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This paper presents insights from the work of the Canadian Community of Practice in Ecosystem Approaches to Health (CoPEH-Canada) and 15 years (2008-2022) of land-based, transdisciplinary, learner-centred, transformative learning and training. We have oriented our learning approaches to Head, Hands, and Heart, which symbolise cognitive, psychomotor, and affective learning, respectively. Psychomotor and affective learning are necessary to grapple with and enact far-reaching structural changes (eg, decolonisation) needed to rekindle healthier, reciprocal relationships with nature and each other. We acknowledge that these approaches have been long understood by Indigenous colleagues and communities. We have developed a suite of teaching techniques and resources through an iterative and evolving pedagogy based on participatory approaches and operating reciprocal, research-pedagogical cycles; integrated different approaches and ways of knowing into our pedagogy; and built a networked Community of Practice for continued learning. Planetary health has become a dominant framing for health-ecosystem interactions. This Viewpoint underscores the depth of existing scholarship, collaboration, and pedagogical expertise in ecohealth teaching and learning that can inform planetary health education approaches.

Recent increases in prescriptions and illegal drug use as well as exposure to environmental contaminants during pregnancy have highlighted the critical importance of placental toxicology in understanding and identifying risks to both mother and fetus. Although advantageous for basic science, current in vitro models often fail to capture the complexity of placental response, likely due to their inability to recreate and monitor aspects of the microenvironment including physical properties, mechanical forces and stiffness, protein composition, cell-cell interactions, soluble and physicochemical factors, and other exogenous cues. Tissue engineering holds great promise in addressing these challenges and provides an avenue to better understand basic biology, effects of toxic compounds and potential therapeutics. The key to success lies in effectively recreating the microenvironment. One strategy to do this would be to recreate individual components and then combine them. However, this becomes challenging due to variables present according to conditions such as tissue location, age, health status and lifestyle. The extracellular matrix (ECM) is known to influence cellular fate by working as a storage of factors. Decellularized ECM (dECM) is a recent tool that allows usage of the original ECM in a refurbished form, providing a relatively reliable representation of the microenvironment. This review focuses on using dECM in modified forms such as whole organs, scaffold sheets, electrospun nanofibers, hydrogels, 3D printing, and combinations as building blocks to recreate aspects of the microenvironment to address general tissue engineering and toxicology challenges, thus illustrating their potential as tools for future placental toxicology studies.

OBJECTIVE To evaluate the effect of intrauterine administration of activated peripheral blood mononuclear cells (PBMC) on intrauterine insemination (IUI) success rates. METHODS This prospective double-blind randomized parallel clinical trial included 213 patients undergoing IUI at the Fertilys clinic. PBMC were isolated on the day of ovulation (day 0; D0) and stimulated with phytohemagglutinin (PHA) and human chorionic gonadotropin (hCG) for 48 hours (day 2; D2). Patients in the PBMC group (n = 108) underwent in utero administration of 1.106 cells on D2, while patients in the control group (n = 105) were administered sperm-washing medium. Distribution of CD4 T lymphocyte populations (n = 61) was assessed on D0 and D2. Pregnancy and live birth rates were also evaluated. RESULTS Demographic and clinical characteristics, pregnancy rates, and live birth rates were not significantly different between the PBMC and control groups. Significantly higher levels of T helper (Th) 2, Th22, and T regulatory cells (P < 0.0001) and lower levels of Th17 cells were observed in hCG-activated PBMC at D2 than at D0. CONCLUSION Intrauterine administration of PBMC was not beneficial in IUI patients. New clinical approaches to better identify patients requiring endometrium immunomodulation needs to be addressed.

Purinergic signaling is a necessary mechanism to trigger or even amplify cell communication. Its ligands, notably adenosine triphosphate (ATP) and adenosine, modulate specific membrane-bound receptors in virtually all human cells. Regardless of the stage of the pregnancy, cellular communication between maternal, placental, and fetal cells is the paramount mechanism to sustain its optimal status. In this review, we describe the crucial role of purinergic signaling on the regulation of the maternal-fetal trophic exchanges, immune control, and endocrine exchanges throughout pregnancy. The nature of the modulation of both ATP and adenosine on the embryo-maternal interface, going through placental invasion until birth delivery depends on the general maternal-fetal health state and consequently on the selective activation of their specific receptors. In addition, an increasing number of studies have been demonstrating the pivotal role of ATP and adenosine in modulating deleterious effects of suboptimal conditions of pregnancy. Here, we discuss the role of purinergic signaling on the balance that coordinates the embryo-maternal exchanges and a promising therapeutic venue in the context of pregnancy disorders.

Introduction: Preeclampsia (PE) is characterized by high blood pressure, proteinuria and/or multi-organ damage, reaching 10% of all pregnancies globally. To date, no medication can treat PE. We recently identified an upregulation of the antiangiogenic protein Thrombospondin-1 (THBS1) in human and experimental PE. THBS1 is a main activator of latent TGF-β. We postulate that THBS1-mediated TGF-β activation can contribute to impair placental angiogenesis during PE. In this study, we aim to test the effects of LSKL, an inhibitor of TGF-β activation by THBS1, on angiogenesis in placentas of a mouse model of PE and in human placental endothelial cells exposed to PE-like conditions. Methods: Heterozygous female mice overexpressing human angiotensinogen and renin (PE) or C57BL/6 (control) were treated with LSKL or control peptide SLLK (280 μM, sc) at gestational day (GD) 14.5 (n=3 pregnant mouse/group). Placentas (n=4-9/pregnancy) were collected at GD 18.5. Placental expressions of TGF-β1, β2, total/phospho SMAD2 were assessed by western blot and angiogenesis by immunohistochemistry. Endothelial cells were extracted by magnetic sorting from human placentas (n=4) of healthy pregnancies. Cells were treated with LSKL or SLLK (30 μM) under hypoxia (0.5% vs. 8% O 2 ) or thrombin (10 u/mL). THBS1 expression in cells was assessed by immunofluorescence. Cell angiogenesis was quantified by the number of closed tubes formed on matrigel (per 15,000 cells, 4h). Results: LSKL treatment reduced the expression of TGF-β2 (P Conclusion: Our results describe a significant pro-angiogenic effect of LSKL treatment by regulating THBS1 and TGF-β2 mechanisms in an experimental model of PE and in human placental endothelial cells exposed to PE-like conditions.

The placental syncytiotrophoblast is a multinucleated layer that regulates transport between the mother and fetus. Fusion of trophoblasts is essential to form this layer, but this process can be disrupted in pregnancy-related disorders such as preeclampsia. Disease progression is also associated with changes in the extracellular matrix (ECM), but whether disease-specific ECM compositions play any causal role in establishing syncytiotrophoblast disease phenotypes remains unknown. Here, we develop a decellularization-based platform to isolate and characterize the role of human placental ECM composition on cell function, while controlling for the confounding effects of matrix structure and mechanics that can arise in conventional tissue decellularization/recellularization experiments. Using this approach, we demonstrate that ECM compositional changes that occur in preeclampsia have a statistically significant effect on adhesion, spreading, and fusion of placental trophoblasts. Proteomic analysis of ECM content then allowed us to identify and recreate selected differences in matrix composition; indicating that replacement of normally present Type IV Collagen by Type I Collagen in preeclampsia significantly affects fusion efficiency. These results indicate that disease-specific matrix compositions can play an important role in trophoblast fusion, suggesting novel matrix-targeting therapeutic strategies for pregnancy-related disorders. More broadly, this work demonstrates the utility of a decellularization-based approach in understanding the functional contributions of matrix composition in driving cellular disease phenotypes.

This article aims to analyse the integration of sex and gender (s/g) by ergonomics students during their internship at the master’s degree level, following training sessions on s/g issues in the workplace. This exploratory research used a descriptive mixed-methods design, encompassing evaluation of students’ intention to use the content from the training (n = 13 students), and a multiple case study (n = 5 ergonomics interventions). The results show that while students found the training relevant, they only minimally integrated s/g in their interventions and when they did, it was primarily from an anthropometric and physiological perspective. In addition to discussing the training format limitations, the article discusses barriers to this integration: combining learning about s/g issues with learning about activity analysis is challenging; employers’ and workers’ organisations may be reluctant to approach s/g issues; and it is difficult for an ergonomist to integrate these issues when the employer’s request does not specify it.

Past research shows that stress during pregnancy predicts adverse birth outcomes. These patterns might differ based on immigration status. Our objective was to analyze differences in relationships between perceived stress during pregnancy and birth outcomes by immigration status. We recruited 81 pregnant women in Canada for a prospective longitudinal study of stress during pregnancy and infant development. Participants completed the Perceived Stress Questionnaire at 16–18, 24–26 and 32–34 weeks of pregnancy. Birth records were available for 73 women, including 24 non-immigrants, 18 long-term immigrants (≥ 5 years), and 31 recent immigrants (

The pleiotropic cytokine leukemia inhibitory factor (LIF) is a key gestational factor known to establish dynamic cellular and molecular cross talk at the feto-maternal interface. Previously, we described the regulatory role of the LIF-trophoblast-IL10 axis in the process of macrophage deactivation in response to pro-inflammatory cytokines. However, the direct regulatory effects of LIF in macrophage and trophoblast cell function remains elusive. In this study, we aimed to examine whether and how LIF regulates the behavior of macrophages and trophoblast cells in response to pro-inflammatory stress factors. We found that LIF modulated the activating effects of interferon-gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in macrophages and trophoblast cells by reducing the phosphorylation levels of signal transducer and activator of transcription-1 (Stat1) and -5 (Stat5). Cell activation with IFNγ inhibited cell invasion and migration but this immobilizing effect was abrogated when macrophages and trophoblast cells were deactivated with LIF; macrophage cell motility restitution could in part be explained by the positive effects of LIF in Stat3 activation and matrix metalloproteinase 9 (MMP-9) expression. Pharmacological inhibition of Stat1 and Stat3 indicated that IFNγ-induced Stat1 activation mediated macrophage motility inhibition, and that cell motility in IFNγ-activated macrophages is restored via LIF-induced Stat3 activation and Stat1 inhibition. Moreover, IFNγ-induced TNFα gene expression was also abrogated by LIF through Stat1 inhibition and Stat3 activation. Finally, we have found that cell invasion of trophoblast cells is inhibited when they were cocultured with GM-CSF-differentiated, IFNγ-stimulated macrophages. This effect, however, was inhibited when macrophages were exposed to LIF. Overall, this in vitro study reveals for the first time the anti-inflammatory and pro-gestational activities of LIF by acting directly on macrophages and trophoblast cells.

The placental syncytiotrophoblast is a giant multinucleated cell that forms a tree-like structure and regulates transport between mother and baby during development. It is maintained throughout pregnancy by continuous fusion of trophoblast cells, and disruptions in fusion are associated with considerable adverse health effects including diseases such as preeclampsia. Developing predictive control over cell fusion in culture models is hence of critical importance in placental drug discovery and transport studies, but this can currently be only partially achieved with biochemical factors. Here, we investigate whether biophysical signals associated with budding morphogenesis during development of the placental villous tree can synergistically direct and enhance trophoblast fusion. We use micropatterning techniques to manipulate physical stresses in engineered microtissues and demonstrate that biomimetic geometries simulating budding robustly enhance fusion and alter spatial patterns of synthesis of pregnancy-related hormones. These findings indicate that biophysical signals play a previously unrecognized and significant role in regulating placental fusion and function, in synergy with established soluble signals. More broadly, our studies demonstrate that biomimetic strategies focusing on tissue mechanics can be important approaches to design, build, and test placental tissue cultures for future studies of pregnancy-related drug safety, efficacy, and discovery.

Background: Although numerous studies have assessed physical activity during pregnancy and relationships with infant outcomes, such as birthweight, few have evaluated sedentary behavior. Our objective was to evaluate sedentary behavior across pregnancy and relationships with infant birthweight in a sociodemographically diverse sample. Methods: We measured device-assessed sedentary behavior and physical activity over three days at 16–18, 24–26, and 32–34 weeks gestation and infant birthweight from medical records among 71 participants. We used linear regression to assess relationships between sedentary behavior at each evaluation period with birthweight-for-gestational age Z-scores (BW-for-GA). Results: There were no linear relationships between sedentary behavior and BW-for-GA at any evaluation period. We observed a modest curvilinear relationship between sedentary behavior at 16–18 weeks and BW-for-GA (R2 = 0.073, p = 0.021). Low and high levels of sedentary behavior predicted lower BW-for-GA. Multivariate models suggested that this relationship was independent of physical activity levels. Conclusions: Considering the high levels of sedentary behavior during pregnancy observed in many studies, even modest associations with birthweight merit further consideration. Relationships might not be evident later in pregnancy or if only linear relationships are considered. More detailed studies could help guide recommendations on sedentary behavior during pregnancy and the development of more comprehensive interventions.

Self-reported maternal prenatal stress (MPS) has been associated with earlier febrile seizure (FS) age of onset in offspring. Studies are needed to understand how the biological systems associated with exposure to psychological MPS are linked to seizure disorders in children. The present study aimed to investigate whether placental markers of MPS are linked to FS incidence and age at first occurrence. A subsample of children with FS (n = 28) and matched controls (n = 84), were drawn from the longitudinal 3D pregnancy cohort (N = 2366 mother-child dyads). Expression of placental genes associated with glucocorticoids, serotonin and fetal/placental growth were analysed from placental tissues, compared between groups and associated with age at first FS. Overall placental normalized gene expression was statistically different (p < .001). Children with FS showed overexpression of the serotonin transporter (mean difference = 0.61, 95% confidence interval [CI] = 0.9-1.13), connexin 43 (mean difference = 0.69, 95% CI = 0.30-1.09), zonula occludens-1 (mean difference = 0.84, 95% CI = 0.42-1.26) and underexpression of glucocorticoid receptor β (mean difference = 0.84, 95% CI = -1.49 to 0.19) and serotonin receptor 2B (mean difference = 1.57, 95% CI = -2.35 to 0.78) compared to controls. Increased expression of the serotonin transporter predicted 37.2% in variation of age at first FS. The correlation matrix showed pregnancy-specific anxiety during the second trimester was moderately associated with age at first FS (r = -0.38) but was not a significant predictor in the regression model. Although our current results do not display a significant effect of self-reported MPS on FS, the present study is the first to show that placental gene biomarkers usually known to be associated with MPS display different expressions in children with FS. Specifically, our results suggest that placental genes associated with the glucocorticoid, serotonergic and fetal/placental growth systems may be candidate mechanisms leading to increased vulnerability offspring in FS. Because self-reported MPS was not found as a significant predictor in our statistical models, future studies are needed to investigate the mechanisms causing the observed changes in placental genes and their association with seizure disorders.

Objectives: Placental insufficiency contributes to altered maternal-fetal amino acid transfer, and thereby to poor fetal growth. An important placental function is the uptake of tryptophan and its metabolism to serotonin (5-HT) and kynurenine metabolites, which are essential for fetal development. We hypothesised that placental 5-HT content will be increased in pregnancies affected with fetal growth restriction (FGR).Methods: The components of the 5-HT synthetic pathway were determined in chorionic villus samples (CVS) from small-for gestation (SGA) and matched control collected at 10-12 weeks of human pregnancy; and in placentae from third trimester FGR and gestation-matched control pregnancies using the Fluidigm Biomarker array for mRNA expression, the activity of the enzyme TPH and 5-HT concentrations using an ELISA.Results: Gene expression for the rate limiting enzymes, TPH1 and TPH2; 5-HT transporter, SLC6A4; and 5-HT receptors HTR5A, HTR5B, HTR1D and HTR1E were detected in all CVS and third trimester placentae. No significant difference in mRNA was observed in SGA compared with control. Although there was no significant change in TPH1 mRNA, the mRNA of TPH2 and SLC6A4 was significantly decreased in FGR placentae (p Conclusion: This study reports differential expression and activity of the key components of the 5-HT synthetic pathway associated with the pathogenesis of FGR. Further studies are required to elucidate the functional consequences of increased placental 5-HT in FGR pregnancies.

Over the last few years, intrauterine administration of autologous peripheral blood mononuclear cells (PBMC) has been proposed as new immunotherapy for patients with unexplained recurrent implantation failure (RIF). In these patients, administration of activated PBMC before embryo transfer results in a 2-fold increase in live birth rates(Yang et al., 2020). In this study we evaluated the role of T cells to promotes human endometrial receptivity. On the day of ovulation, PBMC were isolated from and activated with T cells mitogen, the phytohemagglutinin (PHA) and hCG for 48-h in a conditioned culture medium. Distributions of CD4+ T cells were characterized in 157 patients by flow cytometry before and after PHA/hCG activation. Cytokine production was analyzed by cytometric beads array. We observed in RIF patients a significant decrease in Th2 and natural Treg cells before activation with PHA/hCG and an increase of Th17 cells after activation compared to intrauterine sperm insemination (IUI) and in vitro fertilization (IVF) groups. Furthermore, the hCG/PHA treatment increases anti-inflammatory T cells (Th2 and Treg cells) compared to non-treated T cells. Principal component analysis (PCA) performed on CD4 T cell subtypes revealed a different cellular profile in the RIF compared to the IUI and IVF groups. This inflammatory state change could explain how endometrium immunomodulation by hCG-activated PBMC helps patients with unexplained RIF to reach implantation.

Pregnancy is a complex process requiring tremendous physiological changes in the mother in order to fulfill the needs of the growing fetus, and to give birth, expel the placenta and nurse the newborn. These physiological modifications are accompanied with psychological changes, as well as with variations in habits and behaviors. As a result, this period of life is considered as a sensitive window as impaired functional and physiological changes in the mother can have short- and long-term impacts on her health. In addition, dysregulation of the placenta and of mechanisms governing placentation have been linked to chronic diseases later-on in life for the fetus, in a concept known as the Developmental Origin of Health and Diseases (DOHaD). This concept stipulates that any change in the environment during the pre-conception and perinatal (in utero life and neonatal) period to puberty, can be "imprinted" in the organism, thereby impacting the health and risk of chronic diseases later in life. Pregnancy is a succession of events that is regulated, in large part, by hormones and growth factors. Therefore, small changes in hormonal balance can have important effects on both the mother and the developing fetus. An increasing number of studies demonstrate that exposure to endocrine disrupting compounds (EDCs) affect both the mother and the fetus giving rise to growing concerns surrounding these exposures. This review will give an overview of changes that happen during pregnancy with respect to the mother, the placenta, and the fetus, and of the current literature regarding the effects of EDCs during this specific sensitive window of exposure.

The syncytiotrophoblast is a multinucleated layer that plays a critical role in regulating functions of the human placenta during pregnancy. Maintaining the syncytiotrophoblast layer relies on ongoing fusion of mononuclear cytotrophoblasts throughout pregnancy, and errors in this fusion process are associated with complications such as preeclampsia. While biochemical factors are known to drive fusion, the role of disease-specific extracellular biophysical cues remains undefined. Since substrate mechanics play a crucial role in several diseases, and preeclampsia is associated with placental stiffening, we hypothesize that trophoblast fusion is mechanically regulated by substrate stiffness. We developed stiffness-tunable polyacrylamide substrate formulations that match the linear elasticity of placental tissue in normal and disease conditions, and evaluated trophoblast morphology, fusion, and function on these surfaces. Our results demonstrate that morphology, fusion, and hormone release is mechanically-regulated via myosin-II; optimal on substrates that match healthy placental tissue stiffness; and dysregulated on disease-like and supraphysiologically-stiff substrates. We further demonstrate that stiff regions in heterogeneous substrates provide dominant physical cues that inhibit fusion, suggesting that even focal tissue stiffening limits widespread trophoblast fusion and tissue function. These results confirm that mechanical microenvironmental cues influence fusion in the placenta, provide critical information needed to engineer better in vitro models for placental disease, and may ultimately be used to develop novel mechanically-mediated therapeutic strategies to resolve fusion-related disorders during pregnancy.

Background: Past research shows that psychosocial stress and distress predict sedentary behavior and physical activity, but few studies focus on pregnant women. Our objective was to analyze relationships between psychosocial stress and distress with sedentary behavior and physical activity among pregnant women in Canada. Methods: We analyzed objectively-measured sedentary behavior and physical activity at 16&ndash, 18, 24&ndash, 26, and 32&ndash, 24 weeks pregnancy in a sociodemographically diverse cohort of 70 women in Montreal, Canada. Participants completed the Perceived Stress Questionnaire and wore an accelerometer for 3 days that quantified sitting time and steps per day. We used univariate general linear models to analyze relationships between perceived stress with sedentary behavior and physical activity at each evaluation. To assess generalizability, we analyzed relationships between psychological distress with self-reported leisure-time sedentary behavior and daily energy expenditure in transportation and leisure physical activities among a sample representative of 166,095 women in the Canadian Community Health Survey. Results: In the Montreal cohort, we observed a positive association between perceived stress and sitting time, with small to moderate effect sizes (partial &eta, 2 = 0.08&ndash, 0.16). We observed negative relationships between perceived stress and steps per day at the first two evaluations only, with small to moderate effect sizes (partial &eta, 0.11). Relationships for sedentary behavior were similar in the nationwide sample, but with smaller effect sizes (partial &eta, 2 = 0.02). There were no relationships between distress and physical activity in the nationwide sample. Conclusion: Psychosocial stress represents one risk factor for sedentarity, with relationships evident throughout pregnancy and at the population level. Relationships with physical activity are less consistent, but stress might represent a risk factor for low physical activity in early to mid-pregnancy. Results might guide the development of more comprehensive interventions targeting stress, sedentarity, and physical activity. In particular, integrating psychosocial health into interventions to reduce sedentarity, and including concrete guidelines on sedentary behavior in psychosocial health interventions, might be prioritized.

International audience; We investigated the effects of a natural disaster (a sudden flood) as a source of prenatal maternal stress (PNMS) on the placental glucocorticoid system and glucose transporters. Whether the gestational age at the time of the flood moderated these effects was also evaluated. Placental samples were collected from participants in the 2011 Queensland Flood Study (QF2011) who were pregnant in the first or second trimester at the onset of the flood. Detailed questionnaire results for objective hardship and composite subjective distress were obtained to assess stress levels. Subjective distress was significantly associated with a reduction in placental NR3C1-β mRNA levels for males only (β = -0.491, p = 0.005). In female placentas, objective hardship was marginally linked with lower SLC2A1 mRNA levels while subjective distress was a marginally significant predictor of higher placental SLC2A4 mRNA levels. Gestational age at the time of the flood was a significant moderator of the effect of subjective distress on placental mRNA levels for NR3C1-α (p = 0.046) and HSD11B1 (p = 0.049) in male placentas: if the flood occurred in mid-pregnancy, lower subjective distress predicted higher HSD11B1 while higher subjective distress predicted lower NR3C1-α placental mRNA level. While results did not show any PNMS effects on placental HSD11B2 mRNA and protein levels, and activity, we showed a reduction in placental NR3C1-β mRNA level in male placentas. Our results show evidence of distinct placental glucocorticoid and glucose systems adaptations to PNMS as a function of fetal sex and gestational timing of exposure, with high subjective PNMS in mid-pregnancy associated with lower levels of expression of glucocorticoid-promoting gene in males, leaving the fetus less protected against maternal stress. The exact mechanism by which natural disaster-related PNMS acts on the placenta and the impact on fetal programming requires further investigation.

Serotonin plays a crucial role in mussel survival and reproduction. Although the serotonin system can be affected by metals, the effects of environmental concentrations of metals such as manganese (Mn), lead (Pd), and cadmium (Cd) have never been studied in blue mussels. The present study aimed to determine the effects of exposure to Mn, Pb, or Cd on serotonin levels, monoamine oxidase (MAO) activity, and serotonin transporter (SERT) levels in the blue mussel Mytilus edulis. Mussels were exposed in vivo to increasing and environmentally relevant doses of Mn (10-1000 nM; 0.5-50 μg/L), Pb (0.01-10 nM; 0.002-2 μg/L), or Cd (0.01-10 nM; 0.001-1 μg/L) for 28 d. Serotonin levels, MAO activity, and SERT expression were analyzed in the mussel mantle. Expression of SERT protein was significantly decreased, by up to 81%, following Mn, Pb, or Cd exposure. The activity of MAO in females was almost 2-fold higher, versus males, in nonexposed control mussels. In mussels exposed to 0.1 nM of Pb (0.02 μg/L), MAO activity was increased in males and decreased in females. In Cd-exposed mussels, a sex-dependent, inverted nonmonotonic pattern of MAO activity was observed. These results clearly indicate that low environmental concentrations of Mn, Pb, and Cd affect the serotonin system in blue mussels. Environ Toxicol Chem 2018;37:192-200. © 2017 SETAC.

International audience; Estrogen biosynthesis during pregnancy is dependent on the collaboration between the fetus producing the androgen precursors, and the placenta expressing the enzyme aromatase (CYP19). Disruption of estrogen production by contaminants may result in serious pregnancy outcomes. We used our recently developed in vitro co-culture model of fetoplacental steroidogenesis to screen the effects of three neonicotinoid insecticides on the catalytic activity of aromatase and the production of steroid hormones. A co-culture of H295R human adrenocortical carcinoma cells with fetal characteristics and BeWo human choriocarcinoma cells which display characteristics of the villous cytotrophoblast was exposed for 24h to various concentrations of three neonicotinoids: thiacloprid, thiamethoxam and imidacloprid. Aromatase catalytic activity was determined in both cell lines using the tritiated water-release assay. Hormone production was measured by ELISA. The three neonicotinoids induced aromatase activity in our fetoplacental co-culture and concordingly, estradiol and estrone production were increased. In contrast, estriol production was strongly inhibited by the neonicotinoids. All three pesticides induced the expression of CYP3A7 in H295R cells, and this induction was reversed by co-treatment of H295R cells with exogenous estriol. CYP3A7 is normally expressed in fetal liver and is a key enzyme involved in estriol synthesis. We suggest that neonicotinoids are metabolized by CYP3A7, thus impeding the 16α-hydroxylation of fetal DHEA(-sulfate), which is normally converted to estriol by placental aromatase. We successfully used the fetoplacental co-culture as a physiologically relevant tool to highlight the potential effects of neonicotinoids on estrogen production, aromatase activity and CYP3A7 expression during pregnancy.

The benefits of breastfeeding over formula feed are widely appreciated. However, for many mothers breastfeeding is not possible, highlighting the need for a significant improvement in the contents of formula feed. In this article, the overlooked role of melatonin and the melatonergic pathways in breast milk and in the regulation of wider breast milk components are reviewed. There is a growing appreciation that the benefits of breastfeeding are mediated by its effects in the infant gut, with consequences for the development of the gut-brain axis and the immune system. The melatonergic pathways are intimately associated with highly researched processes in the gut, gut microbiome and gut-brain axis. As the melatonergic pathways are dependent on the levels of serotonin availability as a necessary precursor, decreased melatonin is linked to depression and depression-associated disorders. The association of breastfeeding and the gut-brain axis with a host of medical conditions may be mediated by their regulation of processes that modulate depression susceptibility. The biological underpinnings of depression include increased levels of pro-inflammatory cytokines, oxidative stress, kynurenine pathway activity and dysregulation of the hypothalamic-pituitary adrenal axis, all of which can decrease melatonergic pathway activity. The inclusion of the melatonergic pathways in the biological interactions of breast milk and gut development has significant theoretical and treatment implications, as well as being important to the prevention of a host of infant-, child- and adult-onset medical conditions.

International audience; The role of placental serotonin has been an active topic of research notably because of its crucial role in brain development. However, which cell types synthesize serotonin in human placenta remains unknown. Moreover, it is not known if the two tryptophan hydroxylase isoforms (TPH1 and TPH2), the rate-limiting enzymes in serotonin biosynthesis, are expressed in placenta. Human placentas were obtained in first trimester or at term, and trophoblast cells were isolated and purified using a magnetic cell sorter and placed in primary culture. The tissue sublocalization of each TPH was determined by immunohistochemistry. TPH expression in primary villous trophoblasts was determined by PCR and immunoblotting, and serotonin secretion by LC-MS/MS. Villous cytotrophoblasts, syncytiotrophoblast, fetal capillaries, extravillous cytotrophoblasts, and decidual cells co-expressed TPH1 and TPH2. Moreover, mRNA and protein levels of both TPHs were detected in human primary trophoblast as well as in mouse placental tissues. Finally, human trophoblast cells were shown to produce serotonin de novo. This study demonstrates that both TPH1 and TPH2 are expressed in human and mouse placenta throughout pregnancy and helps to better understand the placental serotonin system, which is crucial for healthy pregnancy and fetal development. It is therefore important to further understand regulation of the placental serotonin system and how its disruption during pregnancy may impact the developing fetus and subsequent child programming.

International audience; Dechlorane Plus (DP) is a chlorinated flame retardant used mainly in electrical wire and cable coating, computer connectors, and plastic roofing materials. Concentrations of DP (syn and anti isomers) are increasingly being reported in aquatic ecosystems worldwide. However, there is exceedingly little information on the exposure-related toxicity of DP in aquatic organisms, especially in bivalves. The objective of this study was to investigate the in vivo and in vitro effects of DP exposure on histopathology, lipid peroxidation (LPO) levels, cyclooxygenase (COX) activity, phagocytosis capacity and efficiency, and DNA strand breakage in the blue mussel (Mytilus edulis) following a 29days exposure (0.001, 0.01, 0.1 and 1.0μg DP/L). Blue mussels accumulated DP in muscle and digestive gland in a dose-dependent manner. LPO levels in gills were found to increase by 82% and 67% at the 0.01 and 1.0μg DP/L doses, respectively, while COX activity in gills decreased by 44% at the 1μg/L dose. No histopathological lesion was found in gonads following DP exposure. Moreover, no change in hemocyte DNA strand breakage, phagocytosis rate, and viability was observed following DP exposure. Present study showed that toxicity of DP may occur primarily via oxidative stress in the blue mussel and potentially other bivalves, and that gills represent the most responsive tissue to this exposure.

Workshops are an important part of the IFPA annual meeting, as they allow for discussion of specialized topics. At the IFPA meeting 2015 there were twelve themed workshops, three of which are summarized in this report. These workshops were related to various aspects of placental biology but collectively covered areas of pregnancy pathologies and placental metabolism: 1) nanomedicine applications and exosome biology; 2) xenobiotics and endocrine disruptors and pregnancy; 3) lipid mediators and placental function. Fil: Albrecht, Claudia. University of Berne; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Caniggia, I.. Lunenfeld-Tanenbaum Research Institute; Canadá Fil: Clifton, V.. Matter Hospital; Australia Fil: Göhner, C.. University of Groningen; Países Bajos Fil: Harris, L.. University of Manchester; Reino Unido Fil: Hemmings, D.. University of Alberta; Canadá Fil: Jawerbaum, Alicia Sandra. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Johnstone, E.. University of Manchester; Reino Unido Fil: Jones, H.. Cincinnati Children's Hospital Medical Center; Estados Unidos Fil: Keelan, J.. University of Western Australia; Australia Fil: Lewis, R.. University of Southampton; Reino Unido Fil: Mitchell, M.. University of Queensland; Australia Fil: Murthi, P.. Monash University; Australia Fil: Powell, T.. University of Colorado Anschutz Medical Campus; Estados Unidos Fil: Saffery, R.. The University of Melbourne; Australia Fil: Smith, R.. University of Newcastle; Reino Unido Fil: Vaillancourt, C.. Université du Québec a Montreal; Canadá Fil: Wadsack, C.. University of Graz; Austria Fil: Salomon, C.. University of Queensland; Australia

International audience; Infection or inflammation during pregnancy is known to lead to maternal immune activation triggering a fetal inflammatory response syndrome associated with deleterious effects, such as brain injury and neurodevelopmental disabilities. Group B Streptococcus (GBS) - one of the most common bacterium colonizing pregnant women - can be responsible for chorioamnionitis. Given that interleukin (IL)-1β has a major role in anti-GBS host defense, we hypothesized that IL-1β-driven innate immune response is implicated in GBS-induced chorioamnionitis. Using a rat model of GBS-induced chorioamnionitis, this study showed that inflammatory response to this pathogen was associated with maternal and placental IL-1β hyper expression. Following placental chemokine (C-X-C motif) ligand 1 (CXCL1) production, polymorphonuclear leukocytes (PMN) placental infiltration started at 24 h post-GBS exposure, and MMP-10 was released within these placentas. At 72 h, PMN infiltration extended to membranes and to membranes' arteries. This was associated with IL-1β release within the fetus blood at 72 h. Such a GBS-associated inflammatory cascade might be deleterious for fetal organs. These results pave the way toward targeted placento-protective anti-inflammatory strategies against GBS-induced chorioamnionitis.

International audience; Editorial

Work that addresses the cumulative impacts of resource extraction on environment, community, and health is necessarily large in scope. This paper presents experiences from initiating research at this intersection and explores implications for the ambitious, integrative agenda of planetary health. The purpose is to outline origins, design features, and preliminary insights from our intersectoral and international project, based in Canada and titled the &ldquo, Environment, Community, Health Observatory&rdquo, (ECHO) Network. With a clear emphasis on rural, remote, and Indigenous communities, environments, and health, the ECHO Network is designed to answer the question: How can an Environment, Community, Health Observatory Network support the integrative tools and processes required to improve understanding and response to the cumulative health impacts of resource development? The Network is informed by four regional cases across Canada where we employ a framework and an approach grounded in observation, &ldquo, taking notice for action&rdquo, and collective learning. Sharing insights from the foundational phase of this five-year project, we reflect on the hidden and obvious challenges of working across scales, sectors, and sites, and the overlap of generative and uncomfortable entanglements associated with health and resource development. Yet, although intersectoral work addressing the cumulative impacts of resource extraction presents uncertainty and unresolved tensions, ultimately we argue that it is worth staying with the trouble.

The aim of this article is to examine the impacts of incorporating sex and gender (s/g) analysis in integrated knowledge translation (iKT) initiatives in the field of ergonomics and occupational health. The article presents findings based on a retrospective analysis of twelve intervention-research (IR) studies, including a thematic content analysis of in-depth interviews conducted with 15 researchers involved in these IRs. The findings offer an overview of various categories of impacts, such as changes in partners' views, in workplace settings and conditions, in practices and policies, and in economic outcomes. In these types of IR, health effects measurement is not the main objective, and direct health outcomes are difficult to assess. Explicitly talking about sex/gender led more often to system-level changes but less often to workplace-level changes, compared to interventions where sex/gender was not identified as a specific object of the intervention.

International audience; We have reviewed the scientific literature related to four diseases in which to serotonin (5-HT) is involved in the etiology, herein named 5-HT-linked diseases, and whose prevalence is influenced by estrogenic status: depression, migraine, irritable bowel syndrome and eating disorders. These diseases all have in common a sex-dimorphic prevalence, with women more frequently affected than men. The co-occurrence between these 5-HT-linked diseases suggests that they have common physiopathological mechanisms. In most 5-HT-linked diseases (except for anorexia nervosa and irritable bowel syndrome), a decrease in the serotonergic tone is observed and estrogens are thought to contribute to the improvement of symptoms by stimulating the serotonergic system. Human pregnancy is characterized by a unique 5-HT and estrogen synthesis by the placenta. Pregnancy-specific disorders, such as hyperemesis gravidarum, gestational diabetes mellitus and pre-eclampsia, are associated with a hyperserotonergic state and decreased estrogen levels. Fetal programming of 5-HT-linked diseases is a complex phenomenon that involves notably fetal-sex differences, which suggest the implication of sex steroids. From a mechanistic point of view, we hypothesize that estrogens regulate the serotonergic system, resulting in a protective effect against 5-HT-linked diseases, but that, in turn, 5-HT affects estrogen synthesis in an attempt to retrieve homeostasis. These two processes (5-HT and estrogen biosynthesis) are crucial for successful pregnancy outcomes, and thus, a disruption of this 5-HT-estrogen relationship may explain pregnancy-specific pathologies or pregnancy complications associated with 5-HT-linked diseases.

Summary: Tryptophan as the precursor of several active compounds, including kynurenine and serotonin, is critical for numerous important metabolic functions. Enhanced tryptophan metabolism toward the kynurenine pathway has been associated with myelodysplastic syndromes (MDSs), which are preleukemic clonal diseases characterized by dysplastic bone marrow and cytopenias. Here, we reveal a fundamental role for tryptophan metabolized along the serotonin pathway in normal erythropoiesis and in the physiopathology of MDS-related anemia. We identify, both in human and murine erythroid progenitors, a functional cell-autonomous serotonergic network with pro-survival and proliferative functions. In vivo studies demonstrate that pharmacological increase of serotonin levels using fluoxetine, a common antidepressant, has the potential to become an important therapeutic strategy in low-risk MDS anemia refractory to erythropoietin. : Sibon et al. identify a cell-autonomous serotonergic network in human and mouse erythroid progenitors. Reduced levels of serotonin lead to decreased proliferation and survival of erythroid progenitors. Increasing serotonin’s concentration through fluoxetine, commonly used to treat depression, could be a valuable therapeutic intervention to correct myelodysplastic-syndrome-related anemia. Keywords: serotonin, Tph1, erythropoiesis, myelodysplastic syndrome, anemia, SSRI

International audience; The prototype death receptor CD95 (Fas) and its ligand, CD95L (FasL), have been thoroughly studied due to their role in immune homeostasis and elimination of infected and transformed cells. The fact that CD95 is present in female reproductive cells and modulated during embryogenesis and pregnancy has raised interest in its role in immune tolerance to the fetoplacental unit. CD95 has been shown to be critical for proper embryonic formation and survival. Moreover, altered expression of CD95 or its ligand causes autoimmunity and has also been directly involved in recurrent pregnancy losses and pregnancy disorders. The objective of this review is to summarize studies that evaluate the mechanisms involved in the activation of CD95 to provide an updated global view of its effect on the regulation of the maternal immune system. Modulation of the CD95 system components may be the immune basis of several common pregnancy disorders.

Lead interferes with cortisol blood concentration, increases the risk of obstetrical complications, and could alter fetal development. The placenta controls maternal cortisol transfer to the fetus by the activity of the type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2), which converts cortisol into inactive cortisone. This study determines the effect of lead on the expression and activity of the placental 11β-HSD2 in human trophoblast-like BeWo cells. Cells were treated with increasing concentration (0–1000 nM) of PbCl2 for 24 h. 11β-HSD2 protein expression was reduced by 45% at 1000 nM of PbCl2 compared to untreated cells, while the activity was significantly reduced by PbCl2 at 10, 100 and 1000 nM. This study shows the direct inhibitory action of lead on placental 11β-HSD2 activity and suggests that this heavy metal reduces the efficiency of the placental protection against the adverse effects of high cortisol level during fetal development.

The biological underpinnings that drive the plethora of breastfeeding benefits over formula-feeding is an area of intense research, given the cognitive and emotional benefits as well as the offsetting of many childhood- and adult-onset medical conditions that breast-feeding provides. In this article, we review the research on the role of melatonin in driving some of these breastfeeding benefits. Melatonin is a powerful antioxidant, anti-inflammatory and antinociceptive as well as optimizing mitochondrial function. Melatonin is produced by the placenta and, upon parturition, maternal melatonin is passed to the infant upon breastfeeding with higher levels in night-time breast milk. As such, some of the benefits of breastfeeding may be mediated by the higher levels of maternal circulating night-time melatonin, allowing for circadian and antioxidant effects, as well as promoting the immune and mitochondrial regulatory aspects of melatonin; these actions may positively modulate infant development. Herein, it is proposed that some of the benefits of breastfeeding may be mediated by melatonin's regulation of the infant's gut microbiota and immune responses. As such, melatonin is likely to contribute to the early developmental processes that affect the susceptibility to a range of adult onset conditions. Early research on animal models has shown promising results for the regulatory role of melatonin.

Background Human studies are inconsistent with respect to an association between treatment with selective serotonin and serotonin–norepinephrine reuptake inhibitors (SSRI/SNRIs) and an increase in the incidence of congenital heart defects. Here we tested the hypothesis that in utero exposure to venlafaxine, a highly prescribed SNRI, increases the incidence of fetal heart defects and alters placental and fetal heart serotonin signaling in the rat. Methods Timed-pregnant Sprague Dawley rats were gavaged daily with venlafaxine hydrochloride (0, 3, 10, 30, or 100 mg/kg/day) from gestation day 8 to 20. On gestation day 21, fetuses were examined for external and internal malformations; placentas and fetal hearts were collected for the analysis of gene expression. Results Venlafaxine had no effect on the number of live fetuses, fetal body weights, or external morphology in the absence of maternal toxicity. However, venlafaxine significantly increased the placental index (fetal body/placental weight ratio) and the incidence of fetal cardiac anomalies. Venlafaxine exposure decreased placental expression of the serotonin transporter (SERT/Slc6a4) at the transcript and protein levels. In contrast, venlafaxine increased SERT expression in the hearts of female, but not male, fetuses. Expression of the serotonin 2B receptor (5-HT2B/Htr2b) and of fibroblast growth factor 8 was induced in fetal hearts. Conclusion In utero venlafaxine exposure altered the placental index and induced fetal cardiac anomalies in rats. We propose that the increased incidence of cardiac anomalies is mediated through alterations in serotonin signaling in the placenta and fetal heart. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1044–1055, 2016. © 2016 Wiley Periodicals, Inc.

Melatonin is an important neuroprotective factor and its receptors are expressed in the fetal brain. During normal pregnancy, maternal melatonin level increases progressively until term and is highly transferred to the fetus, with an important role in brain formation and differentiation. Maternal melatonin provides the first circadian signal to the fetus. This indolamine is also produced de novo and plays a protective role in the human placenta. In pregnancy disorders, both maternal and placental melatonin levels are decreased. Alteration in maternal melatonin level has been associated with disrupted brain programming with long-term effects. Melatonin has strong antioxidant protective effects directly and indirectly via the activation of its receptors. The fetal brain is highly susceptible to oxygenation variation and oxidative stress that can lead to neuronal development disruption. Based on that, several approaches have been tested as a treatment in case of pregnancy disorders and melatonin, through its neuroprotective effect, has been recently accepted against fetal brain injury. This review provides an overview about the protective effects of melatonin during pregnancy and on fetal brain development.