The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

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EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals

This opinion describes the assessment of the risks to public health associated with bisphenol A (BPA) exposure. Exposure was assessed for various groups of the human population in three different ways: (1) external (by diet, drinking water, inhalation, and dermal contact to cosmetics and thermal paper); (2) internal exposure to total BPA (absorbed dose of BPA, sum of conjugated and unconjugated BPA); and (3) aggregated (from diet, dust, cosmetics and thermal paper), expressed as oral human equivalent dose (HED) referring to unconjugated BPA only. The estimated BPA dietary intake was highest in infants and toddlers (up to 0.875 µg/kg bw per day). Women of childbearing age had dietary exposures comparable to men of the same age (up to 0.388 µg/kg bw per day). The highest aggregated exposure of 1.449 µg/kg bw per day was estimated for adolescents. Biomonitoring data were in line with estimated internal exposure to total BPA from all sources. BPA toxicity was evaluated by a weight of evidence approach. “Likely” adverse effects in animals on kidney and mammary gland underwent benchmark dose (BMDL10) response modelling. A BMDL10 of 8 960 µg/kg bw per day was calculated for changes in the mean relative kidney weight in a two generation toxicity study in mice. No BMDL10 could be calculated for mammary gland effects. Using data on toxicokinetics, this BMDL10 was converted to an HED of 609 µg/kg bw per day. The CEF Panel applied a total uncertainty factor of 150 (for inter- and intra-species differences and uncertainty in mammary gland, reproductive, neurobehavioural, immune and metabolic system effects) to establish a temporary Tolerable Daily Intake (t-TDI) of 4 µg/kg bw per day. By comparing this t-TDI with the exposure estimates, the CEF Panel concluded that there is no health concern for any age group from dietary exposure and low health concern from aggregated exposure. The CEF Panel noted considerable uncertainty in the exposure estimates for non-dietary sources, whilst the uncertainty around dietary estimates was relatively low.

Scientific Opinion on the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs: Executive summary

https://www.cell.com/cancer-cell/pdf/S1535-6108(13)00455-8.pdf

Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas

Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding.

The zinc-dependent mammalian histone deacetylase (HDAC) family comprises 11 enzymes, which have specific and critical functions in development and tissue homeostasis. Mounting evidence points to a link between misregulated HDAC activity and many oncologic and nononcologic diseases. Thus the development of HDAC inhibitors for therapeutic treatment garners a lot of interest from academic researchers and biotechnology entrepreneurs. Numerous studies of HDAC inhibitor specificities and molecular mechanisms of action are ongoing. In one of these studies, mass spectrometry was used to characterize the affinities and selectivities of HDAC inhibitors toward native HDAC multiprotein complexes in cell extracts. Such a novel approach reproduces in vivo molecular interactions more accurately than standard studies using purified proteins or protein domains as targets and could be very useful in the isolation of inhibitors with superior clinical efficacy and decreased toxicity compared to the ones presently tested or approved. HDAC inhibitor induced-transcriptional reprogramming, believed to contribute largely to their therapeutic benefits, is achieved through various and complex mechanisms not fully understood, including histone deacetylation, transcription factor or regulator (including HDAC1) deacetylation followed by chromatin remodeling and positive or negative outcome regarding transcription initiation. Although only a very low percentage of protein-coding genes are affected by the action of HDAC inhibitors, about 40% of noncoding microRNAs are upregulated or downregulated. Moreover, a whole new world of long noncoding RNAs is emerging, revealing a new class of potential targets for HDAC inhibition. HDAC inhibitors might also regulate transcription elongation and have been shown to impinge on alternative splicing.

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Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors

Bisphenol A exposure leads to specific microRNA alterations in placental cells

Maternal cigarette smoking during pregnancy is associated with poor fetal outcome and aberrant miRNA expression is associated with adverse pregnancy outcomes. In 25 human placentas, we analyzed the expression of four candidate miRNA previously implicated in growth and developmental processes: miR-16, miR-21, miR-146a, and miR-182, and used three immortalized placental cell lines to identify if specific components of cigarette smoke were responsible for alterations to miRNA expression. miR-16, miR-21, and miR-146a were significantly downregulated in cigarette smoke-exposed placentas compared to controls. TCL-1 cells exposed to both nicotine and benzo(a)pyrene exhibited significant, dose-dependent downregulation of miR-146a. These results suggest that miR-146a is particularly responsive to exposures, and that smoking may elicit some of its downstream effects through alteration of miRNA expression.

Maternal cigarette smoking during pregnancy is associated with downregulation of miR-16, miR-21, and miR-146a in the placenta

Background: There is increasing epidemiologic evidence that arsenic exposure in utero, even at low levels found throughout much of the world, is associated with adverse reproductive outcomes and may contribute to long-term health effects. Animal models, in vitro studies, and human cancer data suggest that arsenic may induce epigenetic alterations, specifically by altering patterns of DNA methylation.

Objectives: In this study we aimed to identify differences in DNA methylation in cord blood samples of infants with in utero, low-level arsenic exposure.

Methods: DNA methylation of cord-blood derived DNA from 134 infants involved in a prospective birth cohort in New Hampshire was profiled using the Illumina Infinium Methylation450K array. In utero arsenic exposure was estimated using maternal urine samples collected at 24–28 weeks gestation. We used a novel cell mixture deconvolution methodology for examining the association between inferred white blood cell mixtures in infant cord blood and in utero arsenic exposure; we also examined the association between methylation at individual CpG loci and arsenic exposure levels.

Results: We found an association between urinary inorganic arsenic concentration and the estimated proportion of CD8+ T lymphocytes (1.18; 95% CI: 0.12, 2.23). Among the top 100 CpG loci with the lowest p-values based on their association with urinary arsenic levels, there was a statistically significant enrichment of these loci in CpG islands (p = 0.009). Of those in CpG islands (n = 44), most (75%) exhibited higher methylation levels in the highest exposed group compared with the lowest exposed group. Also, several CpG loci exhibited a linear dose-dependent relationship between methylation and arsenic exposure.

Conclusions: Our findings suggest that in utero exposure to low levels of arsenic may affect the epigenome. Long-term follow-up is planned to determine whether the observed changes are associated with health outcomes.

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Differential DNA Methylation in Umbilical Cord Blood of Infants Exposed to Low Levels of Arsenic in Utero

Birthweight has been associated with a number of health outcomes throughout life. Crucial to proper infant growth and development is the placenta, and alterations to placental gene function may reflect differences in the intrauterine environment which functionally contribute to infant growth and may ultimately affect the child's health. To examine if epigenetic alteration to the glucocorticoid receptor (GR) gene was linked to infant growth, we analyzed 480 human placentas for differential methylation of the GR gene exon 1F and examined how this variation in methylation extent was associated with fetal growth. Multivariable linear regression revealed a significant association (p < 0.0001) between differential methylation of the GR gene and large for gestational age (LGA) status. Our work is one of the first to link infant growth as a measure of the intrauterine environment and epigenetic alterations to the GR and suggests that DNA methylation may be a critical determinant of placental function.

Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta

Purpose: The central role of microRNAs as regulators of translation has been well established, whereas the relationships between genetic variation in microRNAs and disease risk is only beginning to be explored. A polymorphism in the MIR196A2 locus has shown associations with lung, breast, esophageal, and gastric tumors but has not been examined in head and neck cancers, which share similar pathology and etiology to these diseases. Experimental Design: We studied a polymorphism in the mature sequence of MIR196A2 (rs11614913, C/T) in a population-based case-control study ( n = 1,039) of head and neck squamous cell carcinoma (HNSCC) to determine if MIR196A2 genotype was associated with disease occurrence and patient survival. Results: Presence of any variant allele was associated with a significantly reduced risk for HNSCC (odds ratio, 0.8; 95% confidence interval, 0.56-0.99). Homozygous variant allele carriers with pharyngeal tumors had significantly reduced survival compared with wild-type and heterozygous cases (hazard ratio, 7.4; 95% confidence interval, 1.9–28.2). Expression analysis in a subset of tumors ( n = 83) revealed no significant difference in relative expression of either miR-196a or miR-196a* by MIR196A2 genotype. Conclusion: These data demonstrate a role for MIR196A2 genotype in susceptibility and prognosis of HNSCC. Clin Cancer Res; 16(14); 3713–20. ©2010 AACR.

https://clincancerres.aacrjournals.org/content/clincanres/early/2010/06/25/1078-0432.CCR-10-0657.full.pdf

Michele Avissar-Whiting

Papers

Bisphenol A exposure leads to specific microRNA alterations in placental cells

Maternal cigarette smoking during pregnancy is associated with downregulation of miR-16, miR-21, and miR-146a in the placenta

Differential DNA Methylation in Umbilical Cord Blood of Infants Exposed to Low Levels of Arsenic in Utero

Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta

Mature MicroRNA Sequence Polymorphism in MIR196A2 Is Associated with Risk and Prognosis of Head and Neck Cancer