Thyroid dysfunction caused by exposure to environmental endocrine disruptors and the underlying mechanism: A review.

Thyroid disease has been rapidly increasing, but its causes remain unclear. At present, many studies have focused on the relationship between environmental endocrine disruptors (EEDs) and the pathogenesis of thyroid disease. Herein, we summarize such studies exploring the effects of exposure to common EEDs on thyrotoxicosis, finding that EEDs appear to contribute to the pathogenesis of thyroid-related diseases such as thyroid cancer, goiter, thyroiditis, hyperthyroidism, and hypothyroidism. To explore this causative effect in detail, we have analyzed the following three aspects of how EEDs are believed to exert their impacts on the occurrence and development of thyroid disease: (1) damage to the thyroid tissue structure, including disrupted mitochondria and the stratification of thyroid follicular epithelial cells; (2) disruption of thyroid hormone signaling, including thyroid hormone synthesis and secretion disorders, destruction of normal function of the hypothalamus-pituitary-thyroid axis, disturbed estrogen signaling in the body, alterations to the level of thyroid-stimulating hormone, inhibition of the release of thyroglobulin from thyroid cells, and reductions in the levels of sodium iodide co-transporters, thyroid peroxidase, deiodinase, and transthyretin; and (3) molecular mechanisms underlying the disruption of thyroid function, including competitive binding to T3 and T4 receptors, disturbance of the hypothalamic-pituitary-thyroid axis, activation of the ERK and Akt pathways, oxidative stress, regulation of the expression of the proto-oncogene k-Ras, tumor suppressor gene PTEN, and thyroid TSHR gene, and induction of autophagy in thyroid cells. Overall, this article reviews how EEDs can affect the occurrence and development of thyroid disease via multiple routes, thus providing new ideas to intervene for the prevention, diagnosis, treatment, and prognosis of thyroid disease.

Umbilical cord blood thyroid hormones are inversely related to telomere length and mitochondrial DNA copy number.

Hypothyroidism has been linked to reduced mortality rate and increased lifespan and health span. Telomere shortening, enhanced oxidative stress, and reduced cellular mitochondrial content are important hallmarks of aging shown to be related to age-associated diseases. It was proposed that the status of these markers in early life can be predictive of lifespan and the predisposition to certain age-associated disease in adulthood. Animal studies indicated that prenatal injection of thyroid hormones affects postnatal telomere length. Here, we sought to determine whether thyroid hormones TSH and fT4 are related to the telomere length, mitochondrial DNA copy number (mtDNAcn), and oxidative stress resistance marker GPX in the cord blood of newborns. In this study, we analyzed 70 mothers (18-42 years) and neonate dyads born in 2022 at the Nik Nafs maternity Hospital in Rafsanjan. The relative telomere length (RTL) and mtDNAcn were measured in the genomic DNA of cord blood leukocytes using real-time PCR. GPX enzyme activity was measured in the serum using colorimetric assays. In this study the correlation between these markers and the cord blood TSH and fT4 hormones were assessed using regression models. We found a reverse relationship between TSH levels and RTL in the cord blood of neonates. Additionally, our results displayed increased TSH levels associated with enhanced GPX activity. Regarding the mitochondrial DNA copy number, we found an indirect relationship between fT4 level and mtDNAcn only in male newborns. Future analyses of various oxidative stress markers, mitochondrial biogenesis status, telomerase activity, and the level of DNA damage are warranted to demonstrate the underlying mechanism of our observations.

GLIS3 expression in the thyroid gland in relation to TSH signaling and regulation of gene expression.

Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH). In this study, we demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid development, a time at which GLIS3 target genes, such as Slc5a5 (Nis), become expressed. This, together with observations showing that ubiquitous Glis3KO mice do not display major changes in prenatal thyroid gland morphology, indicated that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of GLIS3 in postnatal thyroid suggested a link between GLIS3 protein expression and blood TSH levels. This was supported by data showing that treatment with TSH, cAMP, or adenylyl cyclase activators or expression of constitutively active PKA enhanced GLIS3 protein stability and transcriptional activity, indicating that GLIS3 activity is regulated at least in part by TSH/TSHR-mediated activation of PKA. The TSH-dependent increase in GLIS3 transcriptional activity would be critical for the induction of GLIS3 target gene expression, including several thyroid hormone (TH) biosynthetic genes, in thyroid follicular cells of mice fed a low iodine diet (LID) when blood TSH levels are highly elevated. Like TH biosynthetic genes, the expression of cell cycle genes is suppressed in ubiquitous Glis3KO mice fed a LID; however, in thyroid-specific Glis3 knockout mice, the expression of cell cycle genes was not repressed, in contrast to TH biosynthetic genes. This indicated that the inhibition of cell cycle genes in ubiquitous Glis3KO mice is dependent on changes in gene expression in GLIS3 target tissues other than the thyroid.

Radiogenomic analysis of cellular tumor-stroma heterogeneity as a prognostic predictor in breast cancer.

BACKGROUND: The tumor microenvironment and intercellular communication between solid tumors and the surrounding stroma play crucial roles in cancer initiation, progression, and prognosis. Radiomics provides clinically relevant information from radiological images; however, its biological implications in uncovering tumor pathophysiology driven by cellular heterogeneity between the tumor and stroma are largely unknown. We aimed to identify radiogenomic signatures of cellular tumor-stroma heterogeneity (TSH) to improve breast cancer management and prognosis analysis. METHODS: This retrospective multicohort study included five datasets. Cell subpopulations were estimated using bulk gene expression data, and the relative difference in cell subpopulations between the tumor and stroma was used as a biomarker to categorize patients into good- and poor-survival groups. A radiogenomic signature-based model utilizing dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was developed to target TSH, and its clinical significance in relation to survival outcomes was independently validated. RESULTS: The final cohorts of 1330 women were included for cellular TSH biomarker identification (n = 112, mean age, 57.3 years ± 14.6) and validation (n = 886, mean age, 58.9 years ± 13.1), radiogenomic signature of TSH identification (n = 91, mean age, 55.5 years ± 11.4), and prognostic (n = 241) assessments. The cytotoxic lymphocyte biomarker differentiated patients into good- and poor-survival groups (p < 0.0001) and was independently validated (p = 0.014). The good survival group exhibited denser cell interconnections. The radiogenomic signature of TSH was identified and showed a positive association with overall survival (p = 0.038) and recurrence-free survival (p = 3 × 10-4). CONCLUSION: Radiogenomic signatures provide insights into prognostic factors that reflect the imbalanced tumor-stroma environment, thereby presenting breast cancer-specific biological implications and prognostic significance.

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease.

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Investigation of common genetic risk factors between thyroid traits and breast cancer.

Breast cancer (BC) risk is suspected to be linked to thyroid disorders, however observational studies exploring the association between BC and thyroid disorders gave conflicting results. We proposed an alternative approach by investigating the shared genetic risk factors between BC and several thyroid traits. We report a positive genetic correlation between BC and thyroxine (FT4) levels (corr = 0.13, p-value = 2.0 × 10-4) and a negative genetic correlation between BC and thyroid-stimulating hormone (TSH) levels (corr = -0.09, p-value = 0.03). These associations are more striking when restricting the analysis to estrogen receptor-positive BC. Moreover, the polygenic risk scores (PRS) for FT4 and hyperthyroidism are positively associated to BC risk (OR = 1.07, 95%CI: 1.00-1.13, p-value = 2.8 × 10-2 and OR = 1.04, 95%CI: 1.00-1.08, p-value = 3.8 × 10-2, respectively), while the PRS for TSH is inversely associated to BC risk (OR = 0.93, 95%CI: 0.89-0.97, p-value = 2.0 × 10-3). Using the PLACO method, we detected 49 loci associated to both BC and thyroid traits (p-value < 5 × 10-8), in the vicinity of 130 genes. An additional colocalization and gene-set enrichment analyses showed a convincing causal role for a known pleiotropic locus at 2q35 and revealed an additional one at 8q22.1 associated to both BC and thyroid cancer. We also found two new pleiotropic loci at 14q32.33 and 17q21.31 that were associated to both TSH levels and BC risk. Enrichment analyses and evidence of regulatory signals also highlighted brain tissues and immune system as candidates for obtaining associations between BC and TSH levels. Overall, our study sheds light on the complex interplay between BC and thyroid traits and provides evidence of shared genetic risk between those conditions.

Eighteen-years follow-up of congenital hypothyroidism by TSHR gene p.Arg109Gln and p.Arg450His variants.

Congenital hypothyroidism (CH) is a common heterogeneous endocrine disorder. The thyroid-stimulating hormone receptor gene (TSHR) is one of the major candidate genes associated with CH. Studies have investigated the possible correlations between the specific clinical features and the presence of TSHR variants. However, only a few reports have focused on the long-term follow-up of patients with CH. Here we present a case of CH-associated TSHR p.Arg109Gln and p.Arg450His rare compound heterozygous variants, with a follow-up performed until adolescence. The patient had high serum TSH levels during newborn screening. Oral administration of levothyroxine (l-T4) was initiated at 1 month of age. The ultrasonogram revealed normal thyroid morphology and blood flow. Reduced uptake of I-123 and negative perchlorate test was observed. A small amount of l-T4 remained needed although l-T4 could be steadily reduced by puberty. The patient was diagnosed with orthotopic, nongoitrous, and permanent CH. He had no nonclassical TSH resistance. Patients with the TSHR p.Arg109Gln compound heterozygous variant exhibit permanent CH with high TSH levels and normal or slightly lower fT4 levels. In the future, genotype identification could help predict the long-term prognosis and reduce the requirement for detailed examinations. More case studies are needed to determine the relationship between genetic variants and clinical features in CH.

A Study to Assess Tyrosine Kinase Inhibitors Induced Thyroid Dysfunction in Newly Diagnosed Chronic Myeloid Leukemia Patients.

INTRODUCTION: The use of TKIs has dramatically improved the prognosis of CML. The aim of this study was to evaluate the effects of TKIs on thyroid function in a prospective manner. MATERIALS: In this prospective study, 55 newly diagnosed adult subjects with positive Philadelphia chromosome in chronic phase of CML without any other apparent underlying diseases were enrolled. Total T3, Free T4, TSH and Anti TPO antibodies were measured at starting and after 12 & 24 weeks of treatment respectively. The study also included a same number control group of sex- and age-matched healthy individuals. RESULT: Approximately 10% of the patients were having subclinical hypothyroidism while the rest were normal regarding thyroid function. There were statistically significant changes within reference ranges in serum concentration of TSH (p = 0.022 and 0.011) 12 weeks and 24 weeks after TKIs initiation, respectively. CONCLUSION: This study showed some significant changes on thyroid function tests.However, without any clinical abnormalities in the course of treatment we didn't initiate replacement. We recommend other studies with larger sample size and longer duration of follow-up. References Singha H, Chakrabarty SK, Sherpa PL, et al. Tyrosine kinase inhibitors induced thyroid dysfunction in newly diagnosed chronic myeloid leukemia patients. Singha H, et al. Thyroid dysfunction caused by tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia.

Association between non-alcoholic fatty liver disease and subclinical hypothyroidism in children with obesity.

PURPOSE: We aimed (i) evaluating the relationship between non-alcoholic fatty liver disease (NAFLD) and thyroid function tests, (ii) testing if the relationship between NAFLD and thyroid dysfunction could be driven by the obesity and the IR degree, and (iii) exploring the influence of the patatin-like phospholipase domain-containing protein-3 (PNPLA3) I148M and the transmembrane 6 superfamily member 2 (TM6SF2) E167K polymorphisms on the association between NAFLD and thyroid function in children. METHODS: We examined 2275 children and adolescents with obesity. Subclinical hypothyroidism (SH) was defined by thyroid-stimulating hormone (TSH) > 4.2 µUI/ml with normal fT3 and fT4. RESULTS: Children with NAFLD showed higher SH prevalence than those without NAFLD (15.7% Vs 7.4%;p = 0.001) and showed an adjusted odds ratio (aOR) to have SH of 1.68 (95% CI:1.01-2.80;p = 0.04) while patients with SH had an aOR to show NAFLD of 2.13(95% CI:1.22-3.73;p = 0.008). Patients having severe obesity and IR degree presented an aOR to show both NAFLD and SH of 3.61 (95% CI:1.78-7.33;p < 0.0001). Subjects with NAFLD carrying the TM6SF2 167 K allele had lower TSH levels than non-carriers (p = 0.03) and showed an aOR to have SH of 0.10 (95% CI: 0.01-0.79;p = 0.02). No differences were found in carriers of the PNPLA3 148 M allele. A general linear model for TSH variance showed a significant association of TSH with TM6SF2 genotypes only in the NAFLD group (p = 0.001). CONCLUSION: Children with obesity and NAFLD presented increase risk of SH and vice versa likely due to the adverse effect of duration of obesity, obesity degree, and IR. The TM6SF2 E167K exerts a protective role against SH in children with obesity and NAFLD.

Association of Thyroid-Stimulating Hormone With All-Cause Mortality: A 2-Sample Mendelian Randomization Study.

CONTEXT: Thyroid-stimulating hormone (TSH), as the most sensitive and specific marker of thyroid status, is associated with multiple health outcomes, including mortality. However, whether TSH levels are causally associated with the risk of mortality remains unclear. OBJECTIVE: This study aims to investigate the causal association between TSH levels and all-cause mortality using Mendelian randomization (MR) analyses. METHODS: MR analyses using single-nucleotide polymorphisms (SNPs) associated with TSH levels (P < 5 × 10-8) as instruments. Mortality data were obtained from the UK Biobank, including 384 344 participants who were recruited from 22 assessment centers across the UK taken between 2006 and 2010. Cox proportional hazards regression was used to estimate the association of the TSH genetic risk score (GRS) with all-cause and cause-specific mortality. RESULTS: 15 557 individuals died during a median of 9.00 years of follow-up in the UK Biobank. A total of 70 SNPs were included in the MR analysis. The main MR analyses showed that 1 SD increase in TSH was associated with a decreased risk of all-cause mortality (OR 0.972, 95% CI 0.948-0.996), which may be largely attributed to respiratory disease mortality (OR 0.881, 95% CI 0.805-0.963). The multivariable hazard ratios (HRs) (95% CI) of all-cause mortality across 3 TSH GRS categories were 1.00 (reference), 0.976 (0.940-1.014), and 0.947 (0.911-0.985), respectively (P for trend < .01). Moreover, except digestive diseases mortality, genetically predicted TSH levels were negatively associated with mortality from CVD, cancer, noncancer diseases causes, and dementia, although not statistically significant. CONCLUSION: Higher TSH levels were causally associated with lower risk of all-cause mortality, which may be largely attributed to respiratory disease mortality.

Thyroid gland dysfunction and vitamin D receptor gene polymorphism in keratoconus.

OBJECTIVES: To detect the serum level of thyroid hormones, vitamin D and vitamin D receptors (VDR) polymorphism in keratoconus (KC) patients and to identify the association between vitamin D deficiency and thyroid dysfunction in KC. METHODS: This cross sectional study included 177 KC patients with no thyroid disorders compared to 85 healthy controls with normal corneal tomography. Measurements of thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free tetraiodothyronine (FT4) and serum 25-OH vitamin D were done using Enzyme linked immusoassay (ELISA test). VDR polymorphisms were tested including [Taq I (rs731236), Apa I (rs7975232) and Bsm I (rs1544410)] using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: An increase in frequency of thyroid disorders (P = 0.04), decrease in serum 25(OH) vitamin D level (P < 0.001), Taq 1 and tt genotype (P < 0.001) were significantly distributed in KC patients. A significantly higher serum 25(OH) vitamin D level was reported in TT genotype, while insufficient level was more common in Tt genotype (P < 0.001). A deficient serum 25(OH) vitamin D level was predominant in tt genotype (P < 0.001). A 95% confidence interval was in TSH (1.603, 2.946), FT4 (24.145, 77.06), hypothyroidism (1.062, 67.63), insufficient (2.936, 11.643) and deficient vitamin D (5.283, 28.704) and all were significant risk factors for KC with (P < 0.05). CONCLUSIONS: Both thyroid disorders and low vitamin D are potential factors for KC development. Studying VDR at the molecular level provides interesting avenues for future research toward the identification of new KC cases.

Association Between Systemic Lupus Erythematosus and Primary Hypothyroidism: Evidence from Complementary Genetic Methods.

INTRODUCTION: Systemic lupus erythematosus (SLE) and hypothyroidism often coexist in observational studies; however, the causal relationship between them remains controversial. METHODS: Complementary genetic approaches, including genetic correlation, Mendelian randomization (MR), and colocalization analysis, were conducted to assess the potential causal association between SLE and primary hypothyroidism using summary statistics from large-scale genome-wide association studies. The association between SLE and thyroid-stimulating hormone (TSH) was further analyzed to help interpret the findings. In addition, findings were verified using a validation data set, as well as through different MR methods with different model assumptions. RESULTS: The linkage disequilibrium score regression revealed a shared genetic structure between SLE and primary hypothyroidism, with the significant genetic correlation estimated to be 0.2488 (P = 6.00 × 10-4). MR analysis with the inverse variance weighted method demonstrated a bidirectional causal relationship between SLE and primary hypothyroidism. The odds ratio (OR) of SLE on primary hypothyroidism was 1.037 (95% CI, 1.013-1.061; P = 2.00 × 10-3) and that of primary hypothyroidism on SLE was 1.359 (95% CI, 1.217-1.520; P < 0.001). The OR of SLE on TSH was 1.007 (95% CI, 1.001-1.013; P = 0.032). However, TSH was not causally associated with SLE (P = 0.152). Similar results were found using different MR methods. In addition, colocalization analysis suggested that shared causal variants existed between SLE and primary hypothyroidism. The results of the validation analysis indicated a bidirectional causal relationship between SLE and primary hypothyroidism, as well as shared loci. CONCLUSION: In summary, a bidirectional causal relationship between SLE and primary hypothyroidism was observed with complementary genetic approaches.

Initial screening of the rs104893657 variant of the PAX8 gene in women with hypothyroidism from Northeastern Slovakia.

OBJECTIVE: Thyroid diseases are among the most common endocrinopathies and metabolic disorders. Hypothyroidism is caused by insufficient production of thyroid hormones with a higher prevalence in women. Causes for the development of endocrine diseases may be mutations in genes that encode peptide hormones. The aim of this scientific study was to determine the genotype and allele frequencies of the rs104893657 variant of the PAX8 gene and to determine the genotype versus phenotype association. METHODS: The study population consisted of 135 women from northeastern Slovakia who were divided on the basis of screening into two groups: a control group without diagnosed hypothyroidism (CG = 67) and a group of women with hypothyroidism (HY = 68). Biochemical markers - thyroid-stimulating hormone (TSH), prealbumin (PREA), calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP) were determined using Cobas Integra 400 plus, Cobas e411 analysers (Roche). Genotyping was performed using TaqMan® SNP Genotyping Assay instrument 7500 Fast Real-Time PCR Systems (Applied Biosystem). RESULTS: Student's t-test revealed a statistically significant difference between CG and HY in biochemical parameters: TSH (p < 0.001), P (p = 0.008). By Chi-square test we found no statistically significant difference in the representation of genotypes (p = 0.788) in the rs104893657 polymorphism of PAX8 gene. The T allele was not associated with hypothyroidism in Slovak women (p = 0.548). In CC genotype we found statistically significant difference between CG and HY in parameters TSH (p < 0.001) and P (p = 0.006). CONCLUSION: The mutant T allele was detected at low frequency in both groups of women studied. The association of the T allele with the development of hypothyroidism in Slovak women was not confirmed. The results of this work provide initial information on the distribution of genotypes and alleles in the studied variant of PAX8 gene in the Slovak female population.

Newborn Genetic Screening Revealed Increased Levels of Biochemical Indicators in Carriers of Heterozygous Variants.

Background: Conventional newborn screening (NBS) is usually based on biochemical methods to predict the risk of inborn errors of metabolism. Recent studies have applied next-generation sequencing in NBS and revealed much more information, including carrier status. Whether these carriers of variants differ from other individuals was not fully determined. Objective: This research investigated the effect of heterozygous carrier status of pathogenic variants on biochemical indicators during NBS. Methods: We enrolled newborns participating in both conventional NBS and our previous Newborn Screening with Targeted Sequencing (NESTS) program from January 2021 to December 2021 in the Shunyi Maternal and Children's Hospital of Beijing Children's Hospital. Newborn levels of phenylalanine (Phe), thyroid stimulating hormone (TSH), and 17-hydroxyprogesterone (17-OHP) were measured to be analyzed together with associated sequencing results. Results: A total of 2351 newborns in the NESTS program was examined in the study. None had biallelic variants in genes related to congenital hypothyroidism (CH), hyperphenylalaninemia (HPA) or congenital adrenal hyperplasia. Forty-nine heterozygous carriers with phenylalanine hydroxylase (PAH) variants had significantly higher levels of Phe (p < 0.0001), and 11 heterozygous carriers of thyroid-stimulating hormone receptor (TSHR) variants had significantly higher levels of TSH (p < 0.05). Although heterozygous carriers had higher biochemical levels, they were below the diagnostic threshold of HPA and CH. Conclusions: Carriers of heterozygous variants in PAH or TSHR had significantly increased biochemical levels of associated factors in NBS. For individuals with higher Phe or TSH levels within the normal reference intervals, attention should be paid to the possibility of heterozygous carrier status.

Genome-wide SNP genotyping as a simple and practical tool to accelerate the development of inbred lines in outbred tree species: An example in cacao (Theobroma cacao L.).

Cacao is a globally important crop with a long history of domestication and selective breeding. Despite the increased use of elite clones by cacao farmers, worldwide plantations are established mainly using hybrid progeny material derived from heterozygous parents, therefore displaying high tree-to-tree variability. The deliberate development of hybrids from advanced inbred lines produced by successive generations of self-pollination has not yet been fully considered in cacao breeding. This is largely due to the self-incompatibility of the species, the long generation cycles (3-5 years) and the extensive trial areas needed to accomplish the endeavor. We propose a simple and accessible approach to develop inbred lines based on accelerating the buildup of homozygosity based on regular selfing assisted by genome-wide SNP genotyping. In this study we genotyped 90 clones from the Brazilian CEPEC´s germplasm collection and 49 inbred offspring of six S1 or S2 cacao families derived from self-pollinating clones CCN-51, PS-13.19, TSH-1188 and SIAL-169. A set of 3,380 SNPs distributed across the cacao genome were interrogated on the EMBRAPA multi-species 65k Infinium chip. The 90 cacao clones showed considerable variation in genome-wide SNP homozygosity (mean 0.727± 0.182) and 19 of them with homozygosity ≥90%. By assessing the increase in homozygosity across two generations of self-pollinations, SNP data revealed the wide variability in homozygosity within and between S1 and S2 families. Even in small families (<10 sibs), individuals were identified with up to ~1.5 standard deviations above the family mean homozygosity. From baseline homozygosities of 0.476 and 0.454, offspring with homozygosities of 0.862 and 0.879 were recovered for clones TSH-1188 and CCN-51 respectively, in only two generations of selfing (81-93% increase). SNP marker assisted monitoring and selection of inbred individuals can be a practical tool to optimize and accelerate the development of inbred lines of outbred tree species. This approach will allow a faster and more accurate exploitation of hybrid breeding strategies in cacao improvement programs and potentially in other perennial fruit and forest trees.

Resistance to Thyroid Hormones: A Case-Series Study.

The aim of the study is to describe the clinical features of two unrelated patients with resistance to thyroid hormones (RTH), the first, a total thyroidectomized patient, and the second, a pregnant woman. We report the features found in her newborn who also showed RTH. Patient 1 is a 38-year-old man with total thyroidectomy managed for excessive thyroid stimulating hormone (TSH) production, which poorly responded to the replacement therapy. He was found with a THRß c.1378G>A p.(Glu460Lys) heterozygous mutation, which was also present in other members of his family (son, brother, and father). Interestingly, Patient 1 had hypertension, dyslipidemia, and hepatic steatosis, which have been recently suggested as RTH-related comorbidities. Patient 2 is a 32-year-old pregnant woman with multinodular goiter, and the THRß heterozygous variant c.959G>C, that, to the best of our knowledge, has been reported in literature only once. Her newborn had tachycardia and increased thyroid hormone levels, and showed the same mutation. After delivery, high parathyroid hormone (PTH) and calcium serum levels were found in Patient 2 and the scintigraphy showed the presence of adenoma of a parathyroid gland. This case-series study provides a practical example of the management of RTH in a thyroidectomized patient, a pregnant woman, and a newborn. A novel RTH pathogenic mutation is described for the second time in literature. Furthermore, the importance of metabolic assessment in patients with RTHß has been highlighted and the possible correlation between RTH and primary hyperparathyroidism is discussed.

Transcriptomic sequencing reveals the potential molecular mechanism by which Tetrabromobisphenol A bis (2-hydroxyethyl ether) exposure exerts developmental neurotoxicity in developing zebrafish (Danio rerio).

Tetrabromobisphenol A bis (2-hydroxyethyl ether) (TBBPA-DHEE) is a derivative of Tetrabromobisphenol A (TBBPA) used as an intermediate flame retardant in engineering polymers. The mechanism of neurodevelopmental toxicity of TBBPA-DHEE remains unclear due to limited toxicological data. We performed behavioral and transcriptomic analyses to assess the neurodevelopmental effects of TBBPA-DHEE on developing zebrafish and potential toxicity mechanisms. Our result shows that exposure to TBBPA-DHEE significantly increased mortality, deformity rate, and reduction in hatch rate, hatchability, and body length relative to the DMSO control. The behavior analysis indicates that TBBPA-DHEE significantly reduced the spontaneous movement of larva compared to the control. The TSH and GH levels were significantly reduced in all the exposure groups in a concentration-dependent manner relative to the DMSO control. TBBPA-DHEE exhibited a significant reduction in locomotor activity across all the exposure groups in the light/dark locomotion test. The transcriptomic analysis result shows that 579 genes were differentially expressed. KEGG analysis shows the enrichment of complement cascade, JAK-STAT signaling pathway, cytokine-cytokine interaction, and phototransduction pathway resulting in a change in mRNA expression of their genes. These observed changes in developmental endpoints, hormonal level, and alteration in mRNA expression of component genes involved in neurodevelopmental pathways could be part of the possible mechanism of the observed toxic effects of TBBPA-DHEE exposure on zebrafish. This study could reveal the possible neurodevelopmental toxicity of TBBPA-DHEE to aquatic species, which could help uncover the health implications of emerging environmental contaminants.

COVID-19 and Thyroid Function: A Bi-Directional Two-Sample Mendelian Randomization Study.

Background: Thyroid dysfunction has been observed among some patients with coronavirus disease (COVID-19). It is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (or its severity) leads to the development of thyroid dysfunction, or vice versa. In this study, we examined the bi-directional causal relationship between host genetic liability to three COVID-19 phenotypes (including SARS-CoV-2 infection, hospitalized and severe COVID-19) and three thyroid dysfunction traits (including hyperthyroidism, hypothyroidism, and autoimmune thyroid disease [AITD]) and three continuous traits of thyroid hormones (including thyrotropin [TSH] and free thyroxine [fT4] within reference range, and TSH in full range). Methods: Summary statistics from the largest available meta-analyses of human genome-wide association studies were retrieved for the following variables: SARS-CoV-2 infection (n = 1,348,701), COVID-19 hospitalization (n = 1,557,411), severe COVID-19 (n = 1,059,456), hyperthyroidism (n = 51,823), hypothyroidism (n = 53,423), AITD (n = 755,406), TSH within reference range (n = 54,288), fT4 within reference range (n = 49,269), and TSH in full range (n = 119,715). Using a two-sample Mendelian randomization (MR) approach, the inverse-variance weighted (IVW) method was adopted as the main MR analysis. Weighted median, contamination mixture, MR-Egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods were applied as sensitivity analyses. Results: Host genetic susceptibility to SARS-CoV-2 infection was causally associated with hypothyroidism in the main IVW analysis (per doubling in prevalence of SARS-CoV-2 infection, odds ratio [OR] = 1.335; 95% confidence interval [CI]: 1.167-1.526; p = 2.4 × 10-5, surpassing the Bonferroni multiple-testing threshold). Similar causal estimates were observed in the sensitivity analyses (weighted median: OR = 1.296; CI: 1.066-1.575; p = 9 × 10-3; contamination mixture: OR = 1.356; CI: 1.095-1.818; p = 0.013; MR-Egger: OR = 1.712; CI: 1.202-2.439; p = 2.92 × 10-3, and MR-PRESSO: OR = 1.335; CI: 1.156-1.542; p = 5.73 × 10-4). Host genetic liability to hospitalized or severe COVID-19 was not associated with thyroid dysfunction or thyroid hormone levels. In the reverse direction, there was no evidence to suggest that genetic predisposition to thyroid dysfunction or genetically determined thyroid hormone levels altered the risk of the COVID-19 outcomes. Conclusions: This bi-directional MR study supports that host response to SARS-CoV-2 viral infection plays a role in the causal association with increased risk of hypothyroidism. Long-term follow-up studies are needed to confirm the expected increased hypothyroidism risk.

Causal Associations of Thyroid Function and Age-Related Macular Degeneration: A Two-Sample Mendelian Randomization Study.

PURPOSE: To determine whether causal association lies between thyroid function and age-related macular degeneration (AMD) risk in human beings. DESIGN: Two-sample Mendelian randomization (MR) study. METHODS: The single-nucleotide polymorphisms associated with free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were selected from a genome-wide association study (GWAS) of 72,167 individuals of European descent. Summary-level data for AMD were obtained from a GWAS published by the International Age-related Macular Degeneration Genomics Consortium of 33,526 individuals (16,144 cases and 17,832 controls). An inverse-variance-weighted (IVW) method was the main MR analysis. Maximum likelihood, weighted median, MR-Egger, MR-pleiotropy residual sum outlier methods were used for the sensitivity analysis. RESULTS: An increase of 1 SD in genetically predicted FT4 levels was found to be significantly associated with an 18.9 % increase in the overall AMD risk (P = .005). In the multivariable MR analysis controlling for TSH level, the causal effect of FT4 level on the risk of AMD remained (odds ratio [OR] = 1.207, P = .004). A 1-SD increase in TSH levels was nominally associated with a 10.0% decrease in the overall AMD risk (P = .032). After adjusting for FT4 level by multivariable MR analysis, no direct causal relationship was found between TSH level and AMD risk (95% CI = 0.810, 1.125, P = .582). CONCLUSIONS: Genetic variants predisposing to higher FT4 levels within the normal range were associated with higher AMD risk. Further studies are required to understand the mechanism underlying this putative causal relationship.