Browse
Submit Data
Databases
API
Help

Dataset Information

13 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Systems biology and birth defects prevention: blockade of the glucocorticoid receptor prevents arsenic-induced birth defects.

ABSTRACT:

Background

The biological mechanisms by which environmental metals are associated with birth defects are largely unknown. Systems biology-based approaches may help to identify key pathways that mediate metal-induced birth defects as well as potential targets for prevention.

Objectives

First, we applied a novel computational approach to identify a prioritized biological pathway that associates metals with birth defects. Second, in a laboratory setting, we sought to determine whether inhibition of the identified pathway prevents developmental defects.

Methods

Seven environmental metals were selected for inclusion in the computational analysis: arsenic, cadmium, chromium, lead, mercury, nickel, and selenium. We used an in silico strategy to predict genes and pathways associated with both metal exposure and developmental defects. The most significant pathway was identified and tested using an in ovo whole chick embryo culture assay. We further evaluated the role of the pathway as a mediator of metal-induced toxicity using the in vitro midbrain micromass culture assay.

Results

The glucocorticoid receptor pathway was computationally predicted to be a key mediator of multiple metal-induced birth defects. In the chick embryo model, structural malformations induced by inorganic arsenic (iAs) were prevented when signaling of the glucocorticoid receptor pathway was inhibited. Further, glucocorticoid receptor inhibition demonstrated partial to complete protection from both iAs- and cadmium-induced neurodevelopmental toxicity in vitro.

Conclusions

Our findings highlight a novel approach to computationally identify a targeted biological pathway for examining birth defects prevention.

SUBMITTER: Ahir BK

PROVIDER: S-EPMC3616967 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling.

Project description:Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by on-target adverse effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach, ligand class analysis, to examine ligands designed to modulate glucocorticoid receptor activity through distinct structural mechanisms. These ligands displayed diverse activity profiles, providing the variance required to identify target genes and coregulator interactions that were highly predictive of their effects on myocyte glucose disposal and protein balance. Their anti-inflammatory effects were linked to glucose disposal but not muscle atrophy. This approach also predicted selective modulation in vivo, identifying compounds that were muscle-sparing or anabolic for protein balance and mitochondrial potential. Ligand class analysis defined the mechanistic links between the ligand-receptor interface and ligand-driven physiological outcomes, a general approach that can be applied to any ligand-regulated allosteric signaling system.

| S-EPMC8783757 | biostudies-literature

Chemical Systems Biology Reveals Mechanisms of Dissociated Glucocorticoid Receptor Signaling

Project description:Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by undesirable on-target effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach called Ligand Class Analysis (LCA) to examine ligands designed to alter the receptor through distinct structural mechanisms. These ligands displayed a full range of activity profiles, providing the variance required to identify ligand-specific gene expression and transcriptional coregulator interaction patterns that were highly predictive of their effects on myocyte glucose disposal and protein balance. Anti-inflammatory effects were linked to inhibition of glucose disposal in skeletal muscle but not to muscle atrophy. This approach successfully predicted dissociated activity in vivo, identifying compounds that were muscle sparing or anabolic for protein balance and mitochondrial potential. LCA defines the mechanistic links between the ligand-receptor interface and the physiological outcomes of the ligands, a general approach that can be applied to any ligand-regulated allosteric signaling system.

2020-09-08 | GSE149453 | GEO

Maternal Occupational Oil Mist Exposure and Birth Defects, National Birth Defects Prevention Study, 1997?2011.

Project description:Workers in various industries can be exposed to oil mists when oil-based fluids are aerosolized during work processes. Oil mists can be inhaled or deposited on the skin. Little research exists on the reproductive effects of oil mist exposure in pregnant workers. We aimed to investigate associations between occupational oil mist exposure in early pregnancy and a spectrum of birth defects using data from 22,011 case mothers and 8140 control mothers in the National Birth Defects Prevention Study. In total, 150 mothers were rated as exposed. Manufacturing jobs, particularly apparel manufacturing, comprised the largest groups of exposed mothers. Mothers of infants with septal heart defects (odds ratio (OR): 1.8, 95% confidence interval (CI): 1.0-3.3), and especially perimembranous ventricular septal defects (OR: 2.5, CI: 1.2-5.2), were more likely to be occupationally exposed to oil mists in early pregnancy than control mothers; and their rater-estimated cumulative exposure was more likely to be higher. This was the first U.S. study evaluating associations between oil mist exposure and a broad spectrum of birth defects. Our results are consistent with previous European studies, supporting a potential association between oil-based exposures and congenital heart defects. Further research is needed to evaluate the reproductive effects of occupational oil mist exposure.

| S-EPMC6539329 | biostudies-literature

Maternal genitourinary infections and risk of birth defects in the National Birth Defects Prevention Study.

Project description:BackgroundGenitourinary infections (GUIs) are common among sexually active women. Yet, little is known about the risk of birth defects associated with GUIs.MethodsUsing data from the National Birth Defects Prevention Study, a multisite, population-based, case-control study, we assessed self-reported maternal GUIs in the month before through the third month of pregnancy (periconception) from 29,316 birth defect cases and 11,545 unaffected controls. We calculated odds ratios (ORs) and 95% confidence intervals to estimate the risk of 52 major structural birth defects associated with GUIs. We also calculated risk of birth defects associated with each type of GUI: urinary tract infection (UTI) and sexually transmitted infection (STI).ResultsIn our analysis, 10% (n = 2,972) of case and 9% (n = 1,014) of control mothers reported a periconceptional GUI. A GUI was significantly associated with 11 of the 52 birth defects examined (ORs ranging from 1.19 to 2.26): encephalocele, cataracts, cleft lip, esophageal atresia, duodenal atresia/stenosis, small intestinal atresia/stenosis, colonic atresia/stenosis, transverse limb deficiency, conoventricular septal defect, atrioventricular septal defect, and secundum atrial septal defect. A periconceptional UTI was significantly associated with nine birth defects (ORs from 1.21 to 2.48), and periconceptional STI was significantly associated with four birth defects (ORs ranging from 1.63 to 3.72).ConclusionsWhile misclassification of GUIs in our analysis is likely, our findings suggest GUIs during the periconceptional period may increase the risk for specific birth defects.

| S-EPMC6543540 | biostudies-literature

Maternal intake of vitamin E and birth defects, national birth defects prevention study, 1997 to 2005.

Project description:BACKGROUND:In a recent study, high maternal periconceptional intake of vitamin E was found to be associated with risk of congenital heart defects (CHDs). To explore this association further, we investigated the association between total daily vitamin E intake and selected birth defects. METHODS:We analyzed data from 4525 controls and 8665 cases from the 1997 to 2005 National Birth Defects Prevention Study. We categorized estimated periconceptional energy-adjusted total daily vitamin E intake from diet and supplements into quartiles (referent, lowest quartile). Associations between quartiles of energy-adjusted vitamin E intake and selected birth defects were adjusted for demographic, lifestyle, and nutritional factors. RESULTS:We observed a statistically significant association with the third quartile of vitamin E intake (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.01-1.35) and all CHDs combined. Among CHD sub-types, we observed associations with left ventricular outflow tract obstruction defects, and its sub-type, coarctation of the aorta and the third quartile of vitamin E intake. Among defects other than CHDs, we observed associations between anorectal atresia and the third quartile of vitamin E intake (OR, 1.66; 95% CI, 1.01-2.72) and hypospadias and the fourth quartile of vitamin E intake (OR, 1.42; 95% CI, 1.09-1.87). CONCLUSION:Selected quartiles of energy-adjusted estimated total daily vitamin E intake were associated with selected birth defects. However, because these few associations did not exhibit exposure-response patterns consistent with increasing risk associated with increasing intake of vitamin E, further studies are warranted to corroborate our findings.

| S-EPMC4465220 | biostudies-literature

Laterality defects in the national birth defects prevention study (1998-2007): birth prevalence and descriptive epidemiology.

Project description:Little is known epidemiologically about laterality defects. Using data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, we analyzed prevalence and selected characteristics in children born with laterality defects born from 1998 to 2007. We identified 517 nonsyndromic cases (378 heterotaxy, 73.1%; 139 situs inversus totalis [SIT], 26.9%) resulting in an estimated birth prevalence of 1.1 per 10,000 live births (95% confidence interval 1.0–1.2). Prevalence did not differ significantly across sites, over time, or by inclusion of pregnancy termination. Laterality defects were more common among preterm cases compared to term cases, and in children born to mothers who were non-white or younger than 20 years compared to white mothers or those age 25–29 years. The distribution of associated cardiac and extra-cardiac defects, excluding the expected heterotaxy anomalies, varied by type of laterality defect. Cases with heterotaxy were significantly more likely than those with SIT to have double outlet right ventricle, atrioventricular canal defects, pulmonary stenosis, non-tetralogy of Fallot pulmonary atresia with ventricular septal defect, totally and partially anomalous pulmonary venous return; also more likely to have orofacial clefts, esophageal atresia, bowel atresias, and omphalocele, though not reaching statistical significance. Relatively more common among cases with SIT were Dandy- Walker malformation, anotia/microtia, and limb deficiency. The similarity in the demographic characteristics of heterotaxy and SIT supports the hypothesis that they are part of a continuum of abnormal left-right axis patterning. These findings on laterality defects may help guide clinical care, future research, and prevention strategies.

| S-EPMC4462240 | biostudies-literature

Chemical Systems Biology Reveals Mechanisms of Dissociated Glucocorticoid Receptor Signaling

Project description:Chemical Systems Biology Reveals Mechanisms of Dissociated Glucocorticoid Receptor Signaling

| PRJNA628707 | ENA

Associations between Maternal Water Consumption and Birth Defects in the National Birth Defects Prevention Study (2000-2005).

Project description:BACKGROUND:Water and water-based beverages constitute a major part of daily fluid intake for pregnant women, yet few epidemiologic studies have investigated the role of water consumption on birth outcomes. METHODS:We used data from the National Birth Defects Prevention Study to conduct a case-control study investigating associations between maternal water consumption during pregnancy and birth defects (BD). We used interview data on water consumption during the first trimester of pregnancy in 14,454 cases (major BDs n ? 50) and 5,063 controls. Total water consumption was analyzed as a continuous variable and in quartiles. We evaluated the role of dietary quality and sugar sweetened beverage consumption. Logistic regression models were used to assess effects of water consumption on risk of BDs with adjustment for relevant covariates. RESULTS:Mean daily maternal water consumption among controls was 4.4 eight-ounce glasses. We observed decreases in estimated risk associated with increases in water consumption for several BDs, including neural tube defects (spina bifida), oral clefts (cleft lip), musculoskeletal defects (gastroschisis, limb deficiencies), and congenital heart defects (hypoplastic left heart syndrome, right-sided obstructions, pulmonary valve stenosis). Our results were generally unchanged when an indicator for overall dietary quality was included; however, there was evidence of effect measure modification by heavy consumption of sugar-sweetened beverages for some defects, but not all. CONCLUSION:These analyses suggest the importance of sufficient water consumption during early pregnancy, above and beyond it being a marker of higher diet quality. Additional analyses are warranted to understand the biological mechanism for this association. Birth Defects Research 109:193-202, 2017. © 2016 Wiley Periodicals, Inc.

| S-EPMC6193258 | biostudies-literature

Maternal thyroid disease, thyroid medication use, and selected birth defects in the National Birth Defects Prevention Study.

Project description:Although thyroid disorders are present in approximately 3% of pregnant women, little is known about the association between maternal thyroid disease and birth defects.We assessed the association between maternal thyroid disease, thyroid medication use, and 38 types of birth defects among 14,067 cases and 5875 controls in the National Birth Defects Prevention Study, a multisite, population-based, case-control study. Infants in this study were born between October 1997 and December 2004. Information on exposures including maternal diseases and use of medications was collected by telephone interview.We found statistically significant associations between maternal thyroid disease and left ventricular outflow tract obstruction heart defects (1.5; 95% CI, 1.0-2.3), hydrocephaly (2.9; 95% CI, 1.6-5.2), hypospadias (1.6; 95% CI, 1.0-2.5), and isolated anorectal atresia (2.4; 95% CI, 1.2-4.6). Estimates for the association between periconceptional use of thyroxine and specific types of birth defects were similar to estimates for any thyroid disease. Given that antithyroid medication use was rare, we could not adequately assess risks for their use for most case groups.Our results are consistent with the positive associations between maternal thyroid disease or thyroid medication use and both hydrocephaly and hypospadias observed in some previous studies. New associations with left ventricular outflow tract obstruction heart defects and anorectal atresia may be chance findings.

| S-EPMC6034621 | biostudies-literature

Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy.

Project description:FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of the glucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one of the major GR target genes in skin, but its role in clinical effects of glucocorticoids is not known. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in the major adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we found that all skin compartments (epidermis, dermis, dermal adipose and CD34+ stem cells) in FKBP51 KO animals were much more resistant to glucocorticoid-induced hypoplasia. Furthermore, despite the absence of inhibitory FKBP51, the basal level of expression and glucocorticoid activation of GR target genes were not increased in FKBP51 KO skin or CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known to negatively regulate Akt and mTOR. We found a significant increase in AktSer473 and mTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usually negative in skin, our results suggest that Akt/mTOR activation could be responsible for the lack of increased GR function and resistance of FKBP51 KO mice to the steroid-induced skin atrophy.

| S-EPMC6205168 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data