Search Results (20)

Climate change is increasing the frequency and intensity of extreme heat events, raising concern about prenatal thermal exposure as a potential risk factor for fetal brain development and offspring neurodevelopment. This systematic review aimed to synthesize evidence on prenatal heat exposure, placental inflammatory or stress-response pathways, and fetal or offspring neurodevelopmental outcomes, while evaluating the placenta–brain axis as a proposed mechanistic hypothesis rather than an established causal pathway. A systematic literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and Embase from database inception to 30 June 2026. Human observational studies, animal experiments, and in vitro mechanistic studies were included when they examined prenatal thermal exposure in relation to either placental function and stress-response mechanisms or fetal-brain and offspring neurodevelopmental outcomes. Ambient environmental heat, infectious fever, behavioral or exogenous heat exposure, experimental maternal hyperthermia, and direct cellular or organoid thermal stimulation were considered separately because these exposures are not biologically equivalent. Across the included studies, distinct prenatal thermal exposures—including ambient environmental heat, infectious fever, behavioral or exogenous heating, and experimentally induced hyperthermia—were associated with congenital central nervous system anomalies, including neural tube defects, as well as later outcomes such as neurodevelopmental delay, language impairment, autism spectrum disorder, cerebral palsy, and altered child-brain morphology. The strongest and most consistent early-pregnancy signal concerned neural tube defects during the periconceptional and neurulation periods, whereas evidence for later neurodevelopmental outcomes identified more heterogeneous susceptibility windows across gestation. Experimental evidence suggested alterations in placental barrier function, glucocorticoid and serotonin-related signaling, inflammatory and oxidative pathways, myelination, apoptosis, and neural-progenitor development. However, only one included experimental study jointly assessed maternal heat stress, placental alterations, and fetal-brain-related outcomes, while the human studies did not measure placental mediators or perform mediation analyses. Evidence from non-heat inflammatory studies therefore provides only indirect mechanistic context. Overall, prenatal heat exposure may contribute to neurodevelopmental vulnerability through multiple direct and indirect pathways, including a biologically plausible but unproven placenta–brain framework. Prospective studies integrating individual-level heat assessment, placental biomarkers, standardized fetal-brain imaging, and longitudinal neurodevelopmental follow-up are required to test this hypothesis. Full article

Background: Tryptophan (Trp) is critical to mothers and their conceptuses, and this amino acid is the precursor to serotonin (5-HT). 5-HT modulates placenta function and fetal neurodevelopment. It is not clear if the placenta directly synthesizes 5-HT or uses the serotonin transporter (SERT/Slc6a4) to accrue 5-HT from the dam. The hypothesis tested herein is that reduction in maternal Trp leads to reductions in maternal Trp, 5-HT, and 5-hydroxy-3-indoleacetic acid (5-HIAA, metabolite of serotonin) and reductions in these metabolites within the placenta and fetal brain of female and male conceptuses. Methods: Female mice were placed on a reduced tryptophan (Trp) diet (0.1%) or control diet (0.2%). Diets were provided for two weeks prior to breeding (periconception period) until conceptuses were collected at approximately 12.5 days post-coitus (dpc). Results: While no reductions in maternal Trp and 5-HT were observed, both metabolites were significantly reduced in the placenta and fetal brain of male and female conceptuses (p < 0.05). Female conceptuses were susceptible to reductions in maternal Trp with 549 and 29 transcripts altered in the female placenta and fetal brain, respectively, of reduced Trp dams compared to control dams. Transcriptomic changes, such as reduced expression in Slc6a4 and Slc6a19 (transporter for Trp), in placenta of female conceptuses correlated with reductions in Trp and 5-HT amounts. Conclusions: Findings might have clinical importance to pregnant women as they reveal even subtle reductions in one amino acid profoundly influence conceptus development and might lead to sexual disparity in risk for later diseases, including neurobehavioral disorders. Full article

Major depressive disorder (MDD) accounts for a substantial share of global disability-adjusted life years and remains inadequately treated despite pharmacological advances. Growing evidence implicates endocrine-disrupting chemicals (EDCs)—particularly phthalates and bisphenols—as environmental contributors to the onset of these conditions. This narrative review examines evidence from PubMed, Scopus, and Web of Science (January 2000–March 2025) on the relationship between early-life exposure to these compounds and the development of mood disorders, with emphasis on molecular and neurobiological mechanisms. Phthalates such as di(2-ethylhexyl) phthalate (DEHP), and bisphenols such as bisphenol A (BPA), are detected ubiquitously in human urine, blood, placenta, and umbilical cord blood. Key mechanisms identified include Nrf2/HO-1-driven oxidative stress and neuronal apoptosis, disruption of calcium signalling and synaptic plasticity via CREB phosphorylation deficits, epigenetic suppression of brain-derived neurotrophic factor (BDNF) via promoter hypermethylation, NF-κB/NLRP3/IL-1β neuroinflammatory cascades, interference with thyroid hormone bioavailability through transthyretin competition, and PPAR-mediated disruption of brain lipid metabolism. Prenatal and early-life exposure has been associated with ADHD, cognitive impairment, autism spectrum disorder, and elevated risk of depressive and anxiety phenotypes in epidemiological cohorts. Psychological vulnerability factors—perceived stress, deficient emotion regulation, and adverse childhood experiences—likely amplify this biological susceptibility through HPA axis sensitisation. Methodological limitations of current evidence, including reliance on single-spot urine samples and residual confounding, are critically appraised. Future research priorities include longitudinal biomonitoring cohorts, brain organoid mechanistic models, and integration of validated psychiatric assessments into environmental health study designs. Full article

The hypothalamic–pituitary–adrenal (HPA) axis coordinates metabolic, immune, and behavioral responses to a changing environment. Its molecular effectors are the nuclear receptors for glucocorticoids and mineralocorticoids (the GRs/MRs), encoded by nr3c1/nr3c2. The MR serves as the high-affinity sensor of basal hormone concentrations, whereas the GR amplifies the stress response and mediates negative feedback. Despite their shared domain architecture, the receptors have diverged functionally: isoform composition, post-translational modifications, and the complement of co-regulators together determine which genes are activated or repressed in a given tissue at a given time. The regulation of the HPA axis activity is a major determinant of embryonic development. Pregnancy adds a placental control layer that meters maternal signals: 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in the syncytiotrophoblast inactivates cortisol, whereas 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) can regenerate it, and systemic buffering by transcortin (cortisol-binding globulin, CBG) limits the free hormone fraction. Under stress, inflammation, or hypoxia, this barrier weakens, exposing the fetus to stronger glucocorticoid pulses during windows of heightened vulnerability for brain and immune development. Such overexposure not only reshapes ongoing transcription but is also epigenetically inscribed: the methylation of alternative nr3c1 promoters, the remodeling of histones, and the shifts in ncRNA profiles recalibrate the axis sensitivity for the long term. At the phenotypic level, this manifests as variability in stress reactivity, cognitive and affective trajectories, and an immune and metabolic risk across later ontogeny. In this review, we integrate evidence on the structure and functions of the GR, the mechanisms of its post-translational and epigenetic regulation, and the role of the placenta, to provide a coherent framework for understanding the multifaceted consequences of prenatal stress and to identify potential targets for early prevention. Full article

Serotonin reuptake inhibitors (SSRIs) are commonly prescribed to pregnant women experiencing depression. Such drugs, however, might adversely affect placenta and fetal brain development. Parietal trophoblast giant cells (pTGCs) in the mouse placenta are postulated to internalize maternal serotonin (5-HT) via transport through SERT, encoded by Slc6a4, and to provide the initial source of 5-HT to the emerging brain via the placental–brain axis. Genetic deletion of Slc6a4 in pTGCs has been hypothesized to impact placental and fetal brain development. A transgenic mouse line with high-affinity SERT, encoded by Slc6a4, was selectively deleted by pairing mice with Cre recombinase linked to Prl2c2, with LoxP sites flanking the Slc6a4 gene. PRL2C2 is solely expressed by pTGCs and other giant cells of the placenta. To compare placental and fetal brain development in selective Slc6a4 KO and WT mice, 5-HT content in the placenta and fetal brains of conceptuses was measured. No significant differences in 5-HT content were evident between knockout (KO) and wild-type (WT) placentas or fetal brains. However, there were significantly fewer pTGCs in KO placentas compared to WT (p ≤ 0.05). Sexually dimorphic differences in gene expression were evident in the placenta and fetal brain between KO and WT counterparts, with female conceptuses showing the most dramatic responses, including decrease in Prl7a2, Prl5a1, Prl3a1, Slc28a3, and Ceacam 15 in female placental samples. These findings suggest that ablation of Slc6a4 in pTGC disrupts the placenta–brain axis in a sex-dependent manner. The results might have important clinical ramifications for pregnant women being treated with SSRIs. Full article

In mice, the fetal brain is dependent upon the placenta for factors that guide its early development. This linkage between the two organs has given rise to the term, the placenta–brain axis. A similar interrelationship between the two organs may exist in humans. We hypothesize that extracellular vesicles (EVs) released from placental trophoblast (TB) cells transport small RNA and other informational biomolecules from the placenta to the brain where their contents have pleiotropic effects. Here, EVs were isolated from the medium in which human trophoblasts (TBs) had been differentiated in vitro from induced pluripotent stem cells (iPSC) and from cultured iPSC themselves, and their small RNA content analyzed by bulk RNA-seq. EVs derived from human TB cells possess unique profiles of miRs, including hsa-miR-0149-3p, hsa-302a-5p, and many long non-coding RNAs (lncRNAs) relative to EVs isolated from parental iPSC. These miRs and their mRNA targets are enriched in neural tissue. Human neural progenitor cells (NPCs), generated from the same iPSC, were exposed to EVs from either TB or iPSC controls. Both sets of EVs were readily internalized. EVs from TB cells upregulate several transcripts in NPCs associated with forebrain formation and neurogenesis; those from control iPSC upregulated a transcriptional phenotype that resembled glial cells more closely than neurons. These results shed light on the possible workings of the placenta–brain axis. Understanding how the contents of small RNA within TB-derived EVs affect NPCs might yield new insights, possible biomarkers, and potential treatment strategies for neurobehavioral disorders that originate in utero, such as autism spectrum disorders (ASDs). Full article

Changes in maternal gut microbiota due to stress and/or ethanol exposure can have lasting effects on offspring’s health, particularly regarding immunity, inflammation response, and susceptibility to psychiatric disorders. The literature search for this review was conducted using PubMed and Scopus, employing keywords and phrases related to maternal stress, ethanol exposure, gut microbiota, microbiome, gut–brain axis, diet, dysbiosis, progesterone, placenta, prenatal development, immunity, inflammation, and depression to identify relevant studies in both preclinical and human research. Only a limited number of reviews were included to support the arguments. The search encompassed studies from the 1990s to the present. This review begins by exploring the role of microbiota in modulating host health and disease. It then examines how disturbances in maternal microbiota can affect the offspring’s immune system. The analysis continues by investigating the interplay between stress and dysbiosis, focusing on how prenatal maternal stress influences both maternal and offspring microbiota and its implications for susceptibility to depression. The review also considers the impact of ethanol consumption on gut dysbiosis, with an emphasis on the effects of prenatal ethanol exposure on both maternal and offspring microbiota. Finally, it is suggested that maternal gut microbiota dysbiosis may be significantly exacerbated by the combined effects of stress and ethanol exposure, leading to immune system dysfunction and chronic inflammation, which could increase the risk of depression in the offspring. These interactions underscore the potential for novel mental health interventions that address the gut–brain axis, especially in relation to maternal and offspring health. Full article

The placenta operates during gestation as the primary communication organ between the mother and fetus. It is essential for gas, nutrient exchange, and fetal waste transfer. The placenta also produces a wide range of hormones and other factors that influence maternal physiology, including survival and activity of the corpus luteum of the ovary, but the means whereby the placenta shapes fetal development remain less clear, although the fetal brain is thought to be dependent upon the placenta for factors that play roles in its early differentiation and growth, giving rise to the term “placenta–brain axis”. Placental hormones transit via the maternal and fetal vasculature, but smaller placental molecules require protection from fetal and maternal metabolism. Such biomolecules include small RNA, mRNA, peptides, lipids, and catecholamines that include serotonin and dopamine. These compounds presumably shuttle to maternal and fetal systems via protective extracellular vesicles (EVs). Placental EVs (pEVs) and their components, in particular miRNA (miRs), are known to play important roles in regulating maternal systems, such as immune, cardiovascular, and reproductive functions. A scant amount is known about how pEVs affect fetal cells and tissues. The composition of pEVs can be influenced by gestational diseases. This review will provide critical insight into the roles of pEVs as the intermediary link between maternal and fetal systems, the impact of maternal pathologies on pEV cargo contents, and how an understanding of biomolecular changes within pEVs in health and disease might be utilized to design early diagnostic and mitigation strategies to prevent gestational diseases and later offspring disorders. Full article

The movement of organic anionic drugs across cell membranes is partly governed by interactions with SLC and ABC transporters in the intestine, liver, kidney, blood–brain barrier, placenta, breast, and other tissues. Major transporters involved include organic anion transporters (OATs, SLC22 family), organic anion transporting polypeptides (OATPs, SLCO family), and multidrug resistance proteins (MRPs, ABCC family). However, the sets of molecular properties of drugs that are necessary for interactions with OATs (OAT1, OAT3) vs. OATPs (OATP1B1, OATP1B3) vs. MRPs (MRP2, MRP4) are not well-understood. Defining these molecular properties is necessary for a better understanding of drug and metabolite handling across the gut–liver–kidney axis, gut–brain axis, and other multi-organ axes. It is also useful for tissue targeting of small molecule drugs and predicting drug–drug interactions and drug–metabolite interactions. Here, we curated a database of drugs shown to interact with these transporters in vitro and used chemoinformatic approaches to describe their molecular properties. We then sought to define sets of molecular properties that distinguish drugs interacting with OATs, OATPs, and MRPs in binary classifications using machine learning and artificial intelligence approaches. We identified sets of key molecular properties (e.g., rotatable bond count, lipophilicity, number of ringed structures) for classifying OATs vs. MRPs and OATs vs. OATPs. However, sets of molecular properties differentiating OATP vs. MRP substrates were less evident, as drugs interacting with MRP2 and MRP4 do not form a tight group owing to differing hydrophobicity and molecular complexity for interactions with the two transporters. If the results also hold for endogenous metabolites, they may deepen our knowledge of organ crosstalk, as described in the Remote Sensing and Signaling Theory. The results also provide a molecular basis for understanding how small organic molecules differentially interact with OATs, OATPs, and MRPs. Full article

The resolution of inflammation is the primary domain of specialised pro-resolving mediators (SPMs), which include resolvins, protectins, and their forms synthesised under the influence of aspirin and the maresins. The role of these SPMs has been discussed by many authors in the literature, with particular reference to neuroinflammation and significant neurological disorders. This review discusses the role of G protein-coupled receptor 18 (GPR18), resolvin D2 (RvD2) activity, and the GPR18-RvD2 signalling axis, as well as the role of small molecule ligands of GPR18 in inflammation in various health disorders (brain injuries, neuropathic pain, neurodegenerative/cardiometabolic/cardiovascular/gastrointestinal diseases, peritonitis, periodontitis, asthma and lung inflammation, Duchenne muscular dystrophy, SARS-CoV-2-induced inflammation, and placenta disorders. The idea of biological intervention through modulating GPR18 signalling is attracting growing attention because of its great therapeutic potential. With this paper, we aimed to present a comprehensive review of the most recent literature, perform a constructive view of data, and point out research gaps. Full article

Caveolin-1 (Cav1) is a major plasma membrane protein that plays important functions in cellular metabolism, proliferation, and senescence. Mice lacking Cav1 show abnormal gene expression in the fetal brain. Though evidence for placental influence on brain development is emerging, whether the ablation of Cav1 affects the regulation of the brain–placental axis remains unexamined. The current study tests the hypothesis that gene expression changes in specific cells of the placenta and the fetal brain are linked to the deregulation of the brain–placental axis in Cav1-null mice. By performing single-nuclei RNA sequencing (snRNA-seq) analyses, we show that the abundance of the extravillious trophoblast (EVT) and stromal cells, but not the cytotrophoblast (CTB) or syncytiotrophoblast (STB), are significantly impacted due to Cav1 ablation in mice. Interestingly, specific genes related to brain development and neurogenesis were significantly differentially expressed in trophoblast cells due to Cav1 deletion. Comparison of single-cell gene expression between the placenta and the fetal brain further showed that specific genes such as plexin A1 (Plxna1), phosphatase and actin regulator 1 (Phactr1) and amyloid precursor-like protein 2 (Aplp2) were differentially expressed between the EVT and STB cells of the placenta, and also, between the radial glia and ependymal cells of the fetal brain. Bulk RNA-seq analysis of the whole placenta and the fetal brain further identified genes differentially expressed in a similar manner between the placenta and the fetal brain due to the absence of Cav1. The deconvolution of reference cell types from the bulk RNA-seq data further showed that the loss of Cav1 impacted the abundance of EVT cells relative to the stromal cells in the placenta, and that of the glia cells relative to the neuronal cells in the fetal brain. Together, the results of this study suggest that the ablation of Cav1 causes deregulated gene expression in specific cell types of the placenta and the fetal brain in mice. Full article

Autism Spectrum Disorder (ASD) is a synaptic disorder with a GABA/glutamate imbalance in the perineuronal nets and structural abnormalities such as increased dendritic spines and decreased long distance connections. Specific pregnancy disorders significantly increase the risk for an ASD phenotype such as preeclampsia, preterm birth, hypoxia phenomena, and spontaneous miscarriages. They are associated with defects in the glycosylation-immune placental processes implicated in neurogenesis. Some glycans epitopes expressed in the placenta, and specifically in the extra-villous trophoblast also have predominant functions in dendritic process and synapse function. Among these, the most important are CD57 or HNK1, CD22, CD24, CD33 and CD45. They modulate the innate immune cells at the maternal–fetal interface and they promote foeto-maternal tolerance. There are many glycan-based pathways of immunosuppression. N-glycosylation pathway dysregulation has been found to be associated with autoimmune-like phenotypes and maternal-autoantibody-related (MAR) autism have been found to be associated with central, systemic and peripheric autoimmune processes. Essential molecular pathways associated with the glycan-epitopes expression have been found to be specifically dysregulated in ASD, notably the Slit/Robo, Wnt, and mTOR/RAGE signaling pathways. These modifications have important effects on major transcriptional pathways with important genetic expression consequences. These modifications lead to defects in neuronal progenitors and in the nervous system’s implementation specifically, with further molecular defects in the GABA/glutamate system. Glycosylation placental processes are crucial effectors for proper maternofetal immunity and endocrine/paracrine pathways formation. Glycans/ galectins expression regulate immunity and neurulation processes with a direct link with gene expression. These need to be clearly elucidated in ASD pathophysiology. Full article

Gut microbiota plays a critical role in physiological regulation throughout life and is specifically modified to meet the demands of individual life stages and during pregnancy. Maternal gut microbiota is uniquely adapted to the pregnancy demands of the mother and the developing fetus. Both animal studies in pregnant germ-free rodents and human studies have supported a critical association between the composition of maternal microbiota during pregnancy and fetal development. Gut microbiota may also contribute to the development of the fetal gut–brain axis (GBA), which is increasingly recognized for its critical role in health and disease. Most studies consider birth as the time of GBA activation and focus on postnatal GBA development. This review focuses on GBA development during the prenatal period and the impact of maternal gut microbiota on fetal GBA development. It is hypothesized that adaptation of maternal gut microbiota to pregnancy is critical for the GBA prenatal development and maturation of GBA postnatally. Consequently, factors affecting maternal gut microbiota during pregnancy, such as maternal obesity, diet, stress and depression, infection, and medication, also affect fetal GBA development and are critical for GBA activity postnatally. Altered maternal gut microbiota during gestation has been shown to have long-term impact postnatally and multigenerational effects. Thus, understanding the impact of maternal gut microbiota during pregnancy on fetal GBA development is crucial for managing fetal, neonatal, and adult health, and should be included among public health priorities. Full article

Although alcohol consumption during pregnancy is a major cause of behavioral and learning disabilities, most FASD infants are late- or even misdiagnosed due to clinician’s difficulties achieving early detection of alcohol-induced neurodevelopmental impairments. Neuroplacentology has emerged as a new field of research focusing on the role of the placenta in fetal brain development. Several studies have reported that prenatal alcohol exposure (PAE) dysregulates a functional placenta–cortex axis, which is involved in the control of angiogenesis and leads to neurovascular-related defects. However, these studies were focused on PlGF, a pro-angiogenic factor. The aim of the present study is to provide the first transcriptomic “placenta–cortex” signature of the effects of PAE on fetal angiogenesis. Whole mouse genome microarrays of paired placentas and cortices were performed to establish the transcriptomic inter-organ “placenta–cortex” signature in control and PAE groups at gestational day 20. Genespring comparison of the control and PAE signatures revealed that 895 and 1501 genes were only detected in one of two placenta–cortex expression profiles, respectively. Gene ontology analysis indicated that 107 of these genes were associated with vascular development, and String protein–protein interaction analysis showed that they were associated with three functional clusters. PANTHER functional classification analysis indicated that “intercellular communication” was a significantly enriched biological process, and 27 genes were encoded for neuroactive ligand/receptors interactors. Protein validation experiments involving Western blot for one ligand–receptor couple (Agt/AGTR1/2) confirmed the transcriptomic data, and Pearson statistical analysis of paired placentas and fetal cortices revealed a negative correlation between placental Atg and cortical AGTR1, which was significantly impacted by PAE. In humans, a comparison of a 38WG control placenta with a 36WG alcohol-exposed placenta revealed low Agt immunolabeling in the syncytiotrophoblast layer of the alcohol case. In conclusion, this study establishes the first transcriptomic placenta–cortex signature of a developing mouse. The data show that PAE markedly unbalances this inter-organ signature; in particular, several ligands and/or receptors involved in the control of angiogenesis. These data support that PAE modifies the existing communication between the two organs and opens new research avenues regarding the impact of placental dysfunction on the neurovascular development of fetuses. Such a signature would present a clinical value for early diagnosis of brain defects in FASD. Full article

Nutrients and xenobiotics cross the blood–placenta barrier, potentially depositing in the fetal brain. The prenatal exposure affects the neuroendocrine and microbial development. The mechanism underlying maternal risk factors reprograming the microbiota–gut–brain axis with long-term effects on psychosocial behaviors in offspring is not clear. In humans, it is not possible to assess the nutrient or xenobiotic deposition in the fetal brain and gastrointestinal system for ethical reasons. Moreover, the maternal–fetal microbe transfer during gestation, natural labor, and breast-feeding constitutes the initial gut microbiome in the progeny, which is inevitable in the most widely utilized rodent models. The social predisposition in precocial birds, including chickens, provides the possibility to test behavioral responses shortly after being hatched. Hence, chickens are advantageous in investigating the ontogenetic origin of behaviors. Chicken embryos are suitable for deposition assessment and mechanistic study due to the accessibility, self-contained development, uniform genetic background, robust microbiota, and easy in vivo experimental manipulation compared to humans and rodents. Therefore, chicken embryos can be used as an alternative to the rodent models in assessing the fetal exposure effect on neurogenesis and investigating the mechanism underlying the ontogenetic origin of neuropsychiatric disorders. Full article