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Environment International Dec 2021Parabens are used as antimicrobial preservatives in personal care products. Few studies have dealt with adverse health outcomes, transplacental transfer, and obesogenic...
In utero exposure to parabens and early childhood BMI z-scores - Associations between placental ethyl paraben, longitudinal BMI trajectories and cord blood metabolic biomarkers.
BACKGROUND
Parabens are used as antimicrobial preservatives in personal care products. Few studies have dealt with adverse health outcomes, transplacental transfer, and obesogenic effects of prenatal exposure to parabens. We examined the association between placental paraben levels and cord blood metabolic biomarkers, considering modulating effects of maternal pre-pregnancy BMI and underlying epigenetic mechanisms, and investigated longitudinal effects of in utero paraben exposure on early childhood trajectories of BMI z-scores.
METHODS
Placental concentrations of four parabens [methyl (MeP), ethyl (EtP), propyl (PrP), and butyl (BuP)] were measured by ultra-performance liquid chromatography/tandem mass spectrometry in 229 placentas of the ENVIRONAGE birth cohort. The association with cord blood metabolic biomarkers [glucose, insulin, γ-glutamyltransferase (GGT), high-density and low-density lipoprotein (HDL and LDL)] was analyzed in multiple regression models with two different sets of, a priori selected potential confounders, additionally stratified for different maternal BMI groups and assessed by causal mediation analysis. The association between placental paraben concentration and differential DNA methylation of CpGs annotated to GGT and longitudinal measurements of BMI z-scores were investigated with adjusted linear mixed models.
RESULTS
The geometric means of placental MeP, EtP, PrP, and BuP levels above the limit of detection (LOD) were 4.42, 1.32, 1.51, and 0.35 ng/g respectively, with only EtP showing sufficient (88%) measurements above LOD for further analyses. An interquartile ratio (IQR) increase in placental EtP was associated with an increase of 12.61 % (95% CI: 1.80 24.57) in the geometric mean of cord GGT activity, and with a decrease of -3.64 % (95% CI: -6.80 to -0.39) in the geometric mean of cord glucose. Placental EtP levels were significantly associated with hypermethylation of cg08612779 annotated to GGT7 after correcting for multiple testing (ß = 0.0017, p = 0.049). An interquartile ratio (IQR) increment in placental EtP was associated with a decrease in longitudinal BMI z-score of 0.27 points (95% CI: -0.46 to -0.088).
CONCLUSION
Prenatal EtP exposure may affect early childhood BMI. The association of placental EtP with cord blood GGT and glucose levels provides a starting point for further research on mechanisms of paraben-related metabolic processes in utero.
Topics: Biomarkers; Body Mass Index; Child, Preschool; Female; Fetal Blood; Humans; Parabens; Placenta; Pregnancy
PubMed: 34474324
DOI: 10.1016/j.envint.2021.106845 -
Current Research in Toxicology Jun 2020Infant exposure to environmental chemicals, such as polychlorinated biphenyls (PCBs), may contribute to developmental programming of long-term metabolic disease risk....
BACKGROUND
Infant exposure to environmental chemicals, such as polychlorinated biphenyls (PCBs), may contribute to developmental programming of long-term metabolic disease risk. PCBs persist given their lipophilicity and long half-lives, allowing them to bio-accumulate in adipose tissue. These compounds can then be excreted into maternal milk resulting in infant exposure.
OBJECTIVE
To determine the level of PCBs in milk from mothers with pre-pregnancy overweight and obese (OW/OB) versus normal weight status (NW) and evaluate the association of milk PCB levels with infant growth over the first 6 months of life.
METHODS
A pilot study of a subset of milk samples from mothers with NW (pre-pregnancy body mass index (BMI) < 25 kg/m, n = 11) and OW/OB (pre-pregnancy BMI ≥ 25 kg/m, n = 8) were examined approximately 2-weeks postpartum. PCB congeners 138 + 163, 132 + 153, 180, and the sum were measured using gas chromatography/mass spectrometry and adjusted for milk fat content. Infant growth was monitored from birth to 6 months for weight-for-age (WFA), length-for-age (LFA), weight-for-length (WFL), head circumference-for-age (HCA), and associations with milk PCB content determined using linear mixed modeling.
RESULTS
Total milk fat content did not differ by maternal weight status ( 0.88). Milk from mothers with OW/OB had significantly higher PCB sum ( = 0.02) and PCB 138 + 163 ( = 0.03). PCB 132 + 153 (β -0.0008, = 0.0218), PCB 180 (β -0.0010, = 0.0279), and PCB sum (β -0.0006, = 0.0138) were negatively associated with HCA Z-score growth to 6 months. PCB 180 was negatively associated with infant WFA (β -0.0015, = 0.0058) and WFL Z-score (β -0.0016, = 0.0263) to 6 months. There were no associations of PCB sum content with WFL, LFA, WFL Z-score over the first 6 months of life.
CONCLUSIONS
Maternal overweight and obesity are associated with higher levels of total PCB congeners (132, 138, 153, 163, 180) in human milk. PCB congeners have negative associations with infant head circumference and weight trajectory over the first 6 months of life.
PubMed: 34345842
DOI: 10.1016/j.crtox.2020.10.002 -
Genome Medicine Aug 2021Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from...
BACKGROUND
Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood.
METHODS
We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function.
RESULTS
Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network.
CONCLUSIONS
Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.
Topics: Adipocytes; Adipose Tissue; Adiposity; Aged; Algorithms; Biomarkers; Body Mass Index; Cells, Cultured; Computational Biology; Diabetes Mellitus, Type 2; Disease Susceptibility; Gene Expression Profiling; Gene Expression Regulation; Gene Knockdown Techniques; Gene Regulatory Networks; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Lod Score; Male; Middle Aged; Obesity, Abdominal; T-Box Domain Proteins; Trans-Activators; Waist-Hip Ratio
PubMed: 34340684
DOI: 10.1186/s13073-021-00939-2 -
Scientific Reports Jul 2021We investigated the genetic causes of major mental disorders (MMDs) including schizophrenia, bipolar disorder I, major depressive disorder and attention deficit...
We investigated the genetic causes of major mental disorders (MMDs) including schizophrenia, bipolar disorder I, major depressive disorder and attention deficit hyperactive disorder, in a large family pedigree from Alpujarras, South of Spain, a region with high prevalence of psychotic disorders. We applied a systematic genomic approach based on karyotyping (n = 4), genotyping by genome-wide SNP array (n = 34) and whole-genome sequencing (n = 12). We performed genome-wide linkage analysis, family-based association analysis and polygenic risk score estimates. Significant linkage was obtained at chromosome 9 (9q33.1-33.2, LOD score = 4.11), a suggestive region that contains five candidate genes ASTN2, BRINP1, C5, TLR4 and TRIM32, previously associated with MMDs. Comprehensive analysis associated the MMD phenotype with genes of the immune system with dual brain functions. Moreover, the psychotic phenotype was enriched for genes involved in synapsis. These results should be considered once studying the genetics of psychiatric disorders in other families, especially the ones from the same region, since founder effects may be related to the high prevalence.
Topics: Attention Deficit Disorder with Hyperactivity; Bipolar Disorder; Cell Cycle Proteins; Chromosomes, Human, Pair 9; Depressive Disorder, Major; Female; Genetic Linkage; Glycoproteins; Humans; Male; Nerve Tissue Proteins; Pedigree; Polymorphism, Single Nucleotide; Psychotic Disorders; Spain
PubMed: 34267256
DOI: 10.1038/s41598-021-93555-4 -
Kidney International Reports Jun 2021Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis....
INTRODUCTION
Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus. Identification of such risk locus may provide clues to the etiology of MN.
METHODS
We identified 3 families with 8 members affected by primary MN. Genotyping was performed using single-nucleotide polymorphism microarrays, and serum was sent for anti-phospholipase A2 receptor (PLA2R) antibody testing. All affected members were male and connected through the maternal line, consistent with X-linked inheritance. Genome-wide multipoint parametric linkage analysis using a model of X-linked recessive inheritance was conducted, and genetic risk scores (GRSs) based on known MN-associated variants were determined.
RESULTS
Anti-PLA2R testing was negative in all affected family members. Linkage analysis revealed a significant logarithm of the odds score (3.260) on the short arm of the X chromosome at a locus of approximately 11 megabases (Mb). Haplotype reconstruction further uncovered a shared haplotype spanning 2 Mb present in all affected individuals from the 3 families. GRSs in familial MN were significantly lower than in anti-PLA2R-associated MN and were not different from controls.
CONCLUSIONS
Our study identifies linkage of familial membranous nephropathy to chromosome Xp11.3-11.22. Family members affected with MN have a significantly lower GRS than individuals with anti-PLA2R-associated MN, suggesting that X-linked familial MN represents a separate etiologic entity.
PubMed: 34169208
DOI: 10.1016/j.ekir.2021.02.025 -
Archives of Sexual Behavior Nov 2021Male sexual orientation is a scientifically and socially important trait shown by family and twin studies to be influenced by environmental and complex genetic factors.... (Meta-Analysis)
Meta-Analysis
Male sexual orientation is a scientifically and socially important trait shown by family and twin studies to be influenced by environmental and complex genetic factors. Individual genome-wide linkage studies (GWLS) have been conducted, but not jointly analyzed. Two main datasets account for > 90% of the published GWLS concordant sibling pairs on the trait and are jointly analyzed here: MGSOSO (Molecular Genetic Study of Sexual Orientation; 409 concordant sibling pairs in 384 families, Sanders et al. (2015)) and Hamer (155 concordant sibling pairs in 145 families, Mustanski et al. (2005)). We conducted multipoint linkage analyses with Merlin on the datasets separately since they were genotyped differently, integrated genetic marker positions, and combined the resultant LOD (logarithm of the odds) scores at each 1 cM grid position. We continue to find the strongest linkage support at pericentromeric chromosome 8 and chromosome Xq28. We also incorporated the remaining published GWLS dataset (on 55 families) by using meta-analytic approaches on published summary statistics. The meta-analysis has maximized the positional information from GWLS of currently available family resources and can help prioritize findings from genome-wide association studies (GWAS) and other approaches. Although increasing evidence highlights genetic contributions to male sexual orientation, our current understanding of contributory loci is still limited, consistent with the complexity of the trait. Further increasing genetic knowledge about male sexual orientation, especially via large GWAS, should help advance our understanding of the biology of this important trait.
Topics: Female; Genetic Linkage; Genome, Human; Genome-Wide Association Study; Humans; Lod Score; Male; Sexual Behavior
PubMed: 34080073
DOI: 10.1007/s10508-021-02035-3 -
Human Genetics Aug 2021Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous,...
Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis-regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.
Topics: Base Sequence; Cell Movement; Chromosomes, Human, Pair 7; Dyslexia; Family; Female; Gene Expression; Genes, Dominant; Genetic Linkage; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Haplotypes; Humans; Inheritance Patterns; Introns; Lod Score; Male; Neuroimaging; Neurons; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Semaphorins; Whole Genome Sequencing
PubMed: 34076780
DOI: 10.1007/s00439-021-02289-w -
Frontiers in Plant Science 2021Hybrid breakdown, a form of postzygotic reproductive barrier, has been reported to hinder gene flow in many crosses between wild and cultivated rice. Here, the...
Hybrid breakdown, a form of postzygotic reproductive barrier, has been reported to hinder gene flow in many crosses between wild and cultivated rice. Here, the phenomenon of hybrid breakdown was observed as low-tillering (i.e., low tiller number) in some progeny of an interspecific cross produced in an attempt to introduce Ng (W1625) chromosomal segments into L. ssp. "Taichung 65" (T65). Low-tillering lines were obtained in BC-derived progeny from a cross between W1625 and "Taichung 65," but the locus for low-tillering could not be mapped in segregating populations. As a second approach to map the locus for low-tillering, we analyzed an F population derived from a cross between the low-tillering lines and a high-yielding cultivar, "Takanari." A major QTL for low-tillering, , was detected between PCR-based markers MS10 and RM307 on the long arm of chromosome 4, with a LOD score of 15.6. The low-tillering phenotype was associated with weak growth and pale yellow phenotype; however, low-tillering plant had less reduction of grain fertility. In an F population (4896 plants), 563 recombinant plants were identified and the low-tillering locus was delimited to a 4.6-Mbp region between markers W1 and C5-indel3729. This region could not be further delimited because recombination is restricted in this region of , which is near the centromere. Understanding the genetic basis of hybrid breakdown, including the low-tillering habit, will be important for improving varieties in rice breeding.
PubMed: 33968097
DOI: 10.3389/fpls.2021.633247 -
Scientific Reports Apr 2021Glucoraphanin is a major secondary metabolite found in Brassicaceae vegetables, especially broccoli, and its degradation product sulforaphane plays an essential role in...
Glucoraphanin is a major secondary metabolite found in Brassicaceae vegetables, especially broccoli, and its degradation product sulforaphane plays an essential role in anticancer. The fine mapping of sulforaphane metabolism quantitative trait loci (QTLs) in broccoli florets is necessary for future marker-assisted selection strategies. In this study, we utilized a doubled haploid population consisting of 176 lines derived from two inbred lines (86,101 and 90,196) with significant differences in sulforaphane content, coupled with extensive genotypic and phenotypic data from two independent environments. A linkage map consisting of 438 simple sequence repeats markers was constructed, covering a length of 1168.26 cM. A total of 18 QTLs for sulforaphane metabolism in broccoli florets were detected, 10 were detected in 2017, and the other 8 were detected in 2018. The LOD values of all QTLs ranged from 3.06 to 14.47, explaining 1.74-7.03% of the biochemical variation between two years. Finally, 6 QTLs (qSF-C3-1, qSF-C3-2, qSF-C3-3, qSF-C3-5, qSF-C3-6 and qSF-C7) were stably detected in more than one environment, each accounting for 4.54-7.03% of the phenotypic variation explained (PVE) and a total of 30.88-34.86% of PVE. Our study provides new insights into sulforaphane metabolism in broccoli florets and marker-assisted selection breeding in Brassica oleracea crops.
Topics: Biomarkers; Brassica; Chromosome Mapping; Genetic Linkage; Genetics, Population; Haploidy; Inheritance Patterns; Isothiocyanates; Lod Score; Quantitative Trait Loci; Sulfoxides
PubMed: 33903705
DOI: 10.1038/s41598-021-88652-3 -
Genetic Variation and Recurrent Haplotypes on Chromosome 6q23-25 Risk Locus in Familial Lung Cancer.Cancer Research Jun 2021Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains...
Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: at 6q25.3, at 6q26, and (6q24.1) and (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work. SIGNIFICANCE: This study identifies four genes associated with lung cancer risk, which could help guide future lung cancer prevention and treatment approaches.
Topics: Biomarkers, Tumor; Chromosome Mapping; Chromosomes, Human, Pair 6; Female; Genetic Linkage; Genetic Predisposition to Disease; Genetic Variation; Genome, Human; Haplotypes; Humans; Lod Score; Lung Neoplasms; Male; Pedigree; Prognosis
PubMed: 33853833
DOI: 10.1158/0008-5472.CAN-20-3196