association-between-telomere-length-thyrotoxicosis-insights-from-two

Association Between Telomere Length and Thyrotoxicosis: Insights from a Two-sample Mendelian Randomization Study

Thyrotoxicosis is an endocrine disorder characterized by excess thyroid hormones, yet its etiologic links to systemic aging biology remain incompletely ...

University of Health and Rehabilitation Sciences

The "Fetal Origins of Adult Disease (FOAD)" hypothesis holds that adverse factors during pregnancy can increase the risk of chronic diseases in offspring. Here, we investigated the effects of prenatal hypoxia (PH) on brain structure and function in adult offspring and explored the role of the N6-methyladenosine (mA) pathway. The results suggest that abnormal cognition in PH offspring may be related to the dysregulation of the mA pathway, specifically increased levels of YTHDF3 in the hippocampus. YTHDF3 interacts with BTG2 and is involved in the decay of  mRNA, leading to the down-regulation of  expression. Deficiency of Cbln1 may contribute to abnormal synaptic function, which in turn causes cognitive impairment in PH offspring. This study provides a scientific clues for understanding the mechanisms of impaired cognition in PH offspring and provides a theoretical basis for the treatment of cognitive impairment in offspring exposed to PH.

YTHDF3 modulates the Cbln1 level by recruiting BTG2 and is implicated in the impaired cognition of prenatal hypoxia offspring.

Pregnancy-induced hypertension (PIH), a prominent determinant of maternal mortality and morbidity worldwide, is hindered by the absence of efficacious biomarkers for early diagnosis, contributing to suboptimal outcomes. Here, we explored potential causal relationships between blood metabolites and the risk of PIH using Mendelian randomization (MR). We employed a two-sample univariable MR approach to empirically estimate the causal relationships between 249 circulating metabolites and PIH. Inverse variance weighted, MR-egger, weight median, simple mode, and weighted mode methods were used for causal estimates. The exposure-to-outcome directionality was confirmed with the MR Steiger test. The Bayesian model averaging MR (MR-BMA) method was applied to detect the predominant causal metabolic traits with alignment for pleiotropy effects. In the primary analysis, analyzing 249 metabolites, we identified 25 causally linked to PIH, including 11 lipid-related traits and 6 associated with fatty acid (un)saturation. Importantly, MR-BMA analyses corroborated the total concentration of branched-chain amino acids(total-BCAA) to be the highest rank causal metabolite, followed by leucine (Leu), phospholipids to total lipids ratio in medium LDL (M-LDL-PL-pct), and Val (all P < 0.05). The directionality of causality predicted by univariable MR and MR-BMA for these metabolites remained consistent. This study highlights the causal connection between metabolites and PIH risk. It highlighted BCAAs as the strongest causal candidates warranting further investigation. Since PIH typically occurs in the second and third trimesters, extending these findings could inform earlier strategies to reduce its risk. Directed acyclic graph of the MR framework investigating the causal relationship between metabolites and PIH. MR: Mendelian randomization; GIVs: genetic instrument variables; SNPs: single-nucleotide polymorphism; IVW: inverse variance weighted; WM: weighted median; PIH: pregnancy-induced hypertension; SM: significant metabolite; MR-BMA: Bayesian model averaging MR.

BMA-based Mendelian randomization identifies blood metabolites as causal candidates in pregnancy-induced hypertension.

Paternal lifestyle and environmental exposures can alter epigenetic changes in sperm and play a critical role in the offspring's future health, yet the underlying mechanisms remain elusive. The present study established a model of paternal obesity and found that the increased levels of H3K27me3 in sperm persist into the 8-cell embryo stage, resulting in a transgenerational decrease of Manf, which causes endoplasmic reticulum stress and activates the GRP78-PERK-EIF2α-ATF4-CHOP axis. This consequently leads to impaired glucose metabolism and apoptosis in the liver of female offspring. Based on these findings, the F0 mice are treated with 3-deazaneplanocin A, an EZH2 inhibitor, which successfully prevented metabolic dysfunction in F0 mice of the high-fat diet (HFD) group. Meanwhile, intravenous injection of recombinant human MANF in F1 female offspring can successfully rescue the metabolic dysfunction in the HFD-F1 group. These results demonstrate that paternal obesity triggers transgenerational metabolic dysfunction through sperm H3K27me3-dependent epigenetic regulation. The present study also identifies the H3K27me3-MANF pathway as a potentially preventive and therapeutic strategy for diabetes, although further studies are needed to validate its clinical applicability.

Paternal Obesity-Induced H3K27me3 Elevation Leads to MANF-Mediated Transgenerational Metabolic Dysfunction in Female Offspring.

Prostate cancer (PCa) is a common cancer in men, making up about 21% of male cancer cases worldwide. Although prostate cancer is common, little is known about its causes, which makes treatment more difficult. Studies suggest that immunity and inflammation are linked to prostate cancer. This study explores whether inflammatory mediators play a role in its development and outcome.

Article	Year
YTHDF3 modulates the Cbln1 level by recruiting BTG2 and is implicated in the impaired cognition of prenatal hypoxia offspring. iScience\| PubMed ID: 38205248	2024
BMA-based Mendelian randomization identifies blood metabolites as causal candidates in pregnancy-induced hypertension. Hypertension research : official journal of the Japanese Society of Hypertension\| PubMed ID: 38951678	2024
Paternal Obesity-Induced H3K27me3 Elevation Leads to MANF-Mediated Transgenerational Metabolic Dysfunction in Female Offspring. Advanced science (Weinheim, Baden-Wurttemberg, Germany)\| PubMed ID: 40041941	2025
Exploring the causal relationship between CX3CL1 and prostate cancer prognosis using Mendelian randomization. Discover oncology\| PubMed ID: 40544418	2025

Weisheng Li

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