Endocrine-disrupting chemicals: Mainstream recognition of health effects and implications for the practicing internist.

Rapidly advancing evidence documents that a broad array of synthetic chemicals found ubiquitously in the environment contribute to disease and disability across the lifespan. Although the early literature focused on early life exposures, endocrine-disrupting chemicals (EDCs) are now understood to contribute substantially to chronic disease in adulthood, especially metabolic, cardiovascular, and reproductive consequences as well as endocrine cancers. The contribution to mortality is substantial, with over 90,000 deaths annually and at least $39 billion/year in lost economic productivity in the United States (US) due to exposure to certain phthalates that are used as plasticizers in food packaging. Importantly, exposures are disproportionately high in low-income and minoritized populations, driving disparities in these conditions. Though non-Hispanic Blacks and Mexican Americans comprise 12.6% and 13.5% of the US population, they bear 16.5% and 14.6% of the disease burden due to EDCs, respectively. Many of these exposures can be modified through safe and simple behavioral changes supported by proactive government action to both limit known hazardous exposures and to proactively screen new industrial chemicals prior to their use. Routine healthcare maintenance should include guidance to reduce EDC exposures, and a recent report by the Institute of Medicine suggests that testing be conducted, particularly in populations heavily exposed to perfluoroalkyl substances-chemicals used in nonstick coatings as well as oil- and water-resistant clothing.

Association of Acculturation and Hispanic/Latino Background with Endogenous Sex and Thyroid-Related Hormones Among Middle-Aged and Older Hispanic/Latino Adults: the HCHS/SOL Study.

BACKGROUND: Hormones are linked to cardiometabolic diseases and may be impacted by acculturation though multiple mechanisms. We evaluated associations of Hispanic/Latino background and acculturation with levels of sex- and thyroid-related hormones and the potential mediating effect of adiposity, lifestyle factors, and sleep apnea syndrome on these associations. METHODS: We studied 1789 adults, aged 45-74, from a sub-cohort of the Hispanic Community Health Survey/Study of Latinos. Peri/pre-menopausal women and individuals on medications related to hormones were excluded. Our study assessed eleven sex- and thyroid-related hormones, Hispanic/Latino background, and five acculturation measures. Associations were assessed using multivariable linear and logistic regression adjusted for survey design and confounding variables. We explored potential mediation using a path analysis. RESULTS: In postmenopausal women, acculturation score-MESA was associated with decreased thyroid-stimulating hormone (ß = - 0.13;95%CI = - 0.22, - 0.03) while age at immigration greater than the median (vs US-born) was associated with decreased (ß = - 14.6; 95%CI = - 28.2, - 0.99) triiodothyronine (T3). In men, language acculturation and acculturation score-MESA were associated with increased estradiol and sex hormone-binding globulin (SHBG) while age at immigration greater and lesser than the median (vs US-born) was associated with decreased SHBG. Hispanic/Latino background (Mexicans as reference) were selectively associated with sex- and thyroid-related hormone levels in both sexes. Current smoking and sleep apnea syndrome partially mediated the association of Cuban and Puerto Rican heritage (vs Mexican) with T3 levels in men and postmenopausal women, respectively. CONCLUSION: Selected acculturation measures were associated with thyroid-related hormones in postmenopausal women and sex-related hormones in men. Understanding the mechanisms involved in the relationship of acculturation and Hispanic/Latino background with hormones warrants additional investigation.

Sex Hormones and Diabetes in 45- to 74-year-old Men and Postmenopausal Women: The Hispanic Community Health Study.

Previous studies demonstrated associations of endogenous sex hormones with diabetes. Less is known about their dynamic relationship with diabetes progression through different stages of the disease, independence of associations, and role of the hypothalamic-pituitary gonadal axis. The purpose of this analysis was to examine relationships of endogenous sex hormones with incident diabetes, prediabetes, and diabetes traits in 693 postmenopausal women and 1015 men aged 45 to 74 years without diabetes at baseline participating in the Hispanic Community Health Study/Study of Latinos and followed for 6 years. Baseline hormones included estradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and, in men, testosterone and bioavailable testosterone. Associations were analyzed using multivariable Poisson and linear regressions. In men, testosterone was inversely associated with conversion from prediabetes to diabetes (incidence rate ratio [IRR] for 1 SD increase in testosterone: 0.821; 95% CI, 0.676, 0.997; P = 0.046), but not conversion from normoglycemia to prediabetes. Estradiol was positively associated with increase in fasting insulin and homeostatic model assessment of insulin resistance. In women, SHBG was inversely associated with change in glycosylated hemoglobin, postload glucose, and conversion from prediabetes to diabetes (IRR = 0.62; 95% CI, 0.44, 0.86, P = 0.005) but not from normoglycemia to prediabetes. Relationships with other hormones varied across glycemic measures. Stronger associations of testosterone and SHBG with transition from prediabetes to diabetes than from normoglycemic to prediabetes suggest they are operative at later stages of diabetes development. Biologic pathways by which sex hormones affect glucose homeostasis await future studies.

Selenomethionine modulates insulin secretion in the MIN6-K8 mouse insulinoma cell line.

Selenium is an essential trace element of interest for its potential role in glucose homeostasis. The present study investigated the impact of selenium supplementation as selenomethionine (SeMet) on insulin secretion in MIN6-K8 cells, a pancreatic ß-cell model. We found that SeMet enhanced percent glucose-induced insulin secretion, while also increasing tolbutamide- and KCl-induced percent insulin secretion. RNA-sequencing showed that SeMet supplementation altered expression of several selenoproteins, including glutathione peroxidase 3 (Gpx3) and selenoprotein P (SelP). Targeted knockdown of Gpx3 increased both percent and total insulin release, while SelP knockdown increased insulin content and insulin release. Collectively, these studies support a putative role for selenium and selenoproteins in the regulation of insulin secretion, glucose homeostasis, and diabetes risk.

Dimethyl sulfoxide acutely enhances regulated insulin secretion in the MIN6-K8 mouse insulinoma cell line.

Diabetes mellitus is a metabolic disorder projected to afflict 700 million people globally by 2045. Fundamental to the progression of diabetes is an insufficient supply of insulin to meet metabolic demand. The MIN6-K8 cell line is a mouse insulinoma model of pancreatic ß-cells frequently used to study the mechanisms of insulin secretion. Here, we evaluated the effects of short-term exposure to dimethyl sulfoxide (DMSO), a polar aprotic solvent commonly used in drug screening, on physiological characteristics of MIN6-K8 cells. Short-term exposure of MIN6-K8 cells to DMSO enhanced glucose-induced and tolbutamide-stimulated insulin secretion without significant effects on basal secretion or potassium responsiveness. Calcium influx was enhanced during glucose and tolbutamide treatments, suggesting that DMSO's mechanism of action is upstream of calcium-dependent insulin granule exocytosis. Based on these studies, investigators should use caution when conducting experiments with DMSO in the MIN6-K8 cell line and should report all DMSO concentrations when used as a solvent.

Multiple organochlorine pesticide exposures and measures of sex steroid hormones in adult males: Cross-sectional findings from the 1999-2004 National Health and Nutrition Examination Survey.

BACKGROUND: Organochlorine pesticides are detectable in serum from most adults. Animal studies provide evidence of pesticide effects on sex hormones, suggesting that exposures may impact human reproductive function. Mounting evidence of sex differences in chronic diseases suggest that perturbations in endogenous sex hormones may influence disease risk. However, the association between organochlorine pesticide exposure and sex hormone levels in males across the lifespan is not well understood. METHODS: We evaluated cross-sectional associations of lipid-adjusted serum concentrations of ß-hexachlorocyclohexane, hexachlorobenzene, heptachlor epoxide, oxychlordane, dichlorodiphenyldichloroethylene (DDE), p,p'-dichlorodiphenyltrichloroethane (DDT), trans-nonachlor, and mirex in relation to sex steroid hormone levels [testosterone (ng/dL), sex hormone binding globulin (SHBG; nmol/L), estradiol (pg/mL), and androstanediol glucuronide (ng/dL)] in a sample of 748 males aged 20 years and older from the 1999-2004 cycles of the National Health and Nutrition Examination Survey (NHANES). Survey-weighted linear regression models were performed to estimate geometric means (GM) and their 95% confidence intervals (CIs) for quartiles of lipid-adjusted pesticide concentrations, adjusting for age, race, body mass index, serum lipids, smoking, education, and survey cycle. RESULTS: Hexachlorobenzene concentration was positively associated with total estradiol (GM Q4 = 43.2 pg/mL (95% CI 36.5-51.1) vs. Q1 GM = 25.6 pg/mL (24.1-27.3), p-trend <0.0001) and free estradiol (GM Q4 = 0.77 pg/mL (95% CI 0.64-0.93) vs. Q1 GM = 0.47 pg/mL (0.44-0.51), p-trend = 0.002). Serum DDT concentration was positively associated with total estradiol (GM Q4 = 31.6 pg/mL (95% CI 25.9-38.5) vs. Q1 GM = 27.3 pg/mL (25.9-28.7), p-trend = 0.05) and free estradiol (GM Q4 = 0.60 pg/mL (95% CI 0.48-0.76) vs. Q1 GM = 0.50 pg/mL (0.47-0.53), p-trend 0.02). There was a suggestive inverse association of DDT and SHBG (GM Q4 = 29.2 nmol/L (95% CI 23.8-35.9) vs. Q1 GM = 33.9 nmol/L (32.3-35.5), p-trend 0.07). A positive association of ß-hexachlorocyclohexane with total estradiol (GM Q4 = 30.3 pg/mL (95% CI 26.5-34.6) vs. Q1 GM = 26.7 pg/mL (24.5-29.0), p-trend = 0.09) was also suggestive but did not reach statistical significance. No distinct associations were observed for other hormone levels or other organochlorine pesticides. CONCLUSIONS: Our findings suggest that select organochlorine pesticides may alter male estradiol levels. The positive associations with estradiol may implicate sex hormones as a possible mechanism for disease risk among those with organochlorine pesticide exposure.

Stress, Sex, and Sugar: Glucocorticoids and Sex-Steroid Crosstalk in the Sex-Specific Misprogramming of Metabolism.

Early-life exposures to environmental insults can misprogram development and increase metabolic disease risk in a sex-dependent manner by mechanisms that remain poorly characterized. Modifiable factors of increasing public health relevance, such as diet, psychological stress, and endocrine-disrupting chemicals, can affect glucocorticoid receptor signaling during gestation and lead to sex-specific postnatal metabolic derangements. Evidence from humans and animal studies indicate that glucocorticoids crosstalk with sex steroids by several mechanisms in multiple tissues and can affect sex-steroid-dependent developmental processes. Nonetheless, glucocorticoid sex-steroid crosstalk has not been considered in the glucocorticoid-induced misprogramming of metabolism. Herein we review what is known about the mechanisms by which glucocorticoids crosstalk with estrogen, androgen, and progestogen action. We propose that glucocorticoid sex-steroid crosstalk is an understudied mechanism of action that requires consideration when examining the developmental misprogramming of metabolism, especially when assessing sex-specific outcomes.

Arsenic modifies serotonin metabolism through glucuronidation in pancreatic ß-cells

In arsenic-endemic regions of the world, arsenic exposure correlates with diabetes mellitus. Multiple animal models of inorganic arsenic (iAs, as As3+) exposure have revealed that iAs-induced glucose intolerance manifests as a result of pancreatic ß-cell dysfunction. To define the mechanisms responsible for this ß-cell defect, the MIN6-K8 mouse ß-cell line was exposed to environmentally relevant doses of iAs. Exposure to 0.1-1 µM iAs for 3 days significantly decreased glucose-induced insulin secretion (GIIS). Serotonin and its precursor, 5-hydroxytryptophan (5-HTP), were both decreased. Supplementation with 5-HTP, which loads the system with bioavailable 5-HTP and serotonin, rescued GIIS, suggesting that recovery of this pathway was sufficient to restore function. Exposure to iAs was accompanied by an increase in mRNA expression of UDP-glucuronosyltransferase 1 family, polypeptide a6a (Ugt1a6a), a phase-II detoxification enzyme that facilitates the disposal of cyclic amines, including serotonin, via glucuronidation. Elevated Ugt1a6a and UGT1A6 expression levels were observed in mouse and human islets, respectively, following 3 days of iAs exposure. Consistent with this finding, the enzymatic rate of serotonin glucuronidation was increased in iAs-exposed cells. Knockdown by siRNA of Ugt1a6a during iAs exposure restored GIIS in MIN6-K8 cells. This effect was prevented by blockade of serotonin biosynthesis, suggesting that the observed iAs-induced increase in Ugt1a6a affects GIIS by targeting serotonin or serotonin-related metabolites. Although it is not yet clear exactly which element(s) of the serotonin pathway is/are most responsible for iAs-induced GIIS dysfunction, this study provides evidence that UGT1A6A, acting on the serotonin pathway, regulates GIIS under both normal and pathological conditions.

Management of lipoprotein X and its complications in a patient with primary sclerosing cholangitis.

Lipoprotein X (LpX) is an abnormal lipoprotein found in conditions such as lecithin:cholesterol acyltransferase deficiency and cholestatic states (e.g., primary biliary cirrhosis and primary sclerosing cholangitis). Management of severe hypercholesterolemia due to LpX with drugs and physical removal methods is not well established in the literature. A case is discussed of a 51-year-old woman who presented with multiple electrolyte abnormalities, xanthomas and neuropathy found to be secondary to LpX in the setting of primary sclerosing cholangitis. This case highlights that oral medications, including statins, may be insufficient to normalize lipid levels or improve clinical symptoms of LpX and presents therapeutic plasma exchange as a safe and effective therapeutic option to treat the morbid sequela of LpX hyperlipidemia.

Multiple Endocrine Disruption by the MET/ALK Inhibitor Crizotinib in Patients With Non-small Cell Lung Cancer.

OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogenous group of disorders that can be subclassified based upon molecular characterization. Anaplastic lymphoma kinase translocation and MET aberrations occur in a subset of NSCLC. Anaplastic lymphoma kinase/MET have been shown to be inhibited by the small molecule tyrosine kinase inhibitor crizotinib. Recently, crizotinib was shown to decrease testosterone in males. Herein, we describe the effects of crizotinib on multiple hormonal axes. MATERIALS AND METHODS: Seven consecutive patients with NSCLC who were receiving crizotinib as part of their standard care were evaluated for hormonal disruptions. RESULTS: Primary hypogonadism was detected in 4/5 of males, whereas mildly elevated prolactin was observed in 4/7 patients. Hypocalcemia was observed in 3/7 patients. Interestingly, 5/7 patients had elevated levels of insulin-like growth factor-1 (IGF-1) levels, and the remaining 2 individuals had levels that were near the upper limits of the normal range. CONCLUSIONS: Because of cellular cross-talk between MET and IGF-1 signaling, elevated IGF-1 levels induced by crizotinib treatment may have implications for long-term drug efficacy. Furthermore, this finding suggests a potential avenue of therapeutic synergy, namely coordinate inhibition of the MET and IGF-1 signaling pathways. Finally, as crizotinib has been recently approved, it is prudent to check hormone and calcium biomarkers and correct noted deficiencies for improved outcomes and quality of life.

The endocrine disrupting chemical tolylfluanid alters adipocyte metabolism via glucocorticoid receptor activation.

Glucocorticoid signaling plays a critical role in regulating energy metabolism. Emerging data implicate environmental endocrine-disrupting chemicals as contributors to the obesity and diabetes epidemics. Previous studies have shown that the phenylsulfamide fungicide tolylfluanid (TF) augments glucocorticoid receptor (GR)-dependent luciferase expression in 3T3-L1 preadipocytes while modulating insulin action in primary murine and human adipocytes. Studies were performed to interrogate glucocorticoid signaling in primary adipocytes exposed to TF. TF mimicked the gene transcription profile of the murine glucocorticoid corticosterone (Cort). Cellular fractionation assays demonstrated that TF treatment promoted the activating serine phosphorylation of GR, augmenting its cytoplasmic-to-nuclear translocation as well as its enrichment at glucocorticoid response elements on the glucocorticoid-induced leucine zipper gene promoter. After acute treatment, Cort or TF promoted insulin receptor substrate-1 (IRS-1) gene and protein expression. Either treatment also enriched GR binding at an identified glucocorticoid response element in the IRS-1 gene. TF or Cort each increased insulin-stimulated lipogenesis, an effect resulting from increased lipogenic gene expression and enhanced insulin-stimulated dephosphorylation of acetyl-coenzyme A carboxylase. The augmentation of insulin-stimulated lipogenesis was mediated through a specific enhancement of Akt phosphorylation at T308. These findings support modulation of IRS-1 levels as a mechanism for glucocorticoid-mediated changes in insulin action in primary adipocytes. Albeit with less affinity than Cort, in silico analysis suggests that TF can interact with the ligand binding pocket of GR. Collectively, these studies identify TF as a structurally unique environmental glucocorticoid. Glucocorticoid signaling may thus represent a novel pathway by which environmental toxicants promote the development of metabolic diseases.

PCB 126 and other dioxin-like PCBs specifically suppress hepatic PEPCK expression via the aryl hydrocarbon receptor.

Dioxins and dioxin-like compounds encompass a group of structurally related heterocyclic compounds that bind to and activate the aryl hydrocarbon receptor (AhR). The prototypical dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic industrial byproduct that incites numerous adverse physiological effects. Global commercial production of the structurally similar polychlorinated biphenyls (PCBs), however, commenced early in the 20(th) century and continued for decades; dioxin-like PCBs therefore contribute significantly to total dioxin-associated toxicity. In this study, PCB 126, the most potent dioxin-like PCB, was evaluated with respect to its direct effects on hepatic glucose metabolism using primary mouse hepatocytes. Overnight treatment with PCB 126 reduced hepatic glycogen stores in a dose-dependent manner. Additionally, PCB 126 suppressed forskolin-stimulated gluconeogenesis from lactate. These effects were independent of acute toxicity, as PCB 126 did not increase lactate dehydrogenase release nor affect lipid metabolism or total intracellular ATP. Interestingly, provision of cells with glycerol instead of lactate as the carbon source completely restored hepatic glucose production, indicating specific impairment in the distal arm of gluconeogenesis. In concordance with this finding, PCB 126 blunted the forskolin-stimulated increase in phosphoenolpyruvate carboxykinase (PEPCK) mRNA levels without affecting glucose-6-phosphatase expression. Myricetin, a putative competitive AhR antagonist, reversed the suppression of PEPCK induction by PCB 126. Furthermore, other dioxin-like PCBs demonstrated similar effects on PEPCK expression in parallel with their ability to activate AhR. It therefore appears that AhR activation mediates the suppression of PEPCK expression by dioxin-like PCBs, suggesting a role for these pollutants as disruptors of energy metabolism.

The novel endocrine disruptor tolylfluanid impairs insulin signaling in primary rodent and human adipocytes through a reduction in insulin receptor substrate-1 levels.

Emerging data suggest that environmental endocrine disrupting chemicals may contribute to the pathophysiology of obesity and diabetes. In a prior work, the phenylsulfamide fungicide tolylfluanid (TF) was shown to augment adipocyte differentiation, yet its effects on mature adipocyte metabolism remain unknown. Because of the central role of adipose tissue in global energy regulation, the present study tested the hypothesis that TF modulates insulin action in primary rodent and human adipocytes. Alterations in insulin signaling in primary mammalian adipocytes were determined by the phosphorylation of Akt, a critical insulin signaling intermediate. Treatment of primary murine adipose tissue in vitro with 100nM TF for 48h markedly attenuated acute insulin-stimulated Akt phosphorylation in a strain- and species-independent fashion. Perigonadal, perirenal, and mesenteric fat were all sensitive to TF-induced insulin resistance. A similar TF-induced reduction in insulin-stimulated Akt phosphorylation was observed in primary human subcutaneous adipose tissue. TF treatment led to a potent and specific reduction in insulin receptor substrate-1 (IRS-1) mRNA and protein levels, a key upstream mediator of insulin's diverse metabolic effects. In contrast, insulin receptor-ß, phosphatidylinositol 3-kinase, and Akt expression were unchanged, indicating a specific abrogation of insulin signaling. Additionally, TF-treated adipocytes exhibited altered endocrine function with a reduction in both basal and insulin-stimulated leptin secretion. These studies demonstrate that TF induces cellular insulin resistance in primary murine and human adipocytes through a reduction of IRS-1 expression and protein stability, raising concern about the potential for this fungicide to disrupt metabolism and thereby contribute to the pathogenesis of diabetes.

A 59 year-old man with sellar lesion.

A 59 year-old man presented with a large sellar mass. Pathologic examination revealed a tumor with two distinct cell populations. The majority of the tumor showed typical pituitary gonadotroph adenoma morphology and staining. Diffusely scattered throughout this tumor were nests of epithelial cells with an appearance typical of adamantinomatous craniopharyngioma and that were proliferating by Ki-67. Moreover, their diffuse distribution within the adenoma portion of the tumor suggests that these areas arose from within the adenoma where squamous rests are not observed. While pituitary adenomas juxtaposed to craniopharyngiomas have been reported, these cases have consisted of distinct masses unlike the intimately admixed tumor described in this case. Moreover, all previous reports of craniopharyngiomas with pituitary adenoma have consisted of prolactinomas. This is the first reported case of a craniopharyngioma with gonadotroph adenoma.