Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 6, Issue 1, 2006

First of all, I would like to thank the Editor-in Chief, Dr. Charles L. Bisgaier and the Bentham Science Publishers for the opportunity to arrange the review forum of "Endocrine Disruption and Reproduction" for publication in this journal. Endocrine disruption, which is associated with an increased risk and incidence of reproductive dysfunction, is a global issue in terms of human reproduction and health. To date, the World Health Organization (WHO), United States National Institute of Environmental Health Sciences (NIEHS) and Environmental Protection Agency (EPA), Health Canada, the UN Environment Programme, UNICEF, and the World WildLife Fund have all identified endocrine disruptors as a critical environmental and health issue in the 21st Century. Thus, the points of view in regard to this global issue need to be emphasized so as to inform readers of the disadvantages of endocrine disrupting chemicals which are persistently present in our environment. We have invited seven articles from contributors who are internationally recognized as experts in the research area of endocrine disruption and reproduction. This review forum provides scientific evidence for the harmful effects of endocrine disruptors, highlights the effects of exposure to multiple endocrine disrupting chemicals and ascertains major sources of exposure in human reproductive functions. Thus, the review articles in this forum would be beneficial to explain how environmental chemicals interfere with physiological systems, adversely affect hormonal balance, or disrupt normal function in the organs which hormones regulate or modulate in the female and male reproductive systems. I wish to express my gratitude to all the contributors and especially the tremendous assistance of Dr. Keith K. C. Choi for putting together this timely forum for the journal.

Endocrine disruptors (EDs) are environmental chemicals that interfere with physiological systems, adversely affecting hormone balance (endocrine system), or disrupting normal function in the organs which hormones regulate or modulate, i.e., the female and male reproductive systems. Although endocrine disruption is a global concern for human health, its impact and significance and the screening strategy for detecting these synthetic or man-made chemicals are not well described in female and male reproductive functions. Thus, this review summarizes the interference of environmental EDs on reproductive development and function, and introduces biomarkers and screening methods for EDs in in vitro and in vivo models, in particular, female reproductive system. These methods include studying of the uterine expression of Calbindin-D9k (CaBP-9k), a cytosolic calcium binding protein regulated by estrogenic or progestogenic compounds. In addition, this review highlights the effect of exposure to multiple EDs on reproductive functions, and brings attention to major sources of exposure.

The environmental endocrine disruptor hypothesis proposes a causal linkage between exposure to certain environmental pollutants and reproductive dysfunction. Although it is well recognized that hormonally active chemicals have the potential to adversely affect health, proof that environmental chemicals at ambient concentrations alter endocrine function in humans and wildlife is lacking. This review will focus on two man-made chemicals, p-nonylphenol, a surfactant product, and methoxychlor, a chlorinated pesticide, that are widely dispersed in the environment as a result of their broad uses in industrial processes and agriculture, respectively. Both chemicals bind to estrogen α and β receptors with low affinity and exhibit weak estrogenic activity in vitro and in vivo. p-Nonylphenol is inactivated if metabolized further, whereas the estrogenic effects of methoxychlor are derived in large part from its more active metabolites, especially dihydroxymethoxychlor. The review draws predominantly on the literature of the last 5 years and is organized to highlight 1. the sources and environmental fate of p-nonylphenol and methoxychlor, 2. effects of treatment with each chemical on endogenous hormone levels, 3. consequences of direct and developmental exposure on the female and male reproductive systems of experimental animals, and 4. effects on mammary gland development. The experimental evidence cited shows that methoxychlor and p-nonylphenol, at high dosages, adversely affects the mammalian reproductive system in females to a greater degree than males. Moreover, exposure during early development has profound and longer-lasting effects than adult exposure.

Cadmium is a heavy metal that has no known beneficial biological role. Although naturally occurring, it owes its presence in today's environment mainly to contamination from consumer goods (electric batteries, paints, etc.), industrial wastes, and soil fertilizers. Cadmium is a constituent of foods (seafood, grains, vegetables) and tobacco smoke, which are its main sources of exposure to the general population. Human exposure has been linked to a vast array of ill effects ranging from those affecting lung, kidney and bone, to those affecting reproductive organs and specific cell functions. By virtue of its demonstrated capacity to alter the rates of ovarian and placental steroidogenesis, thereby adversely impacting normal reproduction in both humans and animals, cadmium has been added to the list of acknowledged endocrine disrupting chemicals (EDCs). Extensive evidence suggests direct effects on specific components of the steroidogenic pathway, including the low density lipoprotein (LDL)-cholesterol receptor and P450 side chain cleavage enzyme. In addition to exerting its effects via both transcriptional and post-transcriptional mechanisms, cadmium may also regulate hormone binding and intracellular second messenger pathways. Women may be at increased risk for the reproductive anomalies associated with exposure and, as demonstrated in numerous studies, the metal may also function as a potent nonsteroidal agent; a xenoestrogen, that can mimic or block the effects of endogenous estrogens. The effects of cadmium on reproduction, combined with its abundance in the human environment, continue to call for more detailed studies dedicated to elucidating the mechanisms that control the metal's influence as an EDC.

Ovarian production of oocytes and steroids is choreographed by hypothalamic-pituitary hormones and locally via ovarian derived growth factors and hormones. Environmental chemicals are known to mimic the actions of gonadal steroids such as estradiol or antagonize hormone actions at target tissues. The presence of environmental contaminants in ovarian follicular fluid has been documented and thus has implications for ovarian function and cancer. However, understanding of the risks to ovarian regulation resulting from exposure to environmental contaminants is limited. Therefore a systematic review of the published literature was conducted to characterize the current state of knowledge concerning the ovarian toxicity of environmental toxicants. Herein we argue that the epidemiological literature provides only weak support in favour of the involvement of environmental toxicants in adverse effects on ovarian function. By comparison animal experiments provide evidence of the biological plausibility for environmental toxicants to adversely affect ovarian physiology. Unlike environmental toxicants a strong association has been established linking cigarette smoking and ovarian toxicity. While previous in vitro studies were limited to examining the effects of test compounds on ovarian steroidogenesis, innovative culture methods are opening the door for investigation of time- and stage-dependent effects of toxicants on folliculogenesis. Although evidence of ovarian toxicity in the human population is scant, we propose that inherent limitations of the epidemiological studies together with evidence of biological plausibility provided by animal studies supports the need for further studies to better characterize the mechanism(s) of toxicant action on the ovary.

In recent years considerable attention has been focused on the adverse effects of environmental toxicants on human reproductive processes. A major class of environmental toxicants is the pesticides which include insecticides, herbicides, fungicides, molluscicides, rodenticides and nematocides. Although some pesticides are no longer used, their metabolites persist for many years and are ubiquitous through long range transport. In this review we will examine the role of insecticides in adverse reproductive outcomes and their mechanisms of action. No attempt is made to link exposure to insecticides and carcinogenesis, immune response, congenital anomalies or other effects. The three groups of insecticides - carbamates, organochlorines, and organophosphates will be discussed in detail. Evidence for and against adverse effects of insecticides as well as the emerging area of interest on nongenomic effects will be covered.

TCDD (2,3,7,8-tetrachorodibenzo-p-dioxin) is a common environmental pollutant causing public concern. The administration of TCDD for experimental animals causes serious biological effect including reproductive, developmental and carcinogenic effect. Accumulated knowledge revealed reproductive interference of TCDD is cause not only by the alteration for hypothalamo-pituital hormonal regulation, but also by direct effect for ovarian function. In this review, the direct effect of TCDD on ovarian function is briefly reviewed. TCDD exert its inhibitory effect on steroidogenic enzyme expression and gonadotropin receptor expression.

Organotin compounds have entered the environment because of their use as antifouling agents in marine paints and as heat stabilizers in vinyl chloride polymers. Consequently, they are present in water supplies and foodstuffs that are consumed by humans. In aquatic environments, organotins, and especially tributyltin (TBT), are toxic to marine species at low concentrations. TBT causes imposex in some marine organisms where the female genitalia become masculinized and which renders them infertile, thought to be a consequence of inhibition of aromatase activity leading to increased levels of androgens and decreased levels of estrogens in the tissues. However, it is becoming increasingly apparent that TBT affects many other biochemical processes in mammalian cells. This review will focus on the mechanisms by which TBT effects mammalian biochemical systems and point towards areas where data are needed in order to determine the risks to human health of exposure to TBT.

The World Health Organisation has declared that obesity is a disease of pandemic significance, which threatens the developing world as well as developed countries. Over recent years rates of overweight and obesity have escalated rapidly to epidemic proportions in many parts of the world, reflecting increasing consumption of energy dense diets high in fats and sugars, compounded by declining levels of physical activity. Using the standard classification, more than 1.1 billion worldwide are estimated to be overweight, of whom around 320 million are obese. The range of normality for BMI has been estimated at between 20-23 kg/m2 across Africa and Asia, but in Europe and North America this range is shifted towards much higher values (25-27 kg/m2), indicating a substantial higher risks to develop obesity and diabetes. In Europe few countries report obesity rates below 10%. Prevalence rates, particularly among women, rise to more than 20% in countries such as the United Kingdom, Germany, Finland and Greece. The burden for the society is made worse by the spreading of the obesity epidemics in childhood in industrially developed as well as in developing countries. Overweight and obesity affects one in 10 children worldwide, but the rate is double in Europe and three times as much across the entire Americas. Furthermore, the emergence of type 2 diabetes in childhood is a serious development. In the USA, for instance, it has been found out that up to 45% of children with newly diagnosed diabetes have type 2 diabetes and most are overweight or obese at diagnosis. Indeed, obesity is closely linked to type 2 diabetes and, in fact, at the present time, it is estimated that 190 million people worldwide have diabetes and that this will increase to 324 million by 2025. This epidemic is taking place in both developed and developing nations. In the U.S. alone, at least 16 million people have type 2 diabetes, with 1 million more diagnosed annually. The strong relationship between obesity and type 2 diabetes have led to the term "diabesity" to suggest a single problem. In addition to diabetes, complications of obesity include dyslipidemia, hypertension, insulin resistance, cardiovascular disease, sleep apnea, certain types of cancers, asthma, deep venous thrombosis, degenerative joint disease, polycystic ovarian disease and depression. For individuals who are severely obese (body mass index of 40 kg/m2 or greater) the risk for obesity-associated morbidities and mortality is even greater. The cost of obesity can be identified not only in economic terms, but also in terms of years of disability that reduces the quality of life as well as life expectancy. Higher body mass index has been shown to account for up to 16% of the burden of disease, expressed as a percentage of disability-adjusted life years (DALYs). In several developed countries obesity has been estimated to account for 2-7% of the total health care costs. For instance, the combined direct and indirect costs to the USA have been evaluated to be $123 billion in 2001. The present monographic issue addresses some relevant aspects of obesity, from the pathophysiology - including substrate metabolism, insulin resistance, inflammation, neuroimagenomics -, to the medical approach -diet and pharmacological therapy-, and the bariatric surgery. Each topic has been reviewed by some of most prominent scientists in the field of obesity and insulin resistance in order to give to the reader a detailed report on the current state of the art.

Obesity is a hereditary condition that affects millions of people and has serious health consequences. Despite recent advances in the understanding of the molecular biology controlling energy homeostasis and large efforts to uncover the genetic underpinnings of obesity in human populations, the exact molecular cause of weight gain in the majority of people remains unknown. By subscribing to the notion that the brain plays a critical role in the control of energy homeostasis and ultimately the genesis of obesity, we acknowledge that the greatest challenge following the identification of the genetic make up of obese individuals will be to understand how these molecular defects work in combination to alter the neurophysiology of those regions of the brain that control energy balance. To identify research strategies for the study of human obesity that complement positional cloning, we have developed a concept that we will refer to as neuroimagenomics (NIG), consisting of an iterative experimental approach combining neuroimaging and gene expression profiling of the human brain. We suggest that neuroimagenomics, which capitalizes on powerful and complementary brain imaging and genomic approaches to the problem, provides an especially promising way to investigate the molecular biology of obesity and assist in the discovery of novel drugs to treat this extraordinary public health problem.

The etiology of obesity is not simple as multiple genetic and environmental factors, first of which is an increasingly sedentary lifestyle, play interacting roles. It is well recognized that persons with obesity carry a high risk of insulin resistance and its metabolic complications, such as impaired glucose tolerance, type 2 diabetes, hyperlipidemia and hypertension, and a significantly increased risk of atherothrombotic cardiovascular disease. Recent data have shown that not only generalized obesity, but rather ectopic fat accumulation, is associated with the risk of comorbidity. This article focuses on the clinical evidence related to the impact of regional adiposity on insulin resistance, with particular attention to central obesity, including fat accumulation in insulin sensitive organs, such as liver, muscle and heart, and the recent interest in adipokines.

Assessment of insulin sensitivity and β-cell function is required in many studies, as these characteristics are of fundamental importance in glucose intolerance and diabetes, and insulin sensitivity is also a potential underlying cause of other pathologies. Clinical investigations on the pathophysiological role of these factors and on the efficacy of drugs for disease prevention and treatment thus necessitate a variety of methods, suitable for the specific needs of each study. Scope of this review is to present critically and in an integrated fashion the methods that are currently in use for the assessment of insulin sensitivity, β-cell function and their relationships. As the considered methods differ in the degree of experimental complexity and reliability, their characteristics are comparatively discussed to provide guidelines for a correct choice and application. It is suggested that the choice of the insulin sensitivity method basically depends on the experimental constraints, as reliability and experimental complexity are inversely related. The assessment of βcell function is more problematic, as the βcell response is complex and only partially understood. The existing methods often provide β cell function indices that quantify different characteristics of the βcell, and cannot be ranked on a unique scale. It is however suggested that the βcell function methods, and in particular the techniques for the study of the relationships between insulin sensitivity and βcell function, should be critically used to avoid inappropriate application and conclusions.

Globalization of occidental way of life is leading to increasing prevalence of obesity and type 2 diabetes, the greatest pandemy of the XXI century. Type 2 diabetes is the result of peripheral insulin resistance and concomitant decreased β cell insulin secretion. Insulin resistance and cardiovascular disease share common pathophysiological mechanisms, as the chronic activation of the innate immune system. This system constitutes the first line of body's defense and it is constituted by different barriers (epithelia, adipose tissue), and different blood and tissue components as macrophages, and neutrophils. Once activated, the innate immune system generates the acute phase response in which different acute phase proteins and cytokines are produced to fight against different aggressions as infections and traumatisms. The aim of this response is to eradicate these agents, to repair the harmed tissues, and, through increased insulin resistance, to optimize the energetic substrates, which will be drained to vital tissues and organs (i.e. brain and the immune system). Evolution pressures have led to survival of the fittest individuals, those with genetics that allows the best defense against infection and periods of famine. The initial evolutive advantages of increased inflammatory responses, hypersecretion of proinflammatory cytokines (TNF-α, interleukin (IL)-1 β, IL-6, IL-18, ....), and antiinflammatory molecules (adiponectin, sCD14), turn into chronic inflammation conditions, such as obesity and type 2 diabetes. Increasing evidence is reported according to which chronic inflammation precedes these conditions. The knowledge of how these metabolic pathways interact with the inflammatory cascade will facilitate new therapeutic approaches.

The long-term effects on weight have only been studied for orlistat and sibutramine. The net effects of these drugs vary between 2-5% loss of weight after 1-2 years of treatment. However, the effects of orlistat and sibutramine on morbidity and mortality have not been studied extensively. In the past decade a huge amount of new knowledge has been gathered on the physiology of energy metabolism, satiety, gut-brain interactions, adipokines, adipogenesis, hypothalamic regulation etc. These studies have provided a multitude of new pharmacological targets for the treatment of obesity. Preclinical and clinical studies will have to prove the efficacy and safety of new drugs aimed at these new targets. The ultimate goal will be to reduce the increased morbidity and mortality, associated with obesity.

Morbid obesity, a condition designated by a body mass index (BMI) ≥ 40 kg/m2 is a major public health problem throughout the world, and is a condition linked to significant morbidity and mortality due to associated co-morbid conditions which include cardiac disease, diabetes mellitus type 2, obstructive sleep apnea, hypertension, dyslipidemia, arthritis, infertility and some forms of cancer. Whereas anti-obesity medications and dietary manipulations result in very limited long-term positive outcomes, surgical treatment of morbid obesity induces long-lasting body weight loss and resolution or improvement of most associated medical conditions, particularly type 2 diabetes mellitus. Several surgical procedures are currently available, including Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion (BPD), vertical banded gastroplasty and adjustable gastric banding. These operations may be performed using laparoscopic techniques to minimize perioperative morbidity and improve postoperative recovery time. In spite of the wide clinical experience with bariatric surgery, the mechanisms underlying the effects of some of these procedure, particularly RYGB, are incompletely understood. Elucidating these mechanisms has become a priority because such knowledge may help understand the relationship between gastrointestinal physiology and insulin resistance as well as possibly identify new targets for the development of novel anti-obesity and antidiabetic medications. This article reviews the current operative techniques for morbid obesity, their indications and outcomes. We also examine available data and hypothesized mechanisms mediating the effects of RYGB.