RESUMEN
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.
RESUMEN
BACKGROUND: PiRNA pathway factors, including evolutionarily conserved Tudor domain-containing proteins, play crucial roles in suppressing transposons and regulating post-meiotic gene expression. TDRD5 is essential for retrotransposon silencing and pachytene piRNA biogenesis; however, a causal link between TDRD5 variants and human infertility has not yet been established. OBJECTIVE: To identify the likely pathogenic variants of TDRD5 in infertile men, characterised by azoospermia or severe oligozoospermia. MATERIAL AND METHODS: Potential candidate variants were identified and confirmed using whole-exome and Sanger sequencing. Haematoxylin and eosin staining, immunofluorescence, and ultrastructural analyses were performed to investigate the structural and functional abnormalities of spermatozoa. The pathogenicity of the identified TDRD5 variants was verified using in vitro experiments. Functional effects of the C-terminal nonsense variant were assessed via histology, immunofluorescence staining, and small-RNA sequencing. Intracytoplasmic sperm injection (ICSI) was also performed to evaluate the efficacy of the clinical treatment. RESULTS: We identified a homozygous missense variant (c.3043G > A, p.A1015T) and a homozygous nonsense variant (c.2293G > T, p.E765*) of TDRD5 in two unrelated infertile men. Both patients exhibited severe oligoasthenoteratozoospermia, characterised by the presence of spermatozoa with multiple heads and/or flagella, as well as acrosomal hypoplasia. In vitro experiments revealed that the p.A1015T variant caused a diffuse distribution of TDRD5 granules, whereas the p.E765* variant led to the production of a C-terminal truncated protein with nuclear localisation, instead of the typical cytoplasmic localisation observed for the wild-type protein. Functional investigations also revealed that truncation of the C-terminal region of TDRD5 could potentially lead to a decline in the expression levels of intermitochondrial cement and chromatoid body components, such as MIWI (PIWIL1) and UPF1, and a slight decrease in the abundance of pachytene piRNA, ultimately resulting in compromised spermiogenesis. ICSI may be an effective treatment for these deficiencies. DISCUSSION AND CONCLUSION: This study implicates TDRD5 as a novel candidate gene in the pathogenesis of human male infertility, emphasising the contribution of piRNA pathway genes to male infertility. In addition, our data suggest that ICSI could be a promising treatment for infertile men harbouring TDRD5 variants.
RESUMEN
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 (m6A) pathway. The results suggest that abnormal cognition in PH offspring may be related to the dysregulation of the m6A pathway, specifically increased levels of YTHDF3 in the hippocampus. YTHDF3 interacts with BTG2 and is involved in the decay of Cbln1 mRNA, leading to the down-regulation of Cbln1 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.