Maternal, placental and fetal exposure to bisphenol A in women with and without preeclampsia.

OBJECTIVES: We aimed to investigate potential association between the exposure of bisphenol A (BPA) and preeclampsia. METHODS: Concentrations of BPA were assessed in 58 pregnancies including 35 normotensive and 23 preeclamptic women, using a highly sensitive gas chromatography-mass spectrometry (GC-MS) method. RESULTS: BPA was detected in maternal blood, fetal blood and placental tissue; and actual concentrations of BPA were determined. Interestingly, significant accumulation of BPA in the placentas of women with preeclampsia compared to normotensive women has been shown. CONCLUSIONS: This is the first study to highlight a significant correlation between preeclampsia and a high accumulation of BPA in the placenta.

Estimation of bisphenol A (BPA) concentrations in pregnant women, fetuses and nonpregnant women in Eastern Townships of Canada.

We determined bisphenol A (BPA) concentrations of 61 pregnant women (PW), their fetuses and 26 nonpregnant women (NPW) in Eastern Townships of Canada; and evaluated potential correlations between maternal and fetal blood, and between peripheral blood and peritoneal fluid. In PW, BPA levels were ranged from non-detected to 4.46ng/ml and from non-detected to 4.60ng/ml for maternal and fetal serum, respectively. In NPW, BPA levels were ranged from 1.30 to 8.17ng/ml and from 0.19 to 13.45ng/ml for serum and peritoneal fluid, respectively. Positive correlation was found between maternal and fetal serum, and between serum and peritoneal fluid. In conclusion, our findings highlight a continuous distribution of BPA between the mother and its fetus and reveal a role of pregnancy in underestimating the actual levels of blood BPA. Our study also provides a temporal-spatial reference on BPA exposure, which is a useful tool in monitoring, comparing and correcting.

A 12-year cohort study on adverse pregnancy outcomes in Eastern Townships of Canada: impact of endometriosis.

The aim of this study was to provide a temporal-spatial reference of adverse pregnancy outcomes (APO) and examine whether endometriosis promotes APO in the same population. Among the 31 068 women who had a pregnancy between 1997 and 2008 in Eastern Townships of Canada, 6749 (21.7%) had APO. These APO increased significantly with maternal age and over time (r(2 )= 0.522, p = 0.008); and were dominated by preterm birth (9.3%), pregnancy-induced hypertension (8.3%) including gestational hypertension (6.5%), low birth weight (6.3%), gestational diabetes (3.4%), pregnancy loss (2.2%) including spontaneous abortion (1.5%) and stillbirth (0.6%), intrauterine growth restriction (2.1%) and preeclampsia (1.8%). Among the 31 068 pregnancies, 784 (2.5%) had endometriosis and 183 (23.3%) had both endometriosis and APO. Endometriosis has been shown to increase the incidence of fetal loss (OR = 2.03; 95% CI = 1.42-2.90, p < 0.0001), including spontaneous abortion (OR = 1.89; 95% CI = 1.23-2.93, p = 0.005) and stillbirth (OR = 2.29; 95% CI = 1.24-5.22, p = 0.012). This study provides a temporal-spatial reference on APO, which is a valuable tool for monitoring, comparing and correcting. It is also the first study to highlight an impact of endometriosis on the incidence of spontaneous abortion and stillbirth.

A positive correlation between hydrogen peroxide and soluble TNF-alpha receptor 2 early in maternal blood and at term in placenta of pregnant women with preeclampsia.

OBJECTIVES: We hypothesized that hydrogen peroxide (H(2)O(2)) and soluble TNF-α receptor 2 (sTNF-R2) co-play a role in the pathogenesis of preeclampsia. METHODS: Correlation of H(2)O(2) and sTNF-R2 was assessed in vivo in maternal blood and placenta, and in vitro in cytotrophoblasts culture. RESULTS: We showed a positive correlation between increased levels of H(2)O(2) and sTNF-R2 early at 10-15 gestational weeks and at term in maternal serum, and in placenta of women with preeclampsia. Our in vitro experiments showed that H(2)O(2) induced the placental synthesis of sTNF-R2. CONCLUSION: We propose to consider H(2)O(2) and sTNF-R2 as potential biomarkers in predicting preeclampsia.

Maternal and fetal exposure to pesticides associated to genetically modified foods in Eastern Townships of Quebec, Canada.

Pesticides associated to genetically modified foods (PAGMF), are engineered to tolerate herbicides such as glyphosate (GLYP) and gluphosinate (GLUF) or insecticides such as the bacterial toxin bacillus thuringiensis (Bt). The aim of this study was to evaluate the correlation between maternal and fetal exposure, and to determine exposure levels of GLYP and its metabolite aminomethyl phosphoric acid (AMPA), GLUF and its metabolite 3-methylphosphinicopropionic acid (3-MPPA) and Cry1Ab protein (a Bt toxin) in Eastern Townships of Quebec, Canada. Blood of thirty pregnant women (PW) and thirty-nine nonpregnant women (NPW) were studied. Serum GLYP and GLUF were detected in NPW and not detected in PW. Serum 3-MPPA and CryAb1 toxin were detected in PW, their fetuses and NPW. This is the first study to reveal the presence of circulating PAGMF in women with and without pregnancy, paving the way for a new field in reproductive toxicology including nutrition and utero-placental toxicities.

Endometrioid ovarian cancer and endometriotic cells exhibit the same alteration in the expression of interleukin-1 receptor II: to a link between endometriosis and endometrioid ovarian cancer.

AIM: Endometrioid carcinoma of the ovary is the third most common type of epithelial ovarian cancer. Endometrioid tumors as well as endometriotic implants are characterized by the presence of epithelial cells, stromal cells, or a combination of booth, that resemble the endometrial cells, suggesting a possible endometrial origin of these tumors. Th1 cytokines including interleukin (IL)-1 have been reported to be involved in both endometriosis and ovarian carcinogenesis. We assessed the expression of receptors of IL-1 (IL-1RI and IL-1RII, the signal transducer and the specific inhibitor of IL-1, respectively) in cells of the most common subtypes of ovarian cancer compared to endometrial cells. MATERIAL & METHODS: IL1-Rs expression was analyzed at the levels of the protein and mRNA using immunofluorescent and real-time polymerase chain reaction methods, respectively. RESULTS: We showed that endometrioid cells exhibit a specific decrease of IL-1RII expression, whereas IL-1RI was constantly expressed in all studied cell subtypes. CONCLUSION: As already reported in endometriotic cells, endometrioid ovarian cancer cells exhibit the same alteration in the expression of IL-1RII, a key protector against tumorigenic effects of IL-1. Our findings highlight a common signature between endometrioid ovarian cancer and implants of endometriosis, which needs to be fully explored.

Endometriosis-associated infertility: a decade's trend study of women from the Estrie region of Quebec, Canada.

Endometriosis (ENDO) has been believed to increase during the last years, but recent data supporting this trend are lacking. The aim of this study was to verify whether the incidence of ENDO, infertility (INF) and the both increased during the last 10 years among women living in the Estrie region of Quebec. This retrospective cross-sectional study was realised using data from the CIRESS (Centre Informatisé de Recherche Evaluative en Services et Soins de Santé) system, the database of the CHUS (Centre Hospitalier Universitaire de Sherbrooke), Sherbrooke, Canada. Among the 6845 studied patients, 2564 had ENDO, 4537 were infertile and 256 suffered from both. According to the last 10 years, a significant increase in the number of cases with ENDO (r2 = 0.717, p = 0.001) and endometriosis-associated infertility (r2 = 0.601, p = 0.003) was noted, while INF remained stable (r2 = 2813 e-005, p = 0.987). We showed a prevalence of ENDO of 10.91%. Women with ENDO were at increased risk for being infertile (OR = 2.30; 95% CI = 2.014-2.626, p <0.0001). An increase of ENDO in women 18-24 years of age has been shown (r2 = 0.418, p = 0.023), suggesting an earlier onset of the disease.

Endometriosis-associated ovarian cancer: A ten-year cohort study of women living in the Estrie Region of Quebec, Canada.

OBJECTIVES: Endometriosis has been believed to increase the risk of developing ovarian cancer, but recent data supporting this hypothesis are lacking. The aim of this study was to verify whether the incidence of endometriosis, ovarian cancer and the both increased during the last 10 years among women living in the Estrie region of Quebec. METHODS: We collected data of women diagnosed with endometriosis, ovarian cancer or both, between 1997 and 2006, from a population living in the Estrie region of Quebec. We performed this retrospective cross-sectional study from the CIRESSS (Centre Informatisé de Recherche Evaluative en Services et Soins de Santé) system, the database of the CHUS (Centre Hospitalier Universitaire of Sherbrooke), Sherbrooke, Canada. RESULTS: Among the 2854 identified patients, 2521 had endometriosis, 292 patients had ovarian cancer and 41 patients had both ovarian cancer and endometriosis. We showed a constant increase in the number of ovarian cancer (OC) between 1997 and 2006 (r2 = 0.557, P = 0.013), which is not the case for endometriosis (ENDO) or endometriosis-associated ovarian cancer (EAOC). The mean age +/- SD was 40.0 +/- 9.9 and 53.9 +/- 11.4 for patients having ENDO and OC, respectively. Mean age of women with EAOC was 48.3 +/- 10.8, suggesting an early onset of ovarian cancer in women having endometriosis of about 5.5 years average, P = 0.003. Women with ENDO were at increased risk for developing OC (Rate Ratio [RR] = 1.6; 95% Confidence Interval [CI] = 1.12-2.09). Pathological analyses showed the predominance of endometrioid type (24.4%) and clear-cell type (21.9%) types in EAOC compared to OC, P = 0.0070 and 0.0029, respectively. However, the serous type is the most widespread in OC (44.5%) in comparison to EAOC (19.51%), P = 0.0023. CONCLUSION: Our findings highlight that the number of cases of ovarian cancer is constantly increasing in the last ten years and that endometriosis represents a serious risk factor which accelerates its apparition by about 5.5 years.

Expression of interleukin-1 (IL-1) ligands system in the most common endometriosis-associated ovarian cancer subtypes.

OBJECTIVES: Endometrioid carcinoma of the ovary is one of the most types of epithelial ovarian cancer associated to endometrioisis. Endometrioid tumors as well as endometriotic implants are characterized by the presence of epithelial cells, stromal cells, or a combination of booth, that resemble the endometrial cells, suggesting a possible endometrial origin of these tumors. Pro-inflammatory cytokines, including interleukin-1 (IL-1) have been reported to be involved in both endometriosis and ovarian carcinogenesis. The major objective of this study was to determine the level expression of IL-1 ligands system (IL-1alpha, IL-1beta and IL-1RA) in the most common subtypes of ovarian cancer cells compared to endometrial cells. METHODS: We used primary endometrial cells, endometrial cell line RL-952 and different subtypes of epithelial ovarian cancer cell lines including TOV-112D (endometrioid), TOV-21G (clear cell) and OV-90 (serous). Immunofluorescence and real-time PCR analysis were used respectively for detecting IL-1 ligands at the levels of cell-associated protein and mRNA. Soluble IL-1 ligands were analyzed by ELISA. RESULTS: We demonstrated that IL-1 ligands were expressed by all endometriosis-associated ovarian cancer subtypes and endometrial cells. In contrast to other cancer ovarian cells, endometrioid cells exhibit a specific decrease of cell-associated IL-1RA expression and its soluble secretion. CONCLUSION: Endometrioid ovarian cancer exhibits an alteration in the expression of IL-1RA, a key protector against tumorogenic effects of IL-1. This alteration evokes the same alteration observed in endometriotic cells in previous studies. This suggests a possible link between the endometrium, the tissue ectopic endometriosis and endometrioid ovarian cancer.

Toxic effects of low doses of Bisphenol-A on human placental cells.

Humans are exposed daily to a great number of xenobiotics and their metabolites present as pollutants. Bisphenol-A (BPA) is extensively used in a broad range of products including baby bottles, food-storage containers, medical equipment, and consumer electronics. Thus, BPA is the most common monomer for polycarbonates intended for food contact. Levels of this industrial product are found in maternal blood, amniotic fluid, follicular fluid, placental tissue, umbilical cord blood, and maternal urine. In this study, we investigated toxic effects of BPA concentrations close to levels found in serum of pregnant women on human cytotrophoblasts (CTB). These cells were isolated from fresh placentas and exposed to BPA for 24 h. Our results showed that very low doses of BPA induce apoptosis (2 to 3 times) as assessed using M30 antibody immunofluorescent detection, and necrosis (1.3 to 1.7 times) as assessed through the cytosolic Adenylate Kinase (AK) activity after cell membrane damage. We also showed that BPA increased significantly the tumor-necrosis factor alpha (TNF-alpha) gene expression and protein excretion as measured by real-time RT-PCR and ELISA luminescent test, respectively. Moreover, we observed that induction of AK activation and TNF-alpha gene expression require lower levels of BPA than apoptosis or TNF-alpha protein excretion. Our findings suggest that exposure of placental cells to low doses of BPA may cause detrimental effects, leading in vivo to adverse pregnancy outcomes such as preeclampsia, intrauterine growth restriction, prematurity and pregnancy loss.

Detrimental effects of high levels of antioxidant vitamins C and E on placental function: considerations for the vitamins in preeclampsia (VIP) trial.

AIM: Supplementation with antioxidant vitamins has been proposed to reduce the risk of preeclampsia and perinatal complications. In a recent study, it has been shown that this supplementation to above physiological doses does not reduce the risk of preeclampsia, but increases the rate of low birthweight babies, suggesting a detrimental effect on placental function, given the lower birthweight. The aim of the present study was to investigate the effects of high levels of antioxidants vitamins C and E on placental cells in vitro. METHODS: Isolated fresh human cytotrophoblasts were exposed to high concentrations of vitamins C and E for 48 h. Then the secretion of human chorionic gonadotropin (hCG) and the production of tumor necrosis factor-alpha (TNF-alpha) were assessed. RESULTS: High levels of vitamins C and E, separately or combined, decrease the secretion of hCG by cytotrophoblasts and increase their production of TNF-alpha. CONCLUSION: Exposure of cytotrophoblasts to high levels of antioxidant vitamins C and E may affect placental function, as reflected by decreased secretion of hCG; and placental immunity, as reflected by increased production of TNF-alpha. Such alterations are known to lead to endothelial dysfunction and adverse pregnancy outcomes, such as fetal growth restriction (FGR).

Maternal circulating interferon-gamma and interleukin-6 as biomarkers of Th1/Th2 immune status throughout pregnancy.

AIM: T cells may be classified as T helper type 1 (Th1) cells, which synthesize cytokines inducing cellular immunity, or T helper type 2 (Th2), which synthesize cytokines inducing humoral immunity. According to the Th1/Th2 paradigm, it has been postulated that successful pregnancy induces an immune Th2 bias, but it is not yet clear how Th1 and Th2 systems vary simultaneously throughout the pregnancy. METHODS: Using maternal circulating interferon-gamma (IFN-gamma) and interleukin-6 (IL-6) as biomarkers of Th1 and Th2 cytokines, respectively, we examined the variation of circulating Th1/Th2 ratio in 35 healthy pregnant women from 10 to 40 weeks of pregnancy. RESULTS: With increasing gestational age, maternal circulating levels of IFN-gamma decrease, whereas those of IL-6 increase. The IFN-gamma/IL-6 ratio switches around the 19th week of pregnancy. CONCLUSIONS: Our results suggest that maternal systemic IFN-gamma and IL-6 concentrations may be biomarkers of Th1/Th2 immune status during pregnancy. Moreover, our findings showed that contrary to the Th1/Th2 paradigm, the Th1 bias may be prevailing at the beginning of pregnancy, balanced in the middle of pregnancy and supplanted by the Th2 bias at the end of pregnancy.

Dual action of H2O2 on placental hCG secretion: implications for oxidative stress in preeclampsia.

OBJECTIVE: Our previously published findings showed that circulating levels of H(2)O(2) were increased and correlated with high levels of hCG in women with preeclampsia, suggesting that oxidative stress modulates placental hormone synthesis. The aim of this study was to investigate in vitro the effects of H(2)O(2) on placental secretion of hCG. DESIGN AND METHODS: In vitro trophoblasts were stimulated with increasing concentrations of H(2)O(2) and the de novo hCG secretion was assayed. RESULTS: Stimulation with low concentrations of H(2)O(2) (1-50 microM) enhances cytotrophoblastic hCG secretion, whereas concentrations of H(2)O(2) >50 microM reduce hCG secretion in a dose-dependent manner. CONCLUSIONS: Our findings emphasize that: (1) H(2)O(2) may have dual action on placental activity and acts not only as a cytotoxic mediator, but also as a signaling molecule able to induce hCG secretion; (2) hCG may be a protective antioxidant released by the placenta to counter low oxidative stress challenge.