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Receptor- and Reactive Intermediate-Mediated Mechanisms of Teratogenesis

  • Peter G. WellsEmail author
  • Crystal J. J. Lee
  • Gordon P. McCallum
  • Julia Perstin
  • Patricia A. Harper
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)

Abstract

Drugs and environmental chemicals can adversely alter the development of the fetus at critical periods during pregnancy, resulting in death, or in structural and functional birth defects in the surviving offspring. This process of teratogenesis may not be evident until a decade or more after birth. Postnatal functional abnormalities include deficits in brain function, a variety of metabolic diseases, and cancer. Due to the high degree of fetal cellular division and differentiation, and to differences from the adult in many biochemical pathways, the fetus is highly susceptible to teratogens, typically at low exposure levels that do not harm the mother. Insights into the mechanisms of teratogenesis come primarily from animal models and in vitro systems, and involve either receptor-mediated or reactive intermediate-mediated processes. Receptor-mediated mechanisms involving the reversible binding of xenobiotic substrates to a specific receptor are exemplified herein by the interaction of the environmental chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or “dioxin”) with the cytosolic aryl hydrocarbon receptor (AHR), which translocates to the nucleus and, in association with other proteins, binds to AH-responsive elements (AHREs) in numerous genes, initiating changes in gene transcription that can perturb development. Alternatively, many xenobiotics are bioactivated by fetal enzymes like the cytochromes P450 (CYPs) and prostaglandin H synthases (PHSs) to highly unstable electrophilic or free radical reactive intermediates. Electrophilic reactive intermediates can covalently (irreversibly) bind to and alter the function of essential cellular macromolecules (proteins, DNA), causing developmental anomalies. Free radical reactive intermediates can enhance the formation of reactive oxygen species (ROS), resulting in oxidative damage to cellular macromolecules and/or altered signal transduction. The teratogenicity of reactive intermediates is determined to a large extent by the balance among embryonic and fetal pathways of xenobiotic bioactivation, detoxification of the xenobiotic reactive intermediate, detoxification of ROS, and repair of oxidative macromolecular damage.

Keywords

Aryl hydrocarbon receptor Dioxin Reactive intermediates Oxidative stress Teratogenesis 

Abbreviations

AED

Antiepileptic drug

AHR

Aryl hydrocarbon receptor

AHRE

Aryl hydrocarbon responsive element

ARNT

Aryl hydrocarbon receptor nuclear translocator

ATM

Ataxia telangiectasia mutated

ATRA

All-trans retinoic acid

B[a]P

Benzo[a]pyrene

CAR

Constitutive androstane receptor

CYP

Cytochrome P450

G6PD

Glucose-6-phosphate dehydrogenase

CSB

Cockayne Syndrome B

GSH

Glutathione

GST

Glutathione S-transferase

LPO

Lipoxygenase

NF-kB

Nuclear factor kappa B

OGG1

Oxoguanine glycosylase 1

PHS

Prostaglandin H synthase

PXR

Pregnane X receptor

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

RAR

Retinoic acid receptor

SOD

Superoxide dismutase

TCDD

2,3,7,8-Tetrachlorodibenzo-p-dioxin (“dioxin”)

UGT

UDP-glucuronosyltransferase

Notes

Acknowledgments

Research from the Wells laboratory was supported by grants from the Canadian Institutes of Health Research (CIHR), the National Cancer Institute of Canada and the National Institute of Environmental Health Sciences (No. R21-ES013848). Research from the Harper laboratory was supported by grants from the CIHR.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Peter G. Wells
    • 1
    Email author
  • Crystal J. J. Lee
  • Gordon P. McCallum
  • Julia Perstin
  • Patricia A. Harper
  1. 1.Division of Biomolecular Sciences, Faculty of PharmacyUniversity of TorontoTorontoCanada

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