Previous studies revealed that phthalate exposure could alter thyroid hormones during the last trimester of pregnancy. However, thyroid hormones are crucial for fetal development during the first ...trimester. We aimed to clarify the effect of phthalate exposure on thyroid hormones during early pregnancy.
We recruited 97 pregnant women who were offered an amniocentesis during the early trimester from an obstetrics clinic in southern Taiwan from 2013 to 2014. After signing an informed consent form, we collected amniotic fluid and urine samples from pregnant women to analyze 11 metabolites, including mono-ethyl phthalate (MEP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethylhexyl) phthalate (MEHP), mono-butyl phthalate (MnBP), of 9 phthalates using liquid chromatography/ tandem mass spectrometry. We collected blood samples from each subject to analyze serum thyroid hormones including thyroxine (T4), free T4, and thyroid-binding globulin (TBG).
Three phthalate metabolites were discovered to be >80% in the urine samples of the pregnant women: MEP (88%), MnBP (81%) and MECPP (86%). Median MnBP and MECPP levels in pregnant Taiwanese women were 21.5 and 17.6 μg/g-creatinine, respectively, that decreased after the 2011 Taiwan DEHP scandal. Results of principal component analysis suggested two major sources (DEHP and other phthalates) of phthalates exposure in pregnant women. After adjusting for age, gestational age, TBG, urinary creatinine, and other phthalate metabolites, we found a significantly negative association between urinary MnBP levels and serum T4 (β = -5.41; p-value = 0.012; n = 97) in pregnant women using Bonferroni correction.
We observed a potential change in the thyroid hormones of pregnant women during early pregnancy after DnBP exposure. Additional study is necessitated to clarify these associations.
Aim
To examine the association of maternal chronic hypertension and pregnancy‐induced hypertension (PIH)/preeclampsia with childhood neurodevelopmental disorders (NDDs) in a large‐scale ...population‐based cohort.
Method
We conducted a linked Taiwan National Health Insurance Research Database cohort study of children born between 2004 and 2008 (n=877 233). Diagnoses of autism spectrum disorder (ASD), attention‐deficit/hyperactivity disorder (ADHD), developmental delay, intellectual disability, cerebral palsy (CP), and epilepsy/infantile spasms were identified from birth to the end of 2015. Cox proportional hazards models were fitted with adjustment for potential confounders to estimate the effect of maternal hypertensive disorder of pregnancy on childhood outcomes.
Results
Compared with the offspring of unexposed mothers, offspring of mothers with chronic hypertension or PIH/preeclampsia exhibited increased risk of developing a wide spectrum of NDDs. Chronic hypertension was associated with increased risks of ADHD (hazard ratio 1.22, 95% confidence interval CI 1.13–1.31), developmental delay (1.29, 1.21–1.38), intellectual disability (1.67, 1.43–1.95), CP (1.45, 1.14–1.85), and epilepsy/infantile spasms (1.31, 1.10–1.56) in the offspring, whereas PIH/preeclampsia was associated with increased risks of ASD (1.27, 1.12–1.43), ADHD (1.23, 1.17–1.29), developmental delay (1.29, 1.24–1.35), intellectual disability (1.53, 1.37–1.71), CP (1.44, 1.22–1.70), and epilepsy/infantile spasms (1.36, 1.22–1.52) in the offspring after adjustment for potential confounders. The co‐occurrence of maternal diabetes, preterm deliveries, or fetal growth restriction further increased the risk.
Interpretation
Chronic hypertension or PIH/preeclampsia seems to be sufficient to increase the risk of childhood NDDs.
What this paper adds
Children exposed to maternal hypertensive disorders have a higher cumulative incidence of neurodevelopmental disorders (NDDs) than unexposed children.
Chronic hypertension or pregnancy‐induced hypertension/preeclampsia seems to be sufficient to increase the risk of childhood NDDs.
Co‐occurrence of maternal diabetes, preterm deliveries, or fetal growth restriction further increases the risk.
What this paper adds
Children exposed to maternal hypertensive disorders have a higher cumulative incidence of neurodevelopmental disorders (NDDs) than unexposed children.
Chronic hypertension or pregnancy‐induced hypertension/preeclampsia seems to be sufficient to increase the risk of childhood NDDs.
Co‐occurrence of maternal diabetes, preterm deliveries, or fetal growth restriction further increases the risk.
This article is commented on by Dachew and Alati on page 1015 of this issue.
Key points
Endocrine gland‐derived vascular endothelial growth factor (EG‐VEGF) is a critical factor that facilitates trophoblast invasion in placenta.
Plasma miR‐141 and miR‐200a levels were ...elevated, while EG‐VEGF was decreased in peripheral blood and placenta of preeclamptic patients. Furthermore, numbers of cilia in the placenta from preeclamptic women were significantly decreased.
Elevated miR‐141 and miR‐200a inhibited the expression of EG‐VEGF, downstream extracellular signal‐regulated kinase (ERK)/matrix metalloproteinase 9 signalling and cilia formation, thus leading to defective trophoblast invasion.
The growth of the primary cilium, which transduced ERK signalling upon EG‐VEGF induction for proper trophoblast invasion, was also inhibited by miR‐141 and miR‐200a upregulation.
Preeclampsia is a severe gestational complication, and inadequate trophoblast invasion during placental development is an important pathoaetiology. Endocrine gland‐derived vascular endothelial growth factor (EG‐VEGF) is a critical factor that facilitates trophoblast invasion in placenta. By binding to the primary cilium, EG‐VEGF initiates the signalling cascade for proper embryo implantation and placental development. The miR‐200 family was predicted to target the EG‐VEGF 5′‐untranslated region, and its specific binding site was confirmed using a dual luciferase and a co‐transfection assay. In the peripheral blood and placenta of preeclamptic patients, EG‐VEGF showed significantly lower expression, whereas plasma miR‐141 and miR‐200a had higher expression compared with the controls. The biological significance of miR‐141 and miR‐200a was verified using an overexpression method in a trophoblast cell line (HTR‐8/SVneo). Elevated miR‐141 and miR‐200a inhibited the expression of EG‐VEGF, matrix metalloproteinase 9 (MMP9) and downstream extracellular signal‐regulated kinase (ERK) signalling, thus leading to defective trophoblast invasion. Additionally, the growth of the primary cilium, which transduces ERK/MMP9 signalling upon EG‐VEGF induction, was inhibited by miR‐141 and miR‐200a upregulation. Furthermore, the number of cilia in the human placenta of preeclamptic women was significantly decreased compared to normal placenta. In conclusion, the study uncovers the clinical correlations among the miR‐200 family, EG‐VEGF and the primary cilium in preeclampsia and the underlying molecular mechanisms. The results indicate that miR‐141 and miR‐200a directly targeted EG‐VEGF, suppressed primary cilia formation and inhibited trophoblast invasion. Thus, miR‐141 and miR‐200a could be explored as promising miRNA biomarkers and therapeutic targets in preeclampsia.
Key points
Endocrine gland‐derived vascular endothelial growth factor (EG‐VEGF) is a critical factor that facilitates trophoblast invasion in placenta.
Plasma miR‐141 and miR‐200a levels were elevated, while EG‐VEGF was decreased in peripheral blood and placenta of preeclamptic patients. Furthermore, numbers of cilia in the placenta from preeclamptic women were significantly decreased.
Elevated miR‐141 and miR‐200a inhibited the expression of EG‐VEGF, downstream extracellular signal‐regulated kinase (ERK)/matrix metalloproteinase 9 signalling and cilia formation, thus leading to defective trophoblast invasion.
The growth of the primary cilium, which transduced ERK signalling upon EG‐VEGF induction for proper trophoblast invasion, was also inhibited by miR‐141 and miR‐200a upregulation.
Septins are critical for numerous cellular processes through the formation of heteromeric filaments and rings indicating the importance of structural regulators in septin assembly. Several ...posttranslational modifications (PTMs) mediate the dynamics of septin filaments in yeast. However, little is known about the role of PTMs in regulating mammalian septin assembly, and the in vivo significance of PTMs on mammalian septin assembly and function remains unknown. Here, we showed that SEPT12 was phosphorylated on Ser198 using mass spectrometry, and we generated SEPT12 phosphomimetic knock-in (KI) mice to study its biological significance. The homozygous KI mice displayed poor male fertility due to deformed sperm with defective motility and loss of annulus, a septin-based ring structure. Immunohistochemistry of KI testicular sections suggested that SEPT12 phosphorylation inhibits septin ring assembly during annulus biogenesis. We also observed that SEPT12 was phosphorylated via PKA, and its phosphorylation interfered with SEPT12 polymerization into complexes and filaments. Collectively, our data indicate that SEPT12 phosphorylation inhibits SEPT12 filament formation, leading to loss of the sperm annulus/septin ring and poor male fertility. Thus, we provide the first in vivo genetic evidence characterizing importance of septin phosphorylation in the assembly, cellular function and physiological significance of septins.
Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal ...diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.
The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.
Free tissue transfer has become the preferred option for complex reconstructions in head and neck cancer ablation. This study reviewed the surgical outcome and analyzed the evolution of microsurgical ...head and neck reconstruction over 20 years in single institute.
A total of 1,918 patients underwent microsurgical head and neck reconstructions in 20-year period. The surgical outcome and complications among these 2,019 flaps (1,223 anterolateral thigh flaps, 372 fibula flaps, 353 radial forearm flaps, 12 jejunal flaps, and 59 others) were retrospectively reviewed and analyzed.
A total of 201 cases required emergent surgical re-exploration and the overall flap success rate was 96.2%. Venous insufficiency was the most common cause for re-exploration. Other major complications included fistula formation (5.4%), partial flap necrosis (7.5%), and infection (17.8%). The fibula flap had frequent complications compared with soft tissue flaps. The familiarity to the ALT flap had minimized complications and allowed for widely versatile uses.
Free tissue transfer is shown to be highly reliable option for head and neck reconstruction. For soft tissue defect, ALT flap is the first choice. Fibula flap is ideal for bone defect reconstruction. In case of complex composite defects, double flaps, which include ALT and fibula flaps could reconstruct bone and soft tissue defects simultaneously with high success rate.
Aim
To assess the risk of a wide spectrum of neurodevelopmental disorders (NDDs) in offspring of mothers with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and gestational ...diabetes mellitus (GDM).
Method
This retrospective cohort study included 877 233 singletons born between 2004 and 2008 in Taiwan. Children were followed up to 2015 for diagnoses of NDDs, including autism spectrum disorder (ASD), attention‐deficit/hyperactivity disorder (ADHD), developmental delay, intellectual disability, cerebral palsy, and epilepsy/infantile spasms using health insurance claims data. We performed Cox regression models to estimate the relative risks of NDDs associated with maternal diabetes. Covariates included parental age, year of birth, child sex, family income, urbanization level, hypertensive disorder, and preterm delivery status.
Results
In utero there were 338 (0.04%) children exposed to T1DM, 8749 (1.00%) to T2DM, and 90 200 (10.28%) to GDM. The effect of T1DM on NDDs was the largest, followed by T2DM, then GDM. T1DM was associated with an increased risk of developmental delay, intellectual disability, and epilepsy/intellectual spasms in offspring. T2DM was associated with an increased risk of ASD, ADHD, developmental delay, intellectual disability, cerebral palsy, and epilepsy/intellectual spasms. GDM was associated with an increased risk of ASD, ADHD, and developmental delay.
Interpretation
Maternal diabetes during pregnancy, including T1DM, T2DM, and GDM, is associated with an increased risk of some NDDs in offspring.
Kaplan–Meier cumulative incidence of developing neurodevelopmental disorders in children born to mothers without diabetes or mothers with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), or gestational diabetes mellitus (GDM).
This original article is commented on by Sheiner on pages 863–864 of this issue.
Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are widely recommended for health promotion. Over the last decade, prescription omega-3 fatty acid products (RxOME3FAs) ...have been approved for medical indications. Nonetheless, there is no comprehensive analysis of safety and tolerability of RxOME3FAs so far.
A systematic review of randomized controlled trials (RCTs) was carried out based on searches in six electronic databases. The studies involving marketed RxOME3FA products were included, and adverse-effect data were extracted for meta-analysis. Subgroup analysis and meta-regression were conducted to explore the sources of potential heterogeneity.
Among the 21 included RCTs (total 24,460 participants; 12,750 from RxOME3FA treatment cohort and 11,710 from control cohort), there was no definite evidence of any RxOME3FA-emerging serious adverse event. Compared with the control group, RxOME3FAs were associated with more treatment-related dysgeusia (fishy taste; p = 0.011) and skin abnormalities (eruption, itching, exanthema, or eczema; p < 0.001). Besides, RxOME3FAs had mild adverse effects upon some non-lipid laboratory measurements elevated fasting blood sugar (p = 0.005); elevated alanine transaminase (p = 0.022); elevated blood urea nitrogen (p = 0.047); decreased hemoglobin (p = 0.002); decreased hematocrit (p = 0.009). Subgroup analysis revealed that EPA/DHA combination products were associated with more treatment-related gastrointestinal adverse events eructation (belching; p = 0.010); nausea (p = 0.044) and low-density lipoprotein cholesterol elevation (p = 0.009; difference in means = 4.106mg/dL).
RxOME3FAs are generally safe and well tolerated but not free of adverse effects. Post-marketing surveillance and observational studies are still necessary to identify long-term adverse effects and to confirm the safety and tolerability profiles of RxOME3FAs.
•Among the 21 included RCTs, there was no definite evidence of any RxOME3FA-emerging serious adverse event.•RxOME3FAs were associated with mild adverse events and minor changes upon laboratory measurements.•The two subgroups of RxOME3FAs,EPA/DHA combinations and EPA-only products, may have slightly different adverse-effect profiles.
Septin‐based ring complexes maintain the sperm annulus. Defective annular structures are observed in the sperm of Sept12‐ and Sept4‐null mice. In addition, sperm capacitation, a process required for ...proper fertilization, is inhibited in Sept4‐null mice, implying that the sperm annulus might play a role in controlling sperm capacitation. Hence, we analyzed sperm capacitation of sperm obtained from SEPT12 Ser196 phosphomimetic (S196E), phosphorylation‐deficient (S196A), and SEPT4‐depleted mutant mice. Capacitation was reduced in the sperm of both the Sept12 S196E‐ and Sept12 S196A‐knock‐in mice. The protein levels of septins, namely, SEPT4 and SEPT12, were upregulated, and these proteins were concentrated in the sperm annulus during capacitation. Importantly, the expression of soluble adenylyl cyclase (sAC), a key enzyme that initiates capacitation, was upregulated, and sAC was recruited to the sperm annulus following capacitation stimulation. We further found that SEPT12, SEPT4, and sAC formed a complex and colocalized to the sperm annulus. Additionally, sAC expression was reduced and disappeared in the annulus of the SEPT12 S196E‐ and S196A‐mutant mouse sperm. In the sperm of the SEPT4‐knockout mice, sAC did not localize to the annulus. Thus, our data demonstrate that SEPT12 phosphorylation status and SEPT4 activity jointly regulate sAC protein levels and annular localization to induce sperm capacitation.
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