Sexual behavior and cardiovascular diseases: univariable and multivariable Mendelian randomization.

Background: To assess the relationship of genetically predicted sexual behavior (age at first sex (AFS) and the number of sexual partners (NSP)) on cardiovascular diseases (CVDs). Methods and results: We performed two-sample Mendelian randomization (MR) with publicly available datasets from the UK Biobank and FinnGen Study, and analyzed genome-wide association results for sexual behaviors and twelve types of CVDs. The univariable MR method provided a total effect of AFS and NSP on CVDs, and showed evidence that early AFS rather than NSP was associated with CVDs, including angina pectoris (AP), atrial fibrillation and flutter (AFF), coronary atherosclerosis (CAS), deep vein thrombosis of the lower extremity (DVT-LE), heart failure (HF), hypertension (HTN), ischaemic stroke (IS), and myocardial infarction (MI). Given sex as a social determinant of CVD risk, we used gender-stratified SNPs to investigate gender differences in the development of CVDs. These results showed a stronger causal relationship of AFS on CVDs in females than in males. Further multivariable MR analyses indicated a direct effect after accounting for insomnia, number of days of vigorous physical activity 10 + minutes (VPA 10 + min), and time spent watching television (TV). Two-step MR demonstrated these three risk factors act as a mediator in AFS associated AP/HTN/HF. Conclusions: We provide evidence that early AFS increased the risk of CVDs. These associations may be partly caused by VPA 10 + min, insomnia, and the time spent on TV. The causality of AFS on CVDs in females was stronger than in males. Conversely, genetically predicted NSP was not associated with CVDs.

Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.

Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet ß-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.

The causal association between smoking initiation, alcohol and coffee consumption, and women's reproductive health: A two-sample Mendelian randomization analysis.

Objective: A number of epidemiological studies have demonstrated that smoking initiation and alcohol and coffee consumption were closely related to women's reproductive health. However, there was still insufficient evidence supporting their direct causality effect. Methods: We utilized two-sample Mendelian randomization (TSMR) analysis with summary datasets from genome-wide association study (GWAS) to investigate the causal relationship between smoking initiation, alcohol and coffee consumption, and women's reproductive health-related traits. Exposure genetic instruments were used as variants significantly related to traits. The inverse-variance weighted (IVW) method was used as the main analysis approach, and we also performed MR-PRESSO, MR-Egger, weighted median, and weighted mode to supplement the sensitivity test. Then, the horizontal pleiotropy was detected by using MRE intercept and MR-PRESSO methods, and the heterogeneity was assessed using Cochran's Q statistics. Results: We found evidence that smoking women showed a significant inverse causal association with the sex hormone-binding globulin (SHBG) levels (corrected ß = -0.033, p = 9.05E-06) and age at menopause (corrected ß = -0.477, p = 6.60E-09) and a potential positive correlation with the total testosterone (TT) levels (corrected ß = 0.033, p = 1.01E-02). In addition, there was suggestive evidence for the alcohol drinking effect on the elevated TT levels (corrected ß = 0.117, p = 5.93E-03) and earlier age at menopause (corrected ß = -0.502, p = 4.14E-02) among women, while coffee consumption might decrease the female SHBG levels (corrected ß = -0.034, p = 1.33E-03). Conclusion: Our findings suggested that smoking in women significantly decreased their SHBG concentration, promoted earlier menopause, and possibly reduced the TT levels. Alcohol drinking had a potential effect on female higher TT levels and earlier menopause, while coffee consumption might lead to lower female SHBG levels.

The Causal Evidence of Birth Weight and Female-Related Traits and Diseases: A Two-Sample Mendelian Randomization Analysis.

Objectives : A large meta-analysis indicated a more pronounced association between lower birth weight (BW) and diseases in women but less concern about the causality between BW and female-related phenotypes and diseases. Methods: Mendelian randomization (MR) analysis was used to estimate the causal relationship between two traits or diseases using summary datasets from genome-wide association studies. Exposure instrumental variables are variants that are strongly associated with traits and are tested using four different statistical methods, including the inverse variance weighting, MR-Egger, weighted median, and weighted mode in MR analysis. Next, sensitivity analysis and horizontal pleiotropy were assessed using leave-one-out and MR-PRESSO packages. Results: The body mass index (BMI) in adulthood was determined by BW (corrected ß = 0.071, p = 3.19E-03). Lower BW could decrease the adult sex hormone-binding globulin (SHBG) level (ß = -0.081, p = 2.08E-06), but it resulted in increased levels of bioavailable testosterone (bio-T) (ß = 0.105, p = 1.25E-05). A potential inverse effect was observed between BW and menarche (corrected ß = -0.048, p = 4.75E-03), and no causal association was confirmed between BW and the risk of endometriosis, leiomyoma, and polycystic ovary syndrome. Conclusion: Our results suggest that BW may play an important role and demonstrates a significant direct influence on female BMI, SHBG and bio-T levels, and menarche.

Gestational diabetes mellitus suppresses fetal testis development in mice†.

The prevalence of gestational diabetes mellitus (GDM) is increasing rapidly. In addition to the metabolic disease risks, GDM might increase the risks of cryptorchidism in children. However, its mechanism involved in abnormalities of the male reproductive system is still unclear. The purpose of this study was to study the effects of GDM on the development of mouse fetal Leydig cells (FLCs) and Sertoli cells (SCs). Pregnant mice were treated on gestational days 6.5 and 12.5 with streptozotocin (100 mg/kg) or vehicle (sodium citrate buffer). Leydig cell and SC development and functions were evaluated by investigating serum testosterone levels, cell number and distribution, genes, and protein expression. GDM decreased serum testosterone levels, the anogenital distance, and the level of desert hedgehog in SCs of testes of male offspring. FLC number was also decreased in testes of GDM offspring by delaying the commitment of stem Leydig cells into the Leydig cell lineage. RNA-seq showed that FOXL2, RSPO1/ß-catenin signaling was activated and Gsk3ß signaling was inhibited in GDM offspring testis. In conclusion, GDM disrupted reproductive tract and testis development in mouse male offspring via altering genes related to development.

Polycystic Ovary Syndrome and Risk of Five Common Psychiatric Disorders Among European Women: A Two-Sample Mendelian Randomization Study.

Background: Observational studies have implied an association between polycystic ovary syndrome (PCOS) and psychiatric disorders. Here we examined whether PCOS might contribute causally to such disorders, focusing on anxiety disorder (AD), bipolar disorder (BIP), major depression disorder (MDD), obsessive compulsive disorder (OCD), and schizophrenia (SCZ). Methods: Causality was explored using two-sample Mendelian randomization (MR) with genetic variants as instrumental variables. The genetic variants were from summary data of genome-wide association studies in European populations. First, potential causal effects of PCOS on each psychiatric disorder were evaluated, and then potential reverse causality was also assessed once PCOS was found to be causally associated with any psychiatric disorder. Causal effects were explored using inverse variance weighting, MR-Egger analysis, simulation extrapolation, and weighted median analysis. Results: Genetically predicted PCOS was positively associated with OCD based on inverse variance weighting (OR 1.339, 95% CI 1.083-1.657, p = 0.007), simulation extrapolation (OR 1.382, 95% CI 1.149-1.662, p = 0.009) and weighted median analysis (OR 1.493, 95% CI 1.145-1.946, p = 0.003). However, genetically predicted OCD was not associated with PCOS. Genetically predicted PCOS did not exert causal effects on AD, BIP, MDD, or SCZ. Conclusions: In European populations, PCOS may be a causal factor in OCD, but not AD, BIP, MDD, or SCZ.

Paternal obesity impairs hepatic gluconeogenesis of offspring by altering Igf2/H19 DNA methylation.

Over the past four decades, the global prevalence of obesity has increased rapidly in all age ranges. Emerging evidence suggests that paternal lifestyle and environmental exposure have a crucial role in the health of offspring. Therefore, the current study investigated the impact of paternal obesity on the metabolic profile of offspring in a male mouse model of obesity. Female offspring of obese fathers fed a high-fat diet (HFD) (60% kcal fat) showed hyperglycemia because of enhanced gluconeogenesis and elevated expression of phosphoenolpyruvate carboxykinase (PEPCK), which is a key enzyme involved in the regulation of gluconeogenesis. Methylation of the Igf2/H19 imprinting control region (ICR) was dysregulated in the liver of offspring, and the sperm, of HFD fathers, suggesting that epigenetic changes in germ cells contribute to this father-offspring transmission. In addition, we explored whether H19 might regulate hepatic gluconeogenesis. Our results showed that overexpression of H19 in Hepa1-6 cells enhanced the expression of PEPCK and gluconeogenesis by promoting nuclear retention of forkhead box O1 (FOXO1), which is involved in the transcriptional regulation of Pepck. Thus, the current study suggests that paternal exposure to HFD impairs the gluconeogenesis of offspring via altered Igf2/H19 DNA methylation.

Airborne Bacteria Enriched PM2.5 Enhances the Inflammation in an Allergic Adolescent Mouse Model Induced by Ovalbumin.

Air pollution events frequently occur in China during the winter. Most investigations of pollution studies have focused on the physical and chemical properties of PM2.5. Many of these studies have indicated that PM2.5 exacerbates asthma or eosinophil inflammation. However, few studies have evaluated the relationship between bacterial loads in PM2.5, and especially pathogenic bacteria and childhood asthma. Airborne PM2.5 samples from heavily polluted air were collected in Hangzhou, China between December 2014 and January 2015. PM2.5 and ovalbumin (OVA) were intratracheally administered twice in 4-week intervals to induce the allergic pulmonary inflammation in adolescent C57/BL6 mice. PM2.5 exposure caused neutrophilic alveolitis and bronchitis. In the presence of OVA, the levels of the Th2 cytokines IL-4, IL-12, and IL-17 were significantly increased in bronchoalveolar lavage fluids (BALF) after PM2.5 exposure, while eosinophil infiltration and mucin secretion were also induced. In addition to adjuvant effects on OVA-induced allergic inflammation, PM2.5 exposure also led to the maturation of dendritic cells. These results suggest that PM2.5 exposure may aggravate lung eosinophilia and that PM2.5-bound microbial can exacerbate allergic and inflammatory lung diseases.