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Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus.

ABSTRACT: This study examined developmental changes and sexual dimorphisms in hypothalamic microRNAs, and whether gestational exposures to environmental endocrine-disrupting chemicals (EDCs) altered their expression patterns. Pregnant rat dams were treated on gestational days 16 and 18 with vehicle, estradiol benzoate, or a mixture of polychlorinated biphenyls. Male and female offspring were euthanized on postnatal days (P) 15, 30, 45, or 90, and microRNA and mRNA targets were quantified in the medial preoptic nucleus (MPN) and ventromedial nucleus (VMN) of the hypothalamus. MicroRNAs showed robust developmental changes in both regions, and were sexually dimorphic in the MPN, but not VMN. Importantly, microRNAs in females were up-regulated by EDCs at P30, and down-regulated in males at P90. Few changes in mRNAs were found. Thus, hypothalamic microRNAs are sensitive to prenatal EDC treatment in a sex-, developmental age-, and brain region-specific manner.

SUBMITTER: Topper VY

PROVIDER: S-EPMC4553128 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus.

Topper Viktoria Y VY Walker Deena M DM Gore Andrea C AC

Molecular and cellular endocrinology 20150717

This study examined developmental changes and sexual dimorphisms in hypothalamic microRNAs, and whether gestational exposures to environmental endocrine-disrupting chemicals (EDCs) altered their expression patterns. Pregnant rat dams were treated on gestational days 16 and 18 with vehicle, estradiol benzoate, or a mixture of polychlorinated biphenyls. Male and female offspring were euthanized on postnatal days (P) 15, 30, 45, or 90, and microRNA and mRNA targets were quantified in the medial pre ...[more]

PMID: 26190835

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Project description:ObjectiveTo conduct a comprehensive systematic review and meta-analysis to estimate the relationship between endocrine-disrupting chemicals (EDCs), including polychlorinated biphenyls (PCBs), poly-brominated diphenyl ethers (PBDEs), phthalates (PAEs), and per- and polyfluoroalkyl substances (PFAS) exposure and risk of gestational diabetes mellitus (GDM).MethodsRelevant studies from their inception to November 2021 were identified by searching EMBASE, PubMed, and Web of Science. The cohort and case-control studies that reported effect size with 95% confidence intervals (CIs) of EDC exposure and GDM were selected. The heterogeneity among the included studies was quantified by I2 statistic. Publication bias was evaluated through the Begg and Egger tests.ResultsTwenty-five articles with a total of 23,796 participants were found. Results indicated that exposure to PCBs has a significant influence on the incidence of GDM (OR = 1.14; 95% CI = 1.00--1.31; n = 8). The risk of GDM was found to be associated with PBDE exposure (OR = 1.32; 95% CI = 1.15-1.53; n = 4). PAEs and PFASs exposure were also positively associated with the risk of GDM, with summary ORs of 1.10 (95% CI = 1.03-1.16; n = 7 for PAEs) and 1.09 (95% CI = 1.02-1.16; n = 11 for PFASs), respectively. When only cohort studies were considered, the summary OR between PCBs exposure and the risk of GDM was 0.99 (95% CI = 0.91-1.09; n = 5). Meanwhile, the summary ORs from cohort studies for PBDEs, PAEs, and PFASs exposure were 1.12 (95% CI = 1.00-1.26; n = 2), 1.08 (95% CI = 1.02-1.15; n = 5), and 1.06 (95% CI = 1.00-1.12; n = 8), respectively. The Beggs and Egger tests did not show publication bias, and the sensitivity analyses did not change the results in this meta-analysis.ConclusionThese results support that exposure to certain EDCs, including PCBs, PBDEs, PAEs, and PFAS, increase the risk of GDM. Further large-sample epidemiologic researches and mechanistic studies are needed to verify the potential relationship and biological mechanisms. These results are of public health significance because the daily EDC exposure is expected to increase the risk of GDM development.

Project description:BackgroundSexual differentiation of the male brain, and specifically the stress circuitry in the hypothalamus, is primarily driven by estrogen exposure during the perinatal period. Surprisingly, this single hormone promotes diverse programs of sex-specific development that vary widely between different cell types and across the developing male brain. The complexity of this phenomenon suggests that additional layers of gene regulation, including microRNAs (miRNAs), must act downstream of estrogen to mediate this specificity.MethodsTo identify noncanonical mediators of estrogen-dependent sex-specific neural development, we assayed the miRNA complement of the mouse PN2 hypothalamus by microarray following an injection of vehicle or the aromatase inhibitor, formestane. Initially, multivariate analyses were used to test the influence of sex and experimental group on the miRNA environment as a whole. Then, we utilized traditional hypothesis testing to identify individual miRNA with significantly sex-biased expression. Finally, we performed a transcriptome-wide mapping of Argonaute footprints by high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (Ago HITS-CLIP) to empirically characterize targeting relationship between estrogen-responsive miRNAs and their messenger RNA (mRNA) targets.ResultsIn this study, we demonstrated that the neonatal hypothalamic miRNA environment has robust sex differences and is dynamically responsive to estrogen. Analyses identified 162 individual miRNAs with sex-biased expression, 92 of which were estrogen-responsive. Examining the genomic distribution of these miRNAs, we found three miRNA clusters encoded within a 175-kb region of chromosome 12 that appears to be co-regulated by estrogen, likely acting broadly to alter the epigenetic programming of this locus. Ago HITS-CLIP analysis uncovered novel miRNA-target interactions within prototypical mediators of estrogen-driven sexual differentiation of the brain, including Esr1 and Cyp19a1. Finally, using Gene Ontology annotations and empirically identified miRNA-mRNA connections, we identified a gene network regulated by estrogen-responsive miRNAs that converge on biological processes relevant to sexual differentiation of the brain.ConclusionsSexual differentiation of the perinatal brain, and that of stress circuitry in the hypothalamus specifically, seems to be particularly susceptible to environmental programming effects. Integrating miRNA into our conceptualization of factors, directing differentiation of this circuitry could be an informative next step in efforts to understand the complexities behind these processes.

Dataset Information

Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus.

Publications

Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus.

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