks. Body weight at weaning was strongly negatively correlated with post-weaning weight gain in both control and BPA-treated male mice, consistent with human data; female offspring were excluded, avoiding complications associated with postpubertal estrogens. Within each treatment group, male offspring were sorted into tertiles based on relative weight gain during the two weeks after weaning, designated as having Rapid (R), Medium (M) or Slow (S) growth rate. BPA exposure was associated with altered growth rate between weaning and postnatal week 12 (young adulthood), when a low-dose (20 mg/kg, i.p.) glucose tolerance test (GTT) was performed. We found altered glucose regulation in response to all doses of BPA. However, glucose tolerance was only significantly impaired (blood glucose levels were elevated) compared to controls in males in the rapid post-weaning growth group exposed perinatally to BPA. We conclude that male mice that are light at weaning, but then experience rapid catch-up growth immediately after weaning, represent a sensitive sub-population that is vulnerable to the metabolic disrupting effects of very low pg/ml fetal serum concentrations of BPA.

Adverse Reproductive and Developmental Health Outcomes Following Prenatal Exposure to a Hydraulic Fracturing Chemical Mixture in Female C57Bl/6 Mice.

Unconventional oil and gas operations using hydraulic fracturing can contaminate surface and groundwater with endocrine-disrupting chemicals. We have previously shown that 23 of 24 commonly used hydraulic fracturing chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors in a human endometrial cancer cell reporter gene assay and that mixtures can behave synergistically, additively, or antagonistically on these receptors. In the current study, pregnant female C57Bl/6 dams were exposed to a mixture of 23 commonly used unconventional oil and gas chemicals at approximately 3, 30, 300, and 3000 µg/kg·d, flutamide at 50 mg/kg·d, or a 0.2% ethanol control vehicle via their drinking water from gestational day 11 through birth. This prenatal exposure to oil and gas operation chemicals suppressed pituitary hormone concentrations across experimental groups (prolactin, LH, FSH, and others), increased body weights, altered uterine and ovary weights, increased heart weights and collagen deposition, disrupted folliculogenesis, and other adverse health effects. This work suggests potential adverse developmental and reproductive health outcomes in humans and animals exposed to these oil and gas operation chemicals, with adverse outcomes observed even in the lowest dose group tested, equivalent to concentrations reported in drinking water sources. These endpoints suggest potential impacts on fertility, as previously observed in the male siblings, which require careful assessment in future studies.

Systematic review of the association between oil and natural gas extraction processes and human reproduction.

This systematic review identified 45 original published research articles related to oil and gas extraction activities and human reproductive endpoints. Reproductive outcomes were categorized as [1] birth outcomes associated with maternal exposure, [2] semen quality, fertility, and birth outcomes associated with adult paternal exposure, [3] reproductive cancers, and [4] disruption of human sex steroid hormone receptors. The results indicate there is moderate evidence for an increased risk of preterm birth, miscarriage, birth defects, decreased semen quality, and prostate cancer. The quality of the evidence is low and/or inadequate for stillbirth, sex ratio, and birth outcomes associated with paternal exposure, and testicular cancer, female reproductive tract cancers, and breast cancer, and the evidence is inconsistent for an increased risk of low birth weight; therefore, no conclusions can be drawn for these health effects. There is ample evidence for disruption of the estrogen, androgen, and progesterone receptors by oil and gas chemicals, which provides a mechanistic rationale for how exposure to oil and gas activities may increase the health risks we have outlined. The results from this systematic review suggest there is a negative impact on human reproduction from exposure to oil and gas activities. Many of the 45 studies reviewed identified potential human health effects. Most of these studies focused on conventional oil and gas activities. Few studies have been conducted to evaluate the impact of unconventional oil and gas operations on human health. The impact of unconventional oil and gas activities may be greater than that of conventional activity, given that unconventional activities employ many of the same approaches and use dozens of known endocrine-disrupting chemicals in hydraulic fracturing.

Endocrine-Disrupting Activity of Hydraulic Fracturing Chemicals and Adverse Health Outcomes After Prenatal Exposure in Male Mice.

Oil and natural gas operations have been shown to contaminate surface and ground water with endocrine-disrupting chemicals. In the current study, we fill several gaps in our understanding of the potential environmental impacts related to this process. We measured the endocrine-disrupting activities of 24 chemicals used and/or produced by oil and gas operations for five nuclear receptors using a reporter gene assay in human endometrial cancer cells. We also quantified the concentration of 16 of these chemicals in oil and gas wastewater samples. Finally, we assessed reproductive and developmental outcomes in male C57BL/6J mice after the prenatal exposure to a mixture of these chemicals. We found that 23 commonly used oil and natural gas operation chemicals can activate or inhibit the estrogen, androgen, glucocorticoid, progesterone, and/or thyroid receptors, and mixtures of these chemicals can behave synergistically, additively, or antagonistically in vitro. Prenatal exposure to a mixture of 23 oil and gas operation chemicals at 3, 30, and 300 µg/kg · d caused decreased sperm counts and increased testes, body, heart, and thymus weights and increased serum testosterone in male mice, suggesting multiple organ system impacts. Our results suggest possible adverse developmental and reproductive health outcomes in humans and animals exposed to potential environmentally relevant levels of oil and gas operation chemicals.

Reduced prevalence of chronic tubal inflammation in tubal pregnancies after levonorgestrel emergency contraception failure.

PURPOSE: The aim of this study was to compare chronic fallopian tubal inflammatory disease and fibrosis between patients with general tubal pregnancy (TP) and TP with levonorgestrel (LNG) emergency contraception (EC) failure. METHODS: We retrospectively studied patients with general TP (n = 79) and TP following LNG-EC failure (n = 81) within the same conception cycle. Information on the gynecological features of each subject was collected. Pelvic inflammatory disease and associated sequelae were assessed by the serum Chlamydia trachomatis (CT) IgG test, laparoscopic evaluation of tubal damage, and histopathological observation of tube tissues. Chi-square and Student's t-tests were employed to determine the difference between the two groups. RESULTS: Compared with general TP, cases of TP following LNG-EC failure subjects were less likely to have a history of previous ectopic pregnancy (5.06% vs. 18.52%, p = 0.009) and adnexal surgery (6.33% vs. 22.22%, p = 0.010). Patients with TP following LNG-EC failure were less likely to have pelvic inflammatory disease and associated sequelae than those with general TP, as revealed by positive reaction to anti-CT IgG (18.18% vs. 35.94%, p = 0.031), assessment of tubal damage (grade I: 5.06% vs. 17.28%; grade II: 2.53% vs. 11.11%; grade III: 1.27% vs. 6.17%; p = 0.001), infiltration of chronic inflammatory cells (10.91% vs. 62.50%, p < 0.001), and positive Masson's staining (7.69% vs. 39.58%; p < 0.001). CONCLUSIONS: Compared with cases of general TP, cases of TP following LNG-EC failure exhibited reduced rates of CT infection, fallopian tubal inflammation, and/or fibrosis.

Investigating human vascular tube morphogenesis and maturation using endothelial cell-pericyte co-cultures and a doxycycline-inducible genetic system in 3D extracellular matrices.

Considerable progress has occurred toward our understanding of the molecular basis for vascular morphogenesis, maturation, and stabilization. A major reason for this progress has been the development of novel in vitro systems to investigate these processes in 3D extracellular matrices. In this chapter, we present models of human endothelial cell (EC) tube formation and EC-pericyte tube co-assembly using serum-free defined conditions in 3D collagen matrices. We utilize both human venous and arterial ECs and show that both cell types readily form tubes and induce pericyte recruitment and both ECs and pericytes work together to remodel the extracellular matrix environment by assembling the vascular basement membrane, a key step in capillary tube network maturation and stabilization. Importantly, we have shown that these events occur under serum-free defined conditions using the hematopoietic stem cell cytokines, SCF, IL-3, and SDF-1α and also including FGF-2. In contrast, the combination of VEGF and FGF-2 fails to support vascular tube morphogenesis or pericyte-induced tube maturation under the same serum-free defined conditions. Furthermore, we present novel assays whereby we have developed both human ECs and pericytes to induce specific genes using a doxycycline-regulated lentiviral system. In this manner, we can upregulate the expression of wild-type or mutant gene products at any stage of vascular morphogenesis or maturation in 3D matrices. These in vitro experimental approaches will continue to identify key molecular requirements and signaling pathways that control fundamental events in tissue vascularization under normal or pathologic conditions. Furthermore, these models will provide new insights into the development of novel disease therapeutic approaches where vascularization is an important pathogenic component and create new ways to assemble capillary tube networks with associated pericytes for tissue engineering applications.

Contraceptive Use and the Risk of Ectopic Pregnancy: A Multi-Center Case-Control Study.

OBJECTIVE: To evaluate the association between the risk of ectopic pregnancy (EP) and the use of common contraceptives during the previous and current conception/menstrual cycle. METHODS: A multi-center case-control study was conducted in Shanghai. Women diagnosed with EP were recruited as the case group (n = 2,411). Women with intrauterine pregnancy (IUP) (n = 2,416) and non-pregnant women (n = 2,419) were matched as controls at a ratio of 1∶1. Information regarding the previous and current use of contraceptives was collected. Multivariate logistic regression analyses were performed to calculate odds ratios (ORs) and the corresponding 95% confidential intervals (CIs). RESULTS: Previous use of intrauterine devices (IUDs) was associated with a slight risk of ectopic pregnancy (AOR1 = 1.87 [95% CI: 1.48-2.37]; AOR2 = 1.84 [1.49-2.27]), and the risk increased with the duration of previous use (P1 for trend <10-4, P2 for trend <10-4). The current use of most contraceptives reduced the risk of both unwanted IUP (condom: AOR = 0.04 [0.03-0.05]; withdrawal method: AOR = 0.10 [0.07-0.13]; calendar rhythm method: AOR = 0.54 [0.40-0.73]; oral contraceptive pills [OCPs]: AOR = 0.03 [0.02-0.08]; levonorgestrel emergency contraception [LNG-EC]: AOR = 0.22 [0.16-0.30]; IUDs: AOR = 0.01 [0.005-0.012]; tubal sterilization: AOR = 0.01 [0.001-0.022]) and unwanted EP (condom: AOR1 = 0.05 [0.04-0.06]; withdrawal method: AOR1 = 0.13 [0.09-0.19]; calendar rhythm method: AOR1 = 0.66 [0.48-0.91]; OCPs: AOR1 = 0.14 [0.07-0.26]; IUDs: AOR1 = 0.17 [0.13-0.22]; tubal sterilization: AOR1 = 0.04 [0.02-0.08]). However, when contraception failed and pregnancy occurred, current use of OCPs (AOR2 = 4.06 [1.64-10.07]), LNG-EC (AOR2 = 4.87 [3.88-6.10]), IUDs (AOR2 = 21.08 [13.44-33.07]), and tubal sterilization (AOR2 = 7.68 [1.69-34.80]) increased the risk of EP compared with the non-use of contraceptives. CONCLUSION: Current use of most contraceptives reduce the risk of both IUP and EP. However, if the contraceptive method fails, the proportions of EP may be higher than those of non-users. In the case of contraceptive failure in the current cycle, EP cases should be differentiated according to current use of OCPs, LNG-EC, IUDs, and tubal sterilization. In addition, attention should be paid to women with previous long-term use of IUDs.

Risk factors for ectopic pregnancy in women with planned pregnancy: a case-control study.

OBJECTIVE: To explore the risk factors for ectopic pregnancy (EP) in women with planned pregnancy. STUDY DESIGN: This case-control study was conducted in women with planned pregnancy and included 900 women diagnosed with EP (case group) and 889 women with intrauterine pregnancy (IUP) as the control group matched in terms of age and gestational week. Socio-demographic characteristics, reproductive history, gynecological and surgical history, previous contraceptive use, and history of infertility were compared between the two groups. Blood samples were collected from all the participants to detect serum chlamydia trachomatis (CT) IgG antibody. The odds ratio (OR) with its 95% confidential interval (CI) of each variable was calculated by univariable conditional logistic regression analysis. Factors significantly different between both groups, as revealed by univariable analysis, were entered into a multivariable logistic regression model by stepwise selection. RESULTS: The risk of EP was associated with previous adnexal surgery (adjusted OR=3.99, 95% CI: 2.40-6.63), uncertainty of previous pelvic inflammatory disease (adjusted OR=6.89, 95% CI: 3.29-14.41), and positive CT IgG serology (adjusted OR=5.26, 95% CI: 3.94-7.04). A history of infertility including tubal infertility (adjusted OR=3.62, 95% CI: 1.52-8.63), non-tubal infertility (adjusted OR=3.34, 95% CI: 1.60-6.93), and in vitro fertilization (IVF) treatment (adjusted OR=5.96, 95% CI: 1.68-21.21) were correlated with the risk of EP. Women who had previously used condoms were less likely to have EP during the current cycle (adjusted OR=0.27, 95% CI: 0.21-0.36). CONCLUSIONS: Besides well-acknowledged risk factors for EP, attention should be paid to women with planned pregnancy who have a history of infertility and/or IVF treatment, to prevent complications from EP.

Control of vascular tube morphogenesis and maturation in 3D extracellular matrices by endothelial cells and pericytes.

An important advance using in vitro EC tube morphogenesis and maturation models has been the development of systems using serum-free defined media. Using this approach, the growth factors and cytokines which are actually necessary for these events can be determined. The first model developed by our laboratory was such a system where we showed that phorbol ester was needed in order to promote survival and tube morphogenesis in 3D collagen matrices. Recently, we have developed a new system in which the hematopoietic stem cell cytokines, stem cell factor (SCF), interleukin-3 (IL-3), and stromal derived factor-1α (SDF-1α) were added in conjunction with FGF-2 to promote human EC tube morphogenesis in 3D collagen matrices under serum-free defined conditions. This new model using SCF, IL-3, SDF-1α, and FGF-2 also works well following the addition of pericytes where EC tube formation occurs, pericytes are recruited to the tubes, and vascular basement membrane matrix assembly occurs following EC-pericyte interactions. In this chapter, we describe several in vitro assay models that we routinely utilize to investigate the molecular requirements that are critical to EC tube formation and maturation events in 3D extracellular matrix environments.

Emergency contraception: potential role of ulipristal acetate.

Unintended pregnancy is a global reproductive health problem. Emergency contraception (EC) provides women with a safe means of preventing unwanted pregnancies after having unprotected intercourse. While 1.5 mg of levonorgestrel (LNG) as a single dose or in 2 doses with 12 hours apart is the currently gold standard EC regimen, a single dose of 30 mg ulipristal acetate (UPA) has recently been proposed for EC use up to 120 hours of unprotected intercourse with similar side effect profiles as LNG. The main mechanism of action of both LNG and UPA for EC is delaying or inhibiting ovulation. However, the 'window of effect' for LNG EC seems to be rather narrow, beginning after selection of the dominant follicular and ending when luteinizing hormone peak begins to rise, whereas UPA appears to have a direct inhibitory effect on follicular rupture which allows it to be also effective even when administered shortly before ovulation, a time period when use of LNG is no longer effective. These experimental findings are in line with results from a series of clinical trials conducted recently which demonstrate that UPA seems to have higher EC efficacy compared to LNG. This review summarizes some of the data available on UPA used after unprotected intercourse with the purpose to provide evidence that UPA, a new type of second-generation progesterone receptor modulator, represents a new evolutionary step in EC treatment.

Effect of levonorgestrel and mifepristone on endometrial receptivity markers in a three-dimensional human endometrial cell culture model.

OBJECTIVE: To investigate the effect of levonorgestrel and mifepristone on the expression of endometrial receptivity markers in a three-dimensional endometrial construct. DESIGN: In vitro study. SETTING: University hospital and research laboratory. PATIENT(S): Twelve fertile donors. INTERVENTION(S): Timed endometrial biopsy. MAIN OUTCOME MEASURE(S): Examine the effect of levonorgestrel along with another well-studied fertility-regulating drug, mifepristone, on the expression of endometrial receptivity factors in a three-dimensional stromal and epithelial cell coculture model by immunohistochemistry. RESULT(S): Both epithelial and stromal cells of in vitro endometrial construct showed the presence of estrogen receptor-alpha, estrogen receptor-beta, progesterone receptors-(A+B), vascular endothelial growth factor, leukemia inhibitory factor, interleukin-1 beta, and cyclooxygenase-2, whereas the expression of progesterone receptor-B (AR), integrin alpha(V)beta(3,) and MUC1 were confined to epithelial cells. Mifepristone up-regulated expression of epithelial estrogen receptor-beta and progesterone receptor-B and down-regulated stromal vascular endothelial growth factor and surface molecules MUC1 and integrin alpha(V)beta(3) as observed in vivo. Levonorgestrel had no effect on the expression of endometrial receptivity markers studied. CONCLUSION(S): This in vitro model expresses progesterone-regulated endometrial receptivity factors seen in the physiologic condition. Treatment with levonorgestrel did not affect the expression of these endometrial receptivity markers in contrast to mifepristone. This in vitro model holds the potential to study endometrial receptivity, the embryo-endometrial interaction, and develop new agents for fertility control.

Expressions of steroid receptors and Ki67 in first-trimester decidua and chorionic villi exposed to levonorgestrel used for emergency contraception.

Levonorgestrel (1.5 mg) is commonly used for emergency contraception to prevent an unwanted pregnancy after an unprotected intercourse. We found that postovulatory administration of 1.5 mg of levonorgestrel to women with a subsequent or existing early pregnancy did not affect the immunohistochemical expressions of estrogen receptors (ER(alpha), ER(beta)), P receptors (PR(B), PR(A+B)), androgen receptor (AR), or proliferation index Ki67 in the first-trimester decidua and chorionic villi.

[Spectrum and synthesis of rare earth activated nanoparticle].

La2O3: Eu(3+) nanoparticles were prepared by Gly assistant combustion synthesis with the sizes from 12-28 nm, and a characterization of XRD was done. Spectral properties of the nanoparticles were compared with the bulk. High resolution spectra were measured. Site selective excitation was employed to probe the local environments of Eu(3+) ions in La2O3 nanoparticles. The luminescent centers on the surface and the center of the nanoparticles were excited respectively. The spectra were related to surface information. The luminescence from C3v site and the site with lower symmetry on the surface was distinguished.