A State-of-the-Science Review of Arsenic's Effects on Glucose Homeostasis in Experimental Models.

BackgroundThe prevalence of type 2 diabetes (T2D) has more than doubled since 1980. Poor nutrition, sedentary lifestyle, and obesity are among the primary risk factors. While an estimated 70% of cases are attributed to excess adiposity, there is an increased interest in understanding the contribution of environmental agents to diabetes causation and severity. Arsenic is one of these environmental chemicals, with multiple epidemiology studies supporting its association with T2D. Despite extensive research, the molecular mechanism by which arsenic exerts its diabetogenic effects remains unclear.ObjectivesWe conducted a literature search focused on arsenite exposure in vivo and in vitro, using relevant end points to elucidate potential mechanisms of oral arsenic exposure and diabetes development.MethodsWe explored experimental results for potential mechanisms and elucidated the distinct effects that occur at high vs. low exposure. We also performed network analyses relying on publicly available data, which supported our key findings.ResultsWhile several mechanisms may be involved, our findings support that arsenite has effects on whole-body glucose homeostasis, insulin-stimulated glucose uptake, glucose-stimulated insulin secretion, hepatic glucose metabolism, and both adipose and pancreatic β-cell dysfunction.DiscussionThis review applies state-of-the-science approaches to identify the current knowledge gaps in our understanding of arsenite on diabetes development. https://doi.org/10.1289/EHP4517

Influence of diet and maternal dioxin on endocrine disruption: puberty, metabolic syndrome, and breast cancer

Total lifetime estrogen (E2) exposure increases mammary cancer risk. TCDD indirectly affects E2 signaling and early life TCDD exposures are also implicated in breast cancer. E2 produced by adipose tissue is an underlying mechanism by which obesity contributes to early puberty, and if obesity and weight gain extend into adulthood, increased postmenopausal breast cancer risk. These observations are further complicated by greater TCDD stores in the adipose of obese- compared to lean- individuals. How several environmental exposures, maternal exposure to TCDD, lifelong exposure to high fat diet (HFD), and pubertal exposure to DMBA, modify the mammary gland was examined. It was expected that HFD and maternal exposure to TCDD would increase mammary cancer risk, through both structural remodeling of the pubertal gland and through molecular changes. Interactions of these exposures and phenotypes were examined using several mouse strains and mouse models of breast cancer, but objectives were primarily pursued using the DMBA mouse model of breast carcinogenesis. Growth trajectories, adiposity, blood glucose levels, and mammary gland development effects of HFD and maternal TCDD were examined as potential causal players in DMBA carcinogenesis. The growth trajectory, adiposity, and fasting blood glucose were increased in DMBA on HFD relative to low-fat diet (LFD). Maternal TCDD exposure increased blood glucose levels and depressed mammary gland growth at PND in DBA/2J mice fed HFD. Maternal TCDD exposure also increased blood glucose levels in DMBA transiently. Mammary lesion incidence was increased by HFD and maternal TCDD exposure. TCDD exposure increased the number of terminal end buds in DMBA on LFD, but decreased them at PND 35 in DMBA on HFD. Among DMBA on HFD, maternal TCDD increased epithelial Cyp1b1 and decreased Comt mRNA in PND 50 mammary glands. Maternal TCDD exposure also increased Cyp1b1 in mammary tumors of offspring. Thus increased steady state levels of E2 and its metabolites were likely associated with increased mammary tumor incidence in DMBA. The interactions of HFD and maternal TCDD exposure on type II diabetes risk, pubertal mammary morphology, mammary tumor incidence and estrogen pathway regulation should be further explored

Oxidative Phosphorylation Impairment by DDT and DDE

There is increasing evidence supporting the characterization of the pesticide DDT and its metabolite, DDE, as obesogens and metabolic disruptors. Elucidating the mechanism is critical to understanding whether the association of DDT and DDE with obesity and diabetes is in fact causal. One area of research investigating the etiology of metabolic diseases is mitochondrial toxicity. Several studies have found associations between mitochondrial defects and insulin resistance, cellular respiration, substrate utilization, and energy expenditure. Although the mitotoxicity of DDT and DDE was established 20–40 years ago, it was not viewed in the light of the diseases faced today; therefore, it is prudent to reexamine the mitotoxicity literature for mechanistic support of DDT and DDE as causal contributors to obesity and diabetes, as well as associated diseases, such as cancer and Alzheimer's disease. This review aims to focus on studies investigating the effect of DDT or DDE on mammalian mitochondrial oxidative phosphorylation. We illustrate that both DDT and DDE impair the electron transport chain (ETC) and oxidative phosphorylation. We conclude that there is reasonable data to suggest that DDT and DDE target specific complexes and processes within the mitochondria, and that these insults could in turn contribute to the role of DDT and DDE in mitochondria-associated diseases

Exponentially Increasing Incidences of Cutaneous Malignant Melanoma in Europe Correlate with Low Personal Annual UV Doses and Suggests 2 Major Risk Factors

For several decades the incidence of cutaneous malignant melanoma (CMM) steadily increased in fair-skinned, indoor-working people around the world. Scientists think poor tanning ability resulting in sunburns initiate CMM, but they do not understand why the incidence continues to increase despite the increased use of sunscreens and formulations offering more protection. This paradox, along with lower incidences of CMM in outdoor workers, although they have significantly higher annual UV doses than indoor workers have, perplexes scientists. We found a temporal exponential increase in the CMM incidence indicating second-order reaction kinetics revealing the existence of 2 major risk factors. From epidemiology studies, we know one major risk factor for getting CMM is poor tanning ability and we now propose the other major risk factor may be the Human Papilloma Virus (HPV) because clinicians find β HPVs in over half the biopsies. Moreover, we uncovered yet another paradox; the increasing CMM incidences significantly correlate with decreasing personal annual UV dose, a proxy for low vitamin D3 levels. We also discovered the incidence of CMM significantly increased with decreasing personal annual UV dose from 1960, when it was almost insignificant, to 2000. UV and other DNA-damaging agents can activate viruses, and UV-induced cytokines can hide HPV from immune surveillance, which may explain why CMM also occurs in anatomical locations where the sun does not shine. Thus, we propose the 2 major risk factors for getting CMM are intermittent UV exposures that result in low cutaneous levels of vitamin D3 and possibly viral infection

Correlation between technetium and lithium in a sample of oxygen-rich AGB variables

The aims of this paper are: 1) to revisit the Tc content of a sample of oxygen-rich asymptotic giant branch (AGB) variables and 2) to increase the number of such stars for which the Li abundance has been measured to provide constraints on theoretical models of extra-mixing processes. To this end, we analysed high-resolution spectra of 18 sample stars for the presence of absorption lines of Tc and Li. The abundance of the latter was determined by comparing the observed spectra to hydrostatic MARCS model spectra. Bolometric magnitudes were established from near-IR photometry and pulsation periods. We reclassify the star V441 Cyg as Tc-rich, and the unusual Mira star R Hya, as well as W Eri, as Tc-poor. The abundance of Li, or an upper limit to it, was determined for all of the sample stars. In all stars with Tc we also detected Li. Most of them have a Li content slightly below the solar photospheric value, except for V441 Cyg, which has ~1000 times the solar abundance. We also found that, similar to Tc, a lower luminosity limit seems to exist for the presence of Li. We conclude that the higher Li abundance found in the cooler and higher luminosity objects could stem from a Li production mechanism operating on the AGB. The stellar mass might have a crucial influence on this (extra-mixing) production mechanism. It was speculated that the declining pulsation period of R Hya is caused by a recent thermal pulse (TP). While not detecting Tc does not rule out a TP, it indicates that the TPs are not strong enough to drive dredge-up in R Hya. V441 Cyg, on the other hand, could either be a low-mass, intrinsic S-star that produced its large amount of Li by extra-mixing processes, or an intermediate-mass star (M>=M_sun) undergoing Li production due to hot bottom burning.Comment: 12 pages, 7 figures, accepted for publication in A&