Translational Toxicology and Therapeutics

Windows of Developmental Susceptibility in Reproduction and Cancer

Michael D. Waters, Claude L. Hughes

• Publisher: Wiley
• Year: 2017
• ISBN:
  9781119023623
• Edition: 1
• Topic: Medicine
• Subtopic: Toxicology

Written by leading research scientists, this book integrates current knowledge of toxicology and human health through coverage of environmental toxicants, genetic / epigenetic mechanisms, and carcinogenicity.

• Provides information on lifestyle choices that can reduce cancer risk
• Offers a systematic approach to identify mutagenic, developmental and reproductive toxicants
• Helps readers develop new animal models and tests to assess toxic impacts of mutation and cancer on human health
• Explains specific cellular and molecular targets of known toxicants operating through genetic and epigenetic mechanisms

Part One
Introduction: The Case for Concern about Mutation and Cancer Susceptibility during Critical Windows of Development and the Opportunity to Translate Toxicology into a Therapeutic Discipline

1
What Stressors Cause Cancer and When?

Claude L. Hughes^1,2,3 and Michael D. Waters⁴

¹Therapeutic Science and Strategy Unit QuintilesIMS Inc., Morrisville, NC, USA

²Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA

³Department of Mathematics, North Carolina State University, Raleigh, NC, USA

⁴Michael Waters Consulting USA, Hillsborough, NC, USA

1.1 Introduction

Translational biomedical research seeks to move laboratory findings based on models (in silico, in vitro, and in vivo) into human clinical trials to more expeditiously develop specific therapeutics, and then back again to the laboratory to inform future discovery [1]. From the background of developmental toxicology, it is well known that toxicant exposures may affect critical events in reproductive development, ranging from early primordial germ cell determination to gonadal differentiation, gametogenesis, external genitalia, or signaling events regulating sexual behavior. Translational genetic toxicology takes advantage of this developmental perspective to assess potential germ line mutagenesis or to study the potential for cancer in the fetus or offspring or the adult as the result of environmental exposures. Translational toxicology must strive to identify applicable therapeutics that can safely and effectively identify and help to mitigate potential harm from natural as well as anthropogenic environmental exposures.

Human exposures to chemicals, physical agents, and social factors are inevitable, thus the human fetus and the adult are subject to exposures and effects that can have lifelong consequences. Particularly, during dynamic developmental intervals described as “critical windows of susceptibility,” exposures may have robust and durable effects that drive long-term health outcomes, including metabolism, functional status of organ systems, and cancer risks [2]. These same dynamic developmental intervals should be seen as “critical windows of responsivity” during which favorable/protective interventions should also be highly impactful offering potential durable reduction in risks of multiple adverse health outcomes, including cancers. To reduce the lifelong occurrence of preventable cancers, timely protective interventions during “critical windows” should include not only minimization of untoward voluntary exposures and substances of abuse but also active use of protective generally recognized as safe (GRAS) interventions/therapies, including nutritional, dietary supplementation, or well-established/repurposed and/or generally recognized as safe and effective (GRASE) pharmaceutical drugs.

This introductory chapter will promote the elucidation of cell stage, life stage, and lifestyle knowledge of specific cellular and molecular targets of known developmental toxicants, develop a systematic integrated approach to the identification of mutagenic and reproductive toxicants, and discuss sensitive, specific, and predictive animal models, to include minimally invasive surrogate markers, and/or in vitro tests to assess reproductive system function during embryonic, postnatal, and adult life. It will argue that integrated testing strategies will be required to account for the many mechanisms associated with development that occur in vivo. A key organizing principle used throughout this book is to consider how exposures that incur risk or other exposures/life events that may reduce risk during particular windows of susceptibility/developmental transitions, and thereby impact cancer occurrence.

In consideration of any cause–effect relationship, typically one thinks of the simple questions: Who, what, where, when, and how? Admittedly, “How?” questions are generally the most difficult because that understanding is a synthesis of potentially causal pathways. We aim to consider that the “Who?” and “When?” questions could be seen as people being exposed at different intervals across their respective life spans. Thus, in addition to information regarding what exposures occur that influence cancer occurrence, what is and is not known about exposures to those agents during life span intervals such as childhood, adolescence, across the broader life span, and/or late in life? Assessment of such timing of exposure with cancer outcomes seems to be a critical element if we aim to develop protective interventional strategies. In other words, whether we aim to reduce exposures or advocate protective lifestyle or therapeutic interventions, we must know when those interventions would most effectively impact later cancer outcomes.

Although there are differences between human development and that of laboratory animal models, developmental models have been extremely useful in assessing risks for key human reproductive and developmental processes. Some of these models will be discussed in Chapters 2 and 3. However, such systems have not been fully integrated with models to assess germ line mutagenesis or to study the potential for cancer in the fetus or offspring as the result of environmental exposures. Again, Chapters 2 and 3 will address current proposals for experimental animal test system integration.

To delve into the impact of exposures during “windows of susceptibility/responsivity,” we must take into account the unique susceptibilities of the fetus. Relatively, new information suggests that some widely held notions relevant to fetal exposures are incorrect [3]. Thus, we now know that amniotic fluid can be reabsorbed into the fetal circulation by fetal swallowing as well as via the fetal intramembranous pathway. The latter pathway is thought to be the most important mechanism for the resorption of toxicants, such as ethanol, into the fetal circulation [4]. Together with swallowing, this is a recycling system, through which toxic substances are excreted into the amniotic fluid and reabsorbed into the fetal circulation, thus extending the duration of each exposure [5,6]. This and other information relevant to fetal exposure in utero will be discussed in Chapter 8.

1.1.1 General Information about Cancer

Each year the American Cancer Society estimates the number of new cancer cases and deaths that will occur in the United States that year. In 2016, a total of 1,685,210 new cancer cases were expected to be diagnosed and about 595,690 cancer deaths were projected to occur in the United States [7]. Among children up to 14 years of age, an estimated 10,380 new cancer cases were expected to occur in 2016.

Population-based cancer registration began in the United States in 1975. Since then, childhood cancer incidence rates have increased by 0.6% per year. In 2016, 1250 cancer deaths were expected to occur among children. Cancer is the second leading cause of death in children ages 1–14 years, exceeded only by accidents. Childhood cancer death rates declined a total of 66% from 1969 (6.5 per 100,000) to 2012 (2.2 per 100,000). According to the American Society, this was largely due to improvements in treatme...

Table of contents

• Cover
• Title Page
• Copyright
• List of Contributors
• Part One: Introduction: The Case for Concern about Mutation and Cancer Susceptibility during Critical Windows of Development and the Opportunity to Translate Toxicology into a Therapeutic Discipline
• Part Two: Exposures that Could Alter the Risk of Cancer Occurrence, and Impact Its Indolent or Aggressive Behavior and Progression Over Time
• Part Three: Gene–Environment Interactions
• Part Four: Categorical and Pleiotropic Nonmutagenic Modes of Action of Toxicants: Causality
• Part Five: Biomarkers for Detecting Premalignant Effects and Responses to Protective Therapies during Critical Windows of Development
• Index
• End User License Agreement