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Pregnant women are daily exposed to environmental contaminants, including endocrine disruptors that can impact the offspring's health. This study aimed to evaluate the effects of maternal oral exposure to a mixture of contaminants at a dose mimicking women's exposure, during folliculogenesis and/or preimplantation period (FED and ED groups, respectively) on the fetoplacental phenotype in a rabbit model. The mixture (DEHP, pp'DDE, ß-HCH, HCB, BDE-47, BPS, PFOS, PFOA) was defined based on data from HELIX and INMA cohorts. FED and ED females or unexposed females (control) were inseminated, their embryos were collected and transferred to unexposed control recipient rabbits at 80 hours post-insemination. The effects of maternal FED and ED exposure were evaluated on fetoplacental growth and development by ultrasound, fetoplacental biometry, fetal metabolism, placental structure and function. The results demonstrated that the mixture weakly affected ultrasound measurements, as only placental volume increased significantly in FED vs ED. Analysis of placental structure demonstrated that the volume fraction of the maternal blood space was increased in FED vs control. Pre- and/or periconception exposure did not affect biometric at the end of gestation, but affected FED fetal biochemistry. Plasma triglyceride concentration was reduced compared to control. However, total cholesterol, urea, ASAT and ALAT in fetal blood were affected in both exposed groups. Multiple factor analysis, including biometric, biochemical, and stereological datasets, indicated that the three groups were significantly different. Additionally, several placental genes were differentially expressed between groups, compared two by two, in a sex-specific manner, with more difference in females than in males. The differentially expressed genes were involved in lipid, cholesterol, and drug/xenobiotic metabolism in both sexes. These results indicate that maternal exposure to environmental contaminants during crucial developmental windows only mildly impaired fetoplacental development but disturbed fetal blood biochemistry and placental gene expression with potential long-term effects on offspring phenotype.
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BACKGROUND: Airborne pollution particles have been shown to translocate from the mother's lung to the fetal circulation, but their distribution and internal placental-fetal tissue load remain poorly explored. Here, we investigated the placental-fetal load and distribution of diesel engine exhaust particles during gestation under controlled exposure conditions using a pregnant rabbit model. Pregnant dams were exposed by nose-only inhalation to either clean air (controls) or diluted and filtered diesel engine exhaust (1 mg/m3) for 2 h/day, 5 days/week, from gestational day (GD) 3 to GD27. At GD28, placental and fetal tissues (i.e., heart, kidney, liver, lung and gonads) were collected for biometry and to study the presence of carbon particles (CPs) using white light generation by carbonaceous particles under femtosecond pulsed laser illumination. RESULTS: CPs were detected in the placenta, fetal heart, kidney, liver, lung and gonads in significantly higher amounts in exposed rabbits compared with controls. Through multiple factor analysis, we were able to discriminate the diesel engine exposed pregnant rabbits from the control group taking all variables related to fetoplacental biometry and CP load into consideration. Our findings did not reveal a sex effect, yet a potential interaction effect might be present between exposure and fetal sex. CONCLUSIONS: The results confirmed the translocation of maternally inhaled CPs from diesel engine exhaust to the placenta which could be detected in fetal organs during late-stage pregnancy. The exposed can be clearly discriminated from the control group with respect to fetoplacental biometry and CP load. The differential particle load in the fetal organs may contribute to the effects on fetoplacental biometry and to the malprogramming of the fetal phenotype with long-term effects later in life.
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Placenta , Emissões de Veículos , Animais , Gravidez , Coelhos , Feminino , Emissões de Veículos/toxicidade , Carbono/toxicidade , Pulmão , FígadoRESUMO
The developmental origins of health and disease (DOHaD) shows that a relationship exists between parental environment at large, foeto-placental development and the risk for the offspring to develop non-transmittable disease(s) in adulthood. This concept has been validated in both humans and livestock. In mammals, after fertilization and time spent free in the maternal reproductive tract, the embryo develops a placenta that, in close relationship with maternal endometrium, is the organ responsible for exchanges between dam and foetus. Any modification of the maternal environment can lead to adaptive mechanisms affecting placental morphology, blood flow, foetal-maternal exchanges (transporters) and/or endocrine function, ultimately modifying placental efficiency. Among deleterious environments, undernutrition, protein restriction, overnutrition, micronutrient deficiencies and food contaminants can be outlined. When placental adaptive capacities become insufficient, foetal growth and organ formation is no longer optimal, including foetal gonadal formation and maturation, which can affect subsequent offspring fertility. Since epigenetic mechanisms have been shown to be key to foetal programming, epigenetic modifications of the gametes may also occur, leading to inter-generational effects. After briefly describing normal gonadal development in domestic species and inter-species differences, this review highlights the current knowledge on intra-uterine programming of offspring fertility with a focus on domestic animals and underlines the importance to assess transgenerational effects on offspring fertility at a time when new breeding systems are developed to face the current climate changes.
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The rates of obesity and being overweight are increasing all around the world, especially among women of childbearing age, in part due to overconsumption of lipids. The aim of this summary review was to present the cellular and molecular effects of a hyperlipidic high-cholesterol (H) diet on the maternal and offspring phenotype at the early embryonic, neonatal, weaning and adult stages while considering the effects of sex and to identify the window(s) of vulnerability linked to this exposure in a rabbit model. Before breeding, the H diet induced dyslipidemia and aortic atherosclerosis lesions and increased the number of atretic follicles. In the offspring, the H diet disrupted the embryonic phenotype and induced fetal hypotrophy associated with sex-specific disturbances of the feto-placental unit. In adulthood, the offspring of the H dams were heavier and hyperphagic and had increased blood pressure associated with disturbed gonadal development in both sexes. Vulnerability windows were explored via embryo transfers. The maternal gestational diet was shown to play a key role in the feto-placental phenotype, and preconception programming was unquestionably also observed. These two periods could represent windows of intervention in the context of obesity or being overweight to limit fetal and placental consequences.
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Placenta , Efeitos Tardios da Exposição Pré-Natal , Animais , Masculino , Gravidez , Feminino , Coelhos , Humanos , Exposição Materna , Sobrepeso , Obesidade/etiologia , Fenótipo , Colesterol , Dieta Hiperlipídica/efeitos adversosRESUMO
Within the past decades, major progress has been accomplished in isolating germ/stem/pluripotent cells, in refining culture medium and conditions and in establishing 3-dimensional culture systems, towards developing organoids for organs involved in reproduction in mice and to some extent in humans. Haploid male germ cells were generated in vitro from primordial germ cells. So were oocytes, with additional support from ovarian cells and subsequent follicle culture. Going on with the female reproductive tract, spherical oviduct organoids were obtained from adult stem/progenitor cells. Multicellular endometrial structures mimicking functional uterine glands were derived from endometrial cells. Trophoblastic stem cells were induced to form 3-dimensional syncytial-like structures and exhibited invasive properties, a crucial point for placentation. Finally, considering the embryo itself, pluripotent embryonic cells together with additional extra-embryonic cells, could self-organize into a blastoid, and eventually into a post-implantation-like embryo. Most of these accomplishments have yet to be reached in farm animals, but much effort is devoted towards this goal. Here, we review the progress and discuss the specific challenges of developing organoids for the study of reproductive biology in these species. We consider the use of such organoids in basic research to delineate the physiological mechanisms involved at each step of the reproductive process, or to understand how they are altered by environmental factors relevant to animal breeding. We evaluate their potential in reproduction of animals with a high genetic value, from a breeding point of view or in the context of preserving local breeds with limited headcounts.
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Animais Domésticos/anatomia & histologia , Técnicas de Cultura de Células/veterinária , Organoides/citologia , Reprodução , Técnicas Reprodutivas/veterinária , Animais , Técnicas de Cultura de Células/métodosRESUMO
BACKGROUND: Results from observational and experimental studies indicate that exposure to air pollutants during gestation reduces birth weight, whereas little is known on potential cardiometabolic consequences for the offspring at adulthood. OBJECTIVES: Our aim was to evaluate the long-term effects of gestational exposure to diesel engine exhaust (DE) on adult offspring phenotype in a rabbit model. METHODS: The protocol was designed to mimic human exposure in large European cities. Females rabbits were exposed to diluted (1 mg/m3) DE (exposed, n = 9) or clean air (controls, n = 7), from 3 days after mating, 2 h/d and 5 d/wk in a nose-only inhalation system throughout gestation (gestation days 3-27). After birth and weaning, 72 offspring (47 exposed and 25 controls) were raised until adulthood (7.5 months) to evaluate their cardio-metabolic status, including the monitoring of body weight and food intake, fasting biochemistry, body composition (iDXA), cardiovascular parameters and glucose tolerance. After a metabolic challenge (high fat diet in males and gestation in females), animals were euthanized for postmortem phenotyping. RESULTS: Sex-specific responses to maternal exposure were observed in adult offspring. Age-related increases in blood pressure (p = 0.058), glycaemia (p = 0.029), and perirenal fat mass (p = 0.026) as well as reductions in HDL-cholesterol (p = 0.025) and fat-to-body weight ratio (p = 0.011) were observed in exposed males, suggesting a metabolic syndrome. Almost only trends were observed in exposed females with higher triglycerides and decreased bone density compared to control females. Metabolic challenges triggered or amplified some biological responses, especially in females. CONCLUSIONS: In utero exposure to air pollution predisposed rabbit offspring to cardiometabolic disorders in a sex-specific manner.
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Poluição do Ar , Doenças Cardiovasculares , Efeitos Tardios da Exposição Pré-Natal , Adulto , Animais , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Masculino , Exposição Materna/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Coelhos , Emissões de Veículos/toxicidadeRESUMO
BACKGROUND: Airborne pollution, especially from diesel exhaust (DE), is known to have a negative effect on the central nervous system in exposed human populations. However, the consequences of gestational exposure to DE on the fetal brain remain poorly explored, with various effects depending on the conditions of exposure, as well as little information on early developmental stages. We investigated the short-term effects of indirect DE exposure throughout gestation on the developing brain using a rabbit model. We analyzed fetal olfactory tissues at the end of gestation and tested behaviors relevant to pups' survival at birth. Pregnant dams were exposed by nose-only inhalation to either clean air or DE with a content of particles (DEP) adjusted to 1 mg/m3 by diluting engine exhaust, for 2 h/day, 5 days/week, from gestational day 3 (GD3) to day 27 (GD27). At GD28, fetal olfactory mucosa, olfactory bulbs and whole brains were collected for anatomical and neurochemical measurements. At postnatal day 2 (PND2), pups born from another group of exposed or control female were examined for their odor-guided behavior in response to the presentation of the rabbit mammary pheromone 2-methyl-3-butyn-2-ol (2MB2). RESULTS: At GD28, nano-sized particles were observed in cilia and cytoplasm of the olfactory sensory neurons in the olfactory mucosa and in the cytoplasm of periglomerular cells in the olfactory bulbs of exposed fetuses. Moreover, cellular and axonal hypertrophies were observed throughout olfactory tissues. Concomitantly, fetal serotoninergic and dopaminergic systems were affected in the olfactory bulbs. Moreover, the neuromodulatory homeostasis was disturbed in a sex-dependent manner in olfactory tissues. At birth, the olfactory sensitivity to 2MB2 was reduced in exposed PND2 pups. CONCLUSION: Gestational exposure to DE alters olfactory tissues and affects monoaminergic neurotransmission in fetuses' olfactory bulbs, resulting in an alteration of olfactory-based behaviors at birth. Considering the anatomical and functional continuum between the olfactory system and other brain structures, and due to the importance of monoamine neurotransmission in the plasticity of neural circuits, such alterations could participate to disturbances in higher integrative structures, with possible long-term neurobehavioral consequences.
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Poluentes Atmosféricos/toxicidade , Comportamento Animal/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Bulbo Olfatório/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Emissões de Veículos/toxicidade , Poluentes Atmosféricos/farmacocinética , Animais , Animais Recém-Nascidos , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Feminino , Exposição por Inalação , Masculino , Bulbo Olfatório/embriologia , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/ultraestrutura , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Coelhos , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/metabolismo , Fatores Sexuais , Transmissão Sináptica/efeitos dos fármacos , Distribuição TecidualRESUMO
Assisted reproductive technologies (ARTs) such as intracytoplasmic sperm injection (ICSI), in vitro embryo culture and embryo transfer (ET) may be associated with alterations in fetal and placental development. In horses, ET has been used for decades. More recently, in vitro embryo production by ICSI and in vitro culture, followed by embryo transfer (ICSI-C) has become an accepted method for clinical foal production. However, no information is available on the effects of ICSI-C or even of standard ET itself on placental and neonatal parameters in horses. We therefore evaluated placental and neonatal morphology and placental gene expression in reining- and cutting-type American Quarter Horse foals produced using different technologies. Thirty foals and placentas (naturally conceived (NC), ET and ICSI-C; 10 in each group) were examined morphometrically. The only parameter that differed significantly between groups was the length of the foal upper hindlimb, which was longer in ET and ICSI-C than in NC foals. Evaluation of placental mRNA expression for 17 genes related to growth and vascularisation showed no difference in gene expression between groups. These data indicate that within this population, use of ARTs was not associated with meaningful changes in foal or placental morphometry or in expression of the placental genes evaluated.
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Tamanho Corporal , Transferência Embrionária/veterinária , Fertilidade , Fertilização in vitro/veterinária , Cavalos/fisiologia , Placenta/metabolismo , Injeções de Esperma Intracitoplásmicas/veterinária , Animais , Animais Recém-Nascidos , Peso ao Nascer , Técnicas de Cultura Embrionária/veterinária , Implantação do Embrião , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Cavalos/genética , Masculino , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
INTRODUCTION: Rabbits are routinely used as a natural model of fetal growth restriction (FGR); however, no studies have confirmed that rabbits have FGR. This study aimed to characterize the fetoplacental unit (FPU) in healthy pregnant rabbits using diffusion-weighted MRI and stereology. A secondary objective of the study was to describe the associations among findings from diffusion-weighted MRI (DW-MRI), fetal weight measurement and histological analysis of the placenta. METHODS: Pregnant rabbits underwent DW-MRI under general anesthesia on embryonic day 28 of pregnancy. MR imaging was performed at 3.0 T. The apparent diffusion coefficient (ADC) values were calculated for the fetal brain, liver, and placenta. The placenta was analyzed by stereology (volume density of trophoblasts, the maternal blood space and fetal vessels). Each fetus and placenta were weighed. Two groups of fetuses were defined according to the position in the uterine horn (Cervix group versus Ovary group). RESULTS: We analyzed 20 FPUs from 5 pregnant rabbits. Fetuses and placentas were significantly lighter in the Cervix group than in the Ovary group (34.7 ± 3.7 g vs. 40.2 ± 5.4 g; p = 0.02). Volume density analysis revealed that the percentage of fetal vessels, the maternal blood space and trophoblasts was not significantly affected by the position of the fetus in the uterine horn. There was no difference in ADC values according to the position of the fetus in the uterine horn, and there was no correlation between ADC values and fetal weight. DISCUSSION: The findings of a multimodal evaluation of the placenta in a rabbit model of FGR suggested is not a natural model of fetal growth restriction.
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STUDY QUESTION: Is exposure to environmental chemicals associated with modifications of placental morphology and function? SUMMARY ANSWER: Phthalates, a class of ubiquitous chemicals, showed an association with altered placental weight, placental vascular resistance (PVR), and placental efficiency. WHAT IS KNOWN ALREADY: Only a few epidemiological studies have assessed the effects of phenols and phthalates on placental health. Their results were affected by exposure measurement errors linked to the rapid excretion of these compounds and the reliance on a limited number of spot urine samples to assess exposure. STUDY DESIGN SIZE DURATION: A prospective mother-child cohort, with improved exposure assessment for non-persistent chemicals, recruited participants between 2014 and 2017. Sample size ranged between 355 (placental parameters measured at birth: placental weight and placental-to-fetal weight ratio (PFR): a proxy for placental efficiency) and 426 (placental parameters measured during pregnancy: placental thickness and vascular resistance). PARTICIPANTS/MATERIALS SETTING METHODS: Phenols (four parabens, two bisphenols, triclosan, and benzophenone-3), 13 phthalate metabolites, and two non-phthalate plasticizer metabolites were measured in within-subject pools of repeated urine samples collected during the second and third trimesters of pregnancy (median = 21 samples/trimester/woman). Placental thickness and PVR were measured during pregnancy. The placenta was weighed at birth and the PFR was computed. Both adjusted linear regression and Bayesian Kernel Machine Regression were used to evaluate associations between phenols and phthalates (alone or as a mixture) and placental parameters. Effect modification by child sex was also investigated. MAIN RESULTS AND THE ROLE OF CHANCE: Several phthalate metabolites were negatively associated with placental outcomes. Monobenzyl phthalate (MBzP) concentrations, during the second and third trimesters of pregnancy, were associated with a decrease in both placental weight at birth (ß = -20.1 g [95% CI: -37.8; -2.5] and ß = -17.4 g [95% CI: -33.2; -1.6], for second and third trimester, respectively) and PFR (ß = -0.5 [95% CI: -1, -0.1] and ß = -0.5 [95% CI: -0.9, -0.1], for the second and third trimester, respectively). Additionally, MBzP was negatively associated with PVR during the third trimester (ß= -0.9 [95% CI: -1.8; 0.1]). Mono-n-butyl phthalate (MnBP), was negatively associated with PVR in both trimesters (ß = -1.3, 95% CI: [-2.3, -0.2], and ß = -1.2, 95% CI: [-2.4, -0.03], for the second and third trimester, respectively). After stratification for child sex, Σ diisononyl phthalate (DiNP) (either second or third-trimester exposures, depending on the outcomes considered) was associated with decreased PVR in the third trimester, as well as decreased placental weight and PFR in males. No associations were observed for phenol biomarkers. LIMITATIONS REASONS FOR CAUTION: False positives cannot be ruled out. Therefore, chemicals that were associated with multiple outcomes (MnBP and DiNP) or reported in existing literature as associated with placental outcomes (MBzP) should be considered as the main results. WIDER IMPLICATIONS OF THE FINDINGS: Our results are consistent with in vitro studies showing that phthalates target peroxisome proliferator-activated receptor γ, in the family of nuclear receptors involved in key placental development processes such as trophoblast proliferation, migration, and invasion. In addition to placental weight at birth, we studied placental parameters during pregnancy, which could provide a broader view of how environmental chemicals affect maternal-fetal exchanges over the course of pregnancy. Our findings contribute to the increasing evidence indicating adverse impacts of phthalate exposure on placental health. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the French Research Agency-ANR (MEMORI project ANR-21-CE34-0022). The SEPAGES cohort was supported by the European Research Council (N°311765-E-DOHaD), the European Community's Seventh Framework Programme (FP7/2007-206-N°308333-892 HELIX), the European Union's Horizon 2020 research and innovation programme (N° 874583 ATHLETE Project, N°825712 OBERON Project), the French Research Agency-ANR (PAPER project ANR-12-PDOC-0029-01, SHALCOH project ANR-14-CE21-0007, ANR-15-IDEX-02 and ANR-15-IDEX5, GUMME project ANR-18-CE36-005, ETAPE project ANR-18-CE36-0005-EDeN project ANR-19-CE36-0003-01), the French Agency for Food, Environmental and Occupational Health & Safety-ANSES (CNAP project EST-2016-121, PENDORE project EST-2016-121, HyPAxE project EST-2019/1/039, PENDALIRE project EST-2022-169), the Plan Cancer (Canc'Air project), the French Cancer Research Foundation Association de Recherche sur le Cancer-ARC, the French Endowment Fund AGIR for chronic diseases-APMC (projects PRENAPAR, LCI-FOT, DysCard), the French Endowment Fund for Respiratory Health, the French Fund-Fondation de France (CLIMATHES-00081169, SEPAGES 5-00099903, ELEMENTUM-00124527). N.J. was supported by a doctoral fellowship from the University Grenoble Alpes. V.M. was supported by a Sara Borrell postdoctoral research contract (CD22/00176), granted by Instituto de Salud Carlos III (Spain) and NextGenerationEU funds. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02852499.
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The fetal development of organs and functions is vulnerable to perturbation by maternal inflammation which may increase susceptibility to disorders after birth. Because it is not well understood how the placenta and fetus respond to acute lung- inflammation, we characterize the response to maternal pulmonary lipopolysaccharide exposure across 24 h in maternal and fetal organs using multi-omics, imaging and integrative analyses. Unlike maternal organs, which mount strong inflammatory immune responses, the placenta upregulates immuno-modulatory genes, in particular the IL-6 signaling suppressor Socs3. Similarly, we observe no immune response in the fetal liver, which instead displays metabolic changes, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. The maternal liver and plasma display similar metabolic alterations, potentially increasing bioavailability of docosahexaenoic acid for the mother and fetus. Thus, our integrated temporal analysis shows that systemic inflammation in the mother leads to a metabolic perturbation in the fetus.
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Feto , Lipopolissacarídeos , Fígado , Pulmão , Placenta , Feminino , Gravidez , Placenta/metabolismo , Placenta/imunologia , Animais , Feto/imunologia , Feto/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Fígado/metabolismo , Fígado/imunologia , Ácidos Docosa-Hexaenoicos/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Camundongos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Adaptação Fisiológica/imunologia , Desenvolvimento Fetal/imunologia , Troca Materno-Fetal/imunologia , Interleucina-6/metabolismo , Interleucina-6/imunologiaRESUMO
In horses, the prevalence of obesity is high and associated with serious metabolic pathologies. Being a broodmare has been identified as a risk factor for obesity. In other species, maternal obesity is known to affect the development of the offspring. This article is a follow-up study of previous work showing that Obese mares (O, n = 10, body condition score > 4.25 at insemination) were more insulin resistant and presented increased systemic inflammation during pregnancy compared to Normal mares (N, n = 14, body condition score < 4 at insemination). Foals born to O mares were more insulin-resistant, presented increased systemic inflammation, and were more affected by osteoarticular lesions. The objective of the present study was to investigate the effect of maternal obesity on placental structure and function, as well as the fatty acid profile in the plasma of mares and foals, colostrum, and milk until 90 days of lactation, which, to our knowledge, has been poorly studied in the horse. Mares from both groups were fed the same diet during pregnancy and lactation. During lactation, mares were housed in pasture. A strong heat wave, followed by a drought, occurred during their 2nd and 3rd months of lactation (summer of 2016 in the Limousin region, France). In the present article, term placental morphometry, structure (stereology), and gene expression (RT-qPCR, genes involved in nutrient transport, growth, and development, as well as vascularization) were studied. Plasma of mares and their foals, as well as colostrum and milk, were sampled at birth, 30 days, and 90 days of lactation. The fatty acid composition of these samples was measured using gas chromatography. No differences between the N and O groups were observed for term placental morphometry, structure, or gene expression. No difference in plasma fatty acid composition was observed between groups in mares. The plasma fatty acid profile of O foals was more pro-inflammatory and indicated an altered placental lipid metabolism between birth and 90 days of age. These results are in line with the increased systemic inflammation and altered glucose metabolism observed until 18 months of age in this group. The colostrum fatty acid profile of O mares was more pro-inflammatory and indicated an increased transfer and/or desaturation of long-chain fatty acids. Moreover, O foals received a colostrum poorer in medium-chain saturated fatty acid, a source of immediate energy for the newborn that can also play a role in immunity and gut microbiota development. Differences in milk fatty acid composition indicated a decreased ability to adapt to heat stress in O mares, which could have further affected the metabolic development of their foals. In conclusion, maternal obesity affected the fatty acid composition of milk, thus also influencing the foal's plasma fatty acid composition and likely participating in the developmental programming observed in growing foals.
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Animal toxicological studies often fail to mimic the complexity of the human exposome, associating low doses, combined molecules and long-term exposure. Since the reproductive potential of a woman begins in the fetal ovary, the literature regarding the disruption of its reproductive health by environmental toxicants remains limited. Studies draw attention to follicle development, a major determinant for the quality of the oocyte, and the preimplantation embryo, as both of them are targets for epigenetic reprogramming. The "Folliculogenesis and Embryo Development EXPOsure to a mixture of toxicants: evaluation in the rabbit model" (FEDEXPO) project emerged from consideration of these limitations and aims to evaluate in the rabbit model the impacts of an exposure to a mixture of known and suspected endocrine disrupting chemicals (EDCs) during two specific windows, including folliculogenesis and preimplantation embryo development. The mixture combines eight environmental toxicants, namely perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB), ß-hexachlorocyclohexane (ß-HCH), 2,2'4,4'-tetrabromodiphenyl ether (BDE-47), di(2-ethylhexyl) phthalate (DEHP) and bisphenol S (BPS), at relevant exposure levels for reproductive-aged women based on biomonitoring data. The project will be organized in order to assess the consequences of this exposure on the ovarian function of the directly exposed F0 females and monitor the development and health of the F1 offspring from the preimplantation stage. Emphasis will be made on the reproductive health of the offspring. Lastly, this multigenerational study will also tackle potential mechanisms for the inheritance of health disruption via the oocyte or the preimplantation embryo.
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The maternal metabolic environment can be detrimental to the health of the offspring. In a previous work, we showed that maternal high-fat (HH) feeding in rabbit induced sex-dependent metabolic adaptation in the fetus and led to metabolic syndrome in adult offspring. As early development representing a critical window of susceptibility, in the present work we aimed to explore the effects of the HH diet on the oocyte, preimplantation embryo and its microenvironment. In oocytes from females on HH diet, transcriptomic analysis revealed a weak modification in the content of transcripts mainly involved in meiosis and translational control. The effect of maternal HH diet on the embryonic microenvironment was investigated by identifying the metabolite composition of uterine and embryonic fluids collected in vivo by biomicroscopy. Metabolomic analysis revealed differences in the HH uterine fluid surrounding the embryo, with increased pyruvate concentration. Within the blastocoelic fluid, metabolomic profiles showed decreased glucose and alanine concentrations. In addition, the blastocyst transcriptome showed under-expression of genes and pathways involved in lipid, glucose and amino acid transport and metabolism, most pronounced in female embryos. This work demonstrates that the maternal HH diet disrupts the in vivo composition of the embryonic microenvironment, where the presence of nutrients is increased. In contrast to this nutrient-rich environment, the embryo presents a decrease in nutrient sensing and metabolism suggesting a potential protective process. In addition, this work identifies a very early sex-specific response to the maternal HH diet, from the blastocyst stage.
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Blastocisto , Dieta Hiperlipídica , Animais , Masculino , Coelhos , Feminino , Dieta Hiperlipídica/efeitos adversos , Blastocisto/fisiologia , Embrião de Mamíferos , Oócitos , Glucose/metabolismo , Desenvolvimento Embrionário/fisiologiaRESUMO
CONTEXT: Maternal obesity has a significant impact on placental development. However, this impact on the placenta's structure and function (ie, nutrient transport and hormone and cytokine production) is a controversial subject. OBJECTIVE: We hypothesized that maternal obesity is associated with morphologic, secretory, and nutrient-related changes and elevated levels of inflammation in the placenta. DESIGN: We collected samples of placental tissue from 2 well-defined groups of pregnant women from 2017 to 2019. We compared the 2 groups regarding placental cytokine and hormone secretion, immune cell content, morphology, and placental nutrient transporter expressions. SETTING: Placenta were collected after caesarean section performed by experienced clinicians at Centre Hospitalier Intercommunal (CHI) of Poissy-Saint-Germain-en-Laye. PATIENTS: The main inclusion criteria were an age between 27 and 37 years old, no complications of pregnancy, and a first-trimester body mass index of 18-25 kg/m2 for the nonobese (control) group and 30-40 kg/m2 for the obese group. RESULTS: In contrast to our starting hypothesis, we observed that maternal obesity was associated with (1) lower placental IL-6 expression and macrophage/leukocyte infiltration, (2) lower placental expression of GLUT1 and SNAT1-2, (3) a lower placental vessel density, and (4) lower levels of placental leptin and human chorionic gonadotropin production. CONCLUSION: These results suggest that the placenta is a plastic organ and could optimize fetal growth. A better understanding of placental adaptation is required because these changes may partly determine the fetal outcome in cases of maternal obesity.
Assuntos
Inflamação/etiologia , Nutrientes/farmacocinética , Obesidade Materna , Placenta , Adulto , Cesárea , Feminino , França , Humanos , Inflamação/metabolismo , Inflamação/patologia , Obesidade Materna/complicações , Obesidade Materna/metabolismo , Obesidade Materna/patologia , Obesidade Materna/cirurgia , Tamanho do Órgão , Placenta/metabolismo , Placenta/patologia , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologia , Complicações na Gravidez/cirurgia , Nascimento a Termo/fisiologiaRESUMO
Context and Aim: Lipid overnutrition in female rabbits, from prepuberty, leads to impaired metabolism (dyslipidemia and increased adiposity) and follicular atresia, and, when continued during gestation, affects offspring phenotype with intrauterine growth retardation (IUGR) and leads to placental and lipid metabolism abnormalities. Growth retardation is already observed in embryo stage, indicating a possible implication of periconceptional exposure. The objective of this study was to discriminate the effects of preconception and gestational exposures on feto-placental development. Materials and Methods: Rabbit 1-day zygotes were collected from female donors under control (CD) or high-fat-high-cholesterol (HD) diet and surgically transferred to the left and right uterus, respectively, of each H (n = 6) or C (n = 7) synchronized recipients. Close to term, four combinations, CC (n = 10), CH (n = 13), HC (n = 13), and HH (n = 6), of feto-placental units were collected, for biometry analyses. Fatty acid (FA) profiles were determined in placental labyrinth, decidua, fetal plasma, and fetal liver by gas chromatography and explored further by principal component analysis (PCA). Candidate gene expression was also analyzed by RT-qPCR in the placenta and fetal liver. Data were analyzed by Kruskal-Wallis followed by Dunn's pairwise comparison test. Combinations of different data sets were combined and explored by multifactorial analysis (MFA). Results: Compared to controls, HH fetuses were hypotrophic with reduced placental efficiency and altered organogenesis, CH presented heavier placenta but less efficient, whereas HC presented a normal biometry. However, the MFA resulted in a good separation of the four groups, discriminating the effects of each period of exposure. HD during gestation led to reduced gene expression (nutrient transport and metabolism) and big changes in FA profiles in both tissues with increased membrane linoleic acid, lipid storage, and polyunsaturated-to-saturated FA ratios. Pre-conception exposure had a major effect on fetal biometry and organogenesis in HH, with specific changes in FA profiles (increased MUFAs and decreased LCPUFAs). Conclusion: Embryo origin left traces in end-gestation feto-placental unit; however, maternal diet during gestation played a major role, either negative (HD) or positive (control). Thus, an H embryo developed favorably when transferred to a C recipient (HC) with normal biometry at term, despite disturbed and altered FA profiles.
RESUMO
The dissection of the veins is the trickiest step of Uterine transplantation (UTx). Performing the anastomosis of a single uterine vein could bring a therapeutic benefit and simplification of surgery and serve for managing unilateral venous thromboses. The objectives of this project were to evaluate the expression of early markers of ischemia-reperfusion and to compare findings following one or two vein anastomoses. Orthotopic uterine auto-transplantations were performed on an ovine model with anastomosis of either two (group 1) or one utero-ovarian veins (group 2). Blood gases, histology and ischemia- reperfusion markers transcripts (PTGS2, IL6, IL8, SOD2, C3, BAX/BCL2 and TLR4) were analyzed as well as PTGS2 protein expression using Western Blot and fluorescence immunolocalization on endometrial biopsies after 3h of reperfusion. Ten ewes were included in the experimentation, 4 were in group1, 3 in group 2, the others being sham operated controls. No significant differences were observed between the two phenotypes. Based on these results, the anastomosis of one single uterine vein appears to be an approach consistent with short-term graft survival. Further experiments will be needed to confirm the reliability of this approach, especially the long-term follow-up of the uterine graft including its ability to support gestation to term.
Assuntos
Útero/transplante , Anastomose Cirúrgica , Animais , Endométrio/metabolismo , Feminino , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/genética , Ovinos , Transcriptoma , Útero/irrigação sanguíneaRESUMO
INTRODUCTION: Pregnant women with sickle cell disease (SCD) are at high risk for sickle cell-related complications, obstetrical complications, and perinatal morbidity. Chronic inflammation and the proangiogenic environment associated with SCD have been associated with endothelial damage. It is unknown whether SCD complications could be associated with placental dysfunction or abnormal placental morphology. Moreover, circulating angiogenic factors in pregnant women with SCD are unexplored. METHODS: Clinical records, placental and blood samples were collected at term delivery for 21 pregnant patients with SCD and 19 HbAA pregnant controls with adapted to gestational age birth weight newborns. Histological and stereological analyses and scanning electron microscopy (SEM) of the placenta, and PlGF and sFlt1 measurements in blood were performed. RESULTS: In the SCD group, the parenchyma-forming villi of placentas were thinner than in controls, and increased fibrinoid necrosis and an overabundance of syncytial knots were seen. SEM revealed elongated intermediate villous endings with a reduction in the number of terminal villi compared to controls, indicating a significant branching defect in SCD placentas. Finally, SCD patients had an imbalance in the angiogenic ratio of sFlt1/PlGF (p = 0.008) with a drop of PlGF concentrations. DISCUSSION: We evidence for the first time both abnormal placenta morphology and altered sFlt1/PlGF ratio in SCD patients, uncorrelated with maintained placental efficiency and fetal growth.
Assuntos
Anemia Falciforme/patologia , Placenta/ultraestrutura , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/fisiopatologia , Estudos de Casos e Controles , Feminino , Humanos , Placenta/fisiopatologia , Fator de Crescimento Placentário/sangue , Gravidez , Estudos Prospectivos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
Foals born to primiparous mares are lighter and less mature than those born to multiparous dams. Factors driving this difference are not totally understood. Using 7 multiparous and 6 primiparous standardbred mares, we demonstrated that, in late gestation, primiparous mares were less insulin resistant compared to multiparous mares, and that their foals had reduced plasma amino-acid concentrations at birth compared to foals born to multiparous mares. Vascular development, as observed through structure and gene expression, and global DNA methylation were also reduced in primiparous placentas. Another group of 8 primiparous mares was orally supplemented with L-arginine (100 g/day, 210d to term). L-arginine improved pregnancy-induced insulin resistance and increased maternal L-arginine and L-ornithine plasma concentrations but foal plasma amino acid concentrations were not affected at birth. At birth, foal weight and placental biometry, structure, ultra-structure and DNA methylation were not modified. Placental expression of genes involved in glucose and fatty acid transfers was increased. In conclusion, maternal insulin resistance in response to pregnancy and placental function are reduced in primiparous pregnancies. Late-gestation L-arginine supplementation may help primiparous mares to metabolically adapt to pregnancy and improve placental function. More work is needed to confirm these effects and ascertain optimal treatment conditions.
Assuntos
Arginina/farmacologia , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Cavalos , Placenta/metabolismo , Gravidez/metabolismo , Animais , Feminino , Resistência à Insulina/fisiologia , Placenta/irrigação sanguíneaRESUMO
Tight metabolic control of type-1 diabetes is essential during gestation, but it could be crucial during the periconception period. Feto-placental consequences of maternal type-1 diabetes around the time of conception need to be explored. Using a rabbit model, type-1 diabetes was induced by alloxan 7 days before mating. Glycemia was maintained at 15-20â¯mmol/L with exogenous insulin injections to prevent ketoacidosis. At 4 days post-conception (dpc), embryos were collected from diabetic (D) or normoglycemic control (C) dams, respectively, and transferred into non-diabetic recipients. At 28dpc, D- and C-feto-placental units were collected for biometry, placental analyses and lipid profiles. D-fetuses were growth-retarded, hyperglycemic and dyslipidemic compared to C-fetuses. The efficiency of D-placentas was associated with an increased gene expression related to nutrient supply and lipid metabolism whereas volume density of fetal vessels decreased. Fetal plasma, placental and fetal liver membranes had specific fatty acid signatures depending on embryonic origin. Tissues from D-fetuses contained more omega-6 polyunsaturated fatty acids. The concentrations of docosahexaenoic acid decreased while linoleic acid increased in the heart of D-fetuses. This study demonstrates that a short exposure to maternal type-1 diabetes in the periconception window, until the blastocyst stage, is able to irreversibly malprogram the feto-placental phenotype, through precocious and persistent structural and molecular adaptations of placenta.