דו״ח מאומת

Obesity rates are increasing globally, making it imperative to comprehend the effects of parental obesity on human reproduction. This review aims to highlight the impact of male obesity on reproductive and offspring outcomes. Male obesity has been shown to affect fertility through various mechanisms, including changes in semen quality, difficulty with natural conception, and worsened assisted reproductive technology outcomes. The evidence regarding the impact of male obesity on success of sperm retrieval is conflicting, but all aforementioned adverse effects may be modifiable with weight loss. Moreover, paternal obesity may influence atypical offspring outcomes, such as placental abnormalities and disruptions in fetal development, which may be moderated by epigenetic pathways. Further research is needed to fully understand the complex relationships and underlying mechanisms involved. Gaining more insight into the impact of male obesity on fertility and offspring outcomes can aid in the development of targeted interventions to improve family planning and the health of future generations.…

PMID: 37882362

Oxidative stress plays a significant role in regulating the mammalian epigenome, with emerging evidence suggesting imbalances in the cellular redox state trigger stress-responsive epigenetic modifications that drive various human diseases. However, it remains unclear whether, like worms, epigenetic changes caused by redox imbalance or mitochondrial stress can move through the mammalian germline, potentially affecting the health of future generations. Antioxidant therapies are commonly used to reduce oxidative damage and are widely employed in cases of male infertility, where high-dose supplementation is often recommended to enhance sperm quality and overall measures of male reproductive health. Interestingly, in non-stressed, ostensibly healthy males, recent research suggests that antioxidants may have a negative influence on sperm epigenetic markers, indicating a potential epigenetic liability. However, whether male antioxidant treatment can induce paternal effects on offspring growth and development remains unknown. Here, we employed micro-CT imaging and geometric morphometrics to determine whether chronic antioxidant supplementation in healthy male mice affects placental growth and craniofacial development in their offspring. Adult C57BL/6J male mice were given a six-week preconception regimen of N-acetyl-L-cysteine (NAC; 400 mg/kg/day) and selenium (0.04 mg/kg/day), which continued throughout breeding with treatment-naïve females. Although we observed modest alterations to the histological patterning of the female placenta, placental weights and efficiency remained unchanged. In contrast, we observed significant changes in facial shape and symmetry in both male and female offspring, with female offspring exhibiting significant reductions in eye spacing and head area. These changes occurred without any macro changes in paternal metabolic health, indicating that antioxidant-induced shifts in redox balance may disrupt developmental programming in the male germline independent of changes in overall health. Our findings emphasize the need for caution when using antioxidants as preconception interventions and broadly suggest that modulation of the paternal redox axis may result in altered developmental programming and teratogenic effects.…

PMID: 40964303

<h4>Problem</h4>Gestational diabetes mellitus (GDM) is a common metabolic complication of pregnancy associated with adverse maternal and fetal outcomes. Nevertheless, the molecular mechanism of placental dysfunction in GDM are still not clear, especially the role of ferroptosis and its interplay with oxidative stress, inflammation, and angiogenesis.<h4>Method of study</h4>Placental tissues from GDM pregnancies were examined to assess oxidative stress, antioxidant defense, ferroptosis regulation, inflammatory signaling, and angiogenic pathways. Expression levels of key molecular markers were evaluated, and correlation analyses were performed to identify mechanistic interrelationships.<h4>Results</h4>GDM placenta demonstrated elevated oxidative stress markers, including P22PHOX and TXNIP, accompanied by reduced antioxidant markers, such as HO-1, NQO1, SOD2, and CAT, indicating impaired cellular defense. Ferroptosis regulation was disrupted, as anti-ferroptotic markers GPX4, SLC7A11, and NRF2 were significantly downregulated, while pro-ferroptotic markers TFR1 and ACSL4 were increased, suggesting enhanced iron accumulation and lipid peroxidation. This was accompanied by heightened inflammation, evidenced by increased IL-6, IL-1β, TNF-α, and NF-κB activation, alongside reduced IL-10 expression. Furthermore, angiogenesis was impaired, reflected by decreased VEGFA, HIF-1α, and SDF-1α levels, highlighting poor vascular development in the placenta. Additionally, Correlation analyses demonstrated strong associations between ferroptosis markers and oxidative stress, inflammatory, and angiogenic pathways, suggesting the possible presence of an interconnected regulatory network.<h4>Conclusions</h4>These findings identify ferroptosis as a central regulator of GDM-associated placental dysfunction, through a possible interconnected network of oxidative stress, inflammation, and impaired angiogenesis. Targeting ferroptosis may offer a possible therapeutic option to restore placental function and improve maternal-fetal outcomes in GDM.…

PMID: 42464732

Gestational diabetes mellitus (GDM) is associated with placental dysfunction, which contributes to adverse pregnancy outcomes. This study aimed to compare transcriptomic profiles and immune signatures in placentas from pregnancies with and without GDM. Placental tissues from 22 participants (12 GDM and 10 controls) were analyzed using ribonucleic acid sequencing. Differentially expressed genes were identified and subjected to gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. X-cell analysis was used to assess immune cell composition. Western blotting validated the expression of selected genes. A total of 1045 differentially expressed genes were identified. Among these, COL22A1, COL8A2, ACTC1, PAX6, PPP2R2C, G6PC were significantly upregulated. In contrast, LEP and ERBB2 were downregulated in GDM placentas. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that extracellular matrix organization, muscle contraction, and calcium signaling pathways were upregulated. Pathways involved in glucose import, amino acid transport, and the endoplasmic reticulum (ER) stress response were downregulated. X-cell analysis suggested alterations in stromal and immune cell composition, with increased myocytes and fibroblasts and reduced M2 macrophages in GDM placentas. We found that various molecular signatures, including composition, metabolism, ER stress, and immune cells, were altered in GDM placentas compared to controls. This study demonstrates that the GDM placentas exhibit significant transcriptomic alterations, including changes in metabolic, ER stress-related, and immune pathways. These findings highlight the role of placental remodeling in the pathophysiology of GDM and may provide insights for future research and potential therapeutic strategies.…

PMID: 42175401

Endocrine disrupting chemicals (EDCs) are exogenous substances widely disseminated both in the environment and in daily-life products which can interfere with the regulation and function of the endocrine system. These substances have gradually entered the food chain, being frequently found in human blood and urine samples. This becomes a particularly serious issue when they reach vulnerable populations such as pregnant women, whose hormones are more unstable and vulnerable to EDCs. The proper formation and activity of the placenta, and therefore embryonic development, may get seriously affected by the presence of these chemicals, augmenting the risk of several pregnancy complications, including intrauterine growth restriction, preterm birth, preeclampsia, and gestational diabetes mellitus, among others. Additionally, some of them also exert a detrimental impact on fertility, thus hindering the reproductive process from the beginning. In several cases, EDCs even induce cross-generational effects, inherited by future generations through epigenetic mechanisms. These are the reasons why a proper understanding of the reproductive and gestational alterations derived from these substances is needed, along with efforts to establish regulations and preventive measures in order to avoid exposition (especially during this particular stage of life).…

PMID: 37960310

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal…

PMID: 37398065

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking…

PMID: 38092039

Nausea and emesis in early pregnancy is a common phenomenon affecting between 50% and 70% of pregnant women, but little is known about the etiology and possible function of this common and often incapacitating condition. Morning sickness has been reported to have a positive effect on pregnancy outcome and is associated with a decreased risk of miscarriage, preterm birth, low birth weight (LBW), and perinatal death. Both human and animal studies have shown that reduced energy intakes in early pregnancy are associated with increased placental weight. Based on evidence from the literature, a hypothesis is proposed that suggests a functional role for the nausea and emesis of pregnancy in stimulating early placental growth. It is suggested that morning sickness, resulting from secretion of hCG and thyroxine, reduces maternal energy intake. As a result, maternal levels of the anabolic hormones, insulin, and insulin growth factor-1 (IGF-1) are lowered. By suppressing maternal tissue synthesis in early pregnancy, we propose that nausea and vomiting in pregnancy helps ensure that nutrient partitioning favors the developing placenta. Evidence is also presented that suggests there may be a positive relationship between morning sickness and preconceptional body mass index (BMI), such that women who are underweight will experience less severe symptoms of morning sickness compared with women with normal preconceptional BMIs.…

PMID: 10775746

Accumulating research shows that prenatal exposure to maternal stress increases the risk for behavioral and mental health problems later in life. This review systematically analyzes the available human studies to identify harmful stressors, vulnerable periods during pregnancy, specificities in the outcome and biological correlates of the relation between maternal stress and offspring outcome. Effects of maternal stress on offspring neurodevelopment, cognitive development, negative affectivity, difficult temperament and psychiatric disorders are shown in numerous epidemiological and case-control studies. Offspring of both sexes are susceptible to prenatal stress but effects differ. There is not any specific vulnerable period of gestation; prenatal stress effects vary for different gestational ages possibly depending on the developmental stage of specific brain areas and circuits, stress system and immune system. Biological correlates in the prenatally stressed offspring are: aberrations in neurodevelopment, neurocognitive function, cerebral processing, functional and structural brain connectivity involving amygdalae and (pre)frontal cortex, changes in hypothalamo-pituitary-adrenal (HPA)-axis and autonomous nervous system.…

PMID: 28757456

Maternal immune activation (MIA) refers to a maternal immune system triggered by infectious or infectious-like stimuli. A cascade of cytokines and immunologic alterations are transmitted to the fetus, resulting in adverse phenotypes most notably in the central nervous system. Epidemiologic studies implicate maternal infections in a variety of neuropsychiatric disorders, most commonly autism spectrum disorders and schizophrenia. In animal models, MIA causes neurochemical and anatomic changes in the brain that correspond to those found in humans with the disorders. As our understanding of the interactions between environment, genetics, and immune system grows, the role of alternative, noninfectious risk factors, such as prenatal stress, obesity, and the gut microbiome also becomes clearer. This review considers how infectious and noninfectious etiologies activate the maternal immune system. Their impact on fetal programming and neuropsychiatric disorders in offspring is examined in the context of human and animal studies.…

PMID: 30430765

Pregnancy constitutes a critical window for fetal nervous system development. Maternal environmental exposure can trigger placenta-mediated intrauterine perturbations, exerting persistent programming effects on fetal neural development and elevating the susceptibility to neurodegenerative diseases in adulthood. This review systematically summarizes typical prenatal exposure types, including air pollutants, heavy metals, endocrine-disrupting chemicals, nutritional imbalance, and maternal stress. Focusing on four core mechanistic pathways-epigenetic modification, oxidative stress, neuroinflammation, and mitochondrial dysfunction-this study integrates epidemiological evidence, animal model data, and molecular mechanistic findings to elaborate how early-life environmental exposure reshapes neurodevelopmental trajectories and mediates long-term neurological damage. Notably, this review highlights the interactive feedback and cascade amplification effects among multiple biological mechanisms, and strictly distinguishes well-established causal associations from speculative inferences. This work constructs a stratified evidence framework for the developmental origin theory of neurodegenerative diseases, providing scientific support for precise pre-pregnancy and prenatal disease prevention and intervention strategies.…

PMID: 42483055