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Polluted Pathways: Mechanisms of Metabolic Disruption by Endocrine Disrupting Chemicals

  • Mechanisms of Toxicity (JR Richardson, Section Editor)
  • Published:
Current Environmental Health Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Environmental toxicants are increasingly implicated in the global decline in metabolic health. Focusing on diabetes, herein, the molecular and cellular mechanisms by which metabolism disrupting chemicals (MDCs) impair energy homeostasis are discussed.

Recent Findings

Emerging data implicate MDC perturbations in a variety of pathways as contributors to metabolic disease pathogenesis, with effects in diverse tissues regulating fuel utilization. Potentiation of traditional metabolic risk factors, such as caloric excess, and emerging threats to metabolism, such as disruptions in circadian rhythms, are important areas of current and future MDC research. Increasing evidence also implicates deleterious effects of MDCs on metabolic programming that occur during vulnerable developmental windows, such as in utero and early post-natal life as well as pregnancy.

Summary

Recent insights into the mechanisms by which MDCs alter energy homeostasis will advance the field’s ability to predict interactions with classical metabolic disease risk factors and empower studies utilizing targeted therapeutics to treat MDC-mediated diabetes.

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Abbreviations

EDCs:

Endocrine disrupting chemicals

GDM:

Gestational diabetes mellitus

MDCs:

Metabolism disrupting chemicals

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

GLUT2:

glucose transporter 2

GI:

Gastrointestinal

ATP:

Adenosine triphosphate

ADP:

Adenosine diphosphate

KATP :

Potassium sensitive ATP channel

TPT:

Triphenyltin

GLP-1:

Glucagon-like peptide-1

GIP:

Gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide

cAMP:

Cyclic AMP

NAD(P)H:

Nicotinamide adenine dinucleotide phosphate

SNAP-25:

Synaptosome-associated protein 25 kDa

GPCR:

G-Protein-coupled receptor

TBT:

Tributyltin

PKA:

Protein kinase A

PCB:

Polychlorinated biphenyl

CamKII:

Calcium/calmodulin-dependent protein kinase II

cGMP:

cyclic guanosine monophosphate

BPA:

Bisphenol A

GSIS:

Glucose-stimulated insulin secretion

PAH:

Polycyclic aromatic hydrocarbon

ncmER:

non-classical membrane estrogen receptor

ERβ:

Estrogen receptor beta

CREB:

response element binding protein

ERα:

Estrogen receptor alpha

ERK:

Extracellular signal-regulated kinase

ER:

Endoplasmic reticulum

DEHP:

Diethylhexylphthalate

ROS:

Reactive oxygen species

DNA:

Deoxyribonucleic acid

NAC:

N-Acetylcysteine

JNK:

c-Jun N-terminal kinase

NOD:

Non-obese diabetic

IRS:

Insulin receptor substrate

PI3-K:

Phosphatidylinositol 3 kinase

PIP3 :

Phosphatidylinositol triphosphate

PDK1:

Phosphoinositide-dependent kinase 1

PKB:

Protein Kinase B

PM:

Particulate matter

TCDD:

2,3,7,8-Tetrachlorodibenzo dioxin

TF:

Tolylfluanid

POP:

Persistent organic pollutant

PFOA:

Perfluorooctanoic acid

PEPCK:

Phosphoenolpyruvate carboxykinase

AhR:

Aryl hydrocarbon receptor

PFOS:

Perfluorooctanesulfonic acid

HNF4α:

Hepatocyte nuclear factor 4 alpha

PPARγ:

Peroxisome proliferator activated receptor gamma

GR:

glucocorticoid receptor

TNFα:

Tumor necrosis factor alpha

AMPK:

5′ Adenosine monophosphate-activated protein kinase

IL-1β:

Interleukin 1 beta

NFκB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

MAPK:

Mitogen-activated protein kinase

IL-6:

Interleukin 6

NEFA:

Non-esterified fatty acids

Srebpc1:

Sterol regulatory element-binding protein 1

PPARα:

Peroxisome proliferator activated receptor alpha

Cpt1b:

Carnitine palmitoyltransferase 1B

CDK4:

Cyclin-dependent kinase-4

SGLT-2:

Sodium-glucose cotransporter-2

DPP4:

Dipeptidyl peptidase 4

GLP-1:

Glucagon-like peptide-1

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Acknowledgments

This work was supported by the National Institutes of Health (T32DK007011 to M.S.M.), the American Diabetes Association (Junior Faculty Development Award 1-17-JDF-033 to R.M.S.), the Ministerio de Economia y Competitividad (SAF2014-58335-P to A.N.), and Generalitat Valenciana (PROMETEOII/2015/016 to A.N.). CIBERDEM is an initiative of the Instituto de Salud Carlos III.

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  1. Section of Endocrinology, Diabetes, and Metabolism; Department of Medicine, University of Chicago, Chicago, IL, USA

    Mizuho S. Mimoto

  2. Institute of Bioengineering and Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas, CIBERDEM, Universidad Miguel Hernández de Elche, Alicante, Spain

    Angel Nadal

  3. Division of Endocrinology, Diabetes, and Metabolism; Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott, Suite 625E M/C 640, Chicago, IL, USA

    Robert M. Sargis

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  1. Mizuho S. Mimoto
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Correspondence to Robert M. Sargis.

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Mizuho S. Mimoto and Angel Nadal declare that they have no conflict of interest.

Robert M. Sargis reports honoraria from CVS Health.

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Mimoto, M.S., Nadal, A. & Sargis, R.M. Polluted Pathways: Mechanisms of Metabolic Disruption by Endocrine Disrupting Chemicals. Curr Envir Health Rpt 4, 208–222 (2017). https://doi.org/10.1007/s40572-017-0137-0

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