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Nongenetic, environmental factors contribute to maternal morbidity and mortality through chemical exposures via air, water, soil, food, and consumer products. Pregnancy represents a particularly sensitive window of susceptibility during which physiological changes to every major organ system increase sensitivity to chemicals that can impact a woman's long-term health. Nonchemical stressors, such as low socioeconomic status, may exacerbate the effects of chemical exposures on maternal health. Racial/ethnic minorities are exposed disproportionately to both chemicals and nonchemical stressors, which likely contribute to the observed health disparities for maternal morbidities and mortality. Epidemiological studies linking exposures to adverse maternal health outcomes underscore the importance of environmental health impacts, and mechanistic studies in model systems reveal how chemicals perturb biological pathways and processes. Environmental stressors are associated with a variety of immediate maternal health impacts, including hypertensive disorders of pregnancy, fibroids, and infertility, as well as long-term maternal health impacts, such as higher risk of breast cancer and metabolic disorders. Identifying and reducing a pregnant woman's environmental exposures is not only beneficial to her offspring but also important to preserve her short- and long-term health.

The increasing incidence of obesity is a serious global public health challenge. Although the obesity epidemic is largely fueled by poor nutrition and lack of exercise, certain chemicals have been shown to potentially have a role in its aetiology. A substantial body of evidence suggests that a subclass of endocrine-disrupting chemicals (EDCs), which interfere with endocrine signalling, can disrupt hormonally regulated metabolic processes, especially if exposure occurs during early development. These chemicals, so-called 'obesogens' might predispose some individuals to gain weight despite their efforts to limit caloric intake and increase levels of physical activity. This Review discusses the role of EDCs in the obesity epidemic, the latest research on the obesogen concept, epidemiological and experimental findings on obesogens, and their modes of action. The research reviewed here provides knowledge that health scientists can use to inform their research and decision-making processes.

Recent data indicate that approximately 12% of children in the United States are affected by neurodevelopmental disorders, including attention deficit hyperactivity disorder, learning disorders, intellectual disabilities, and autism spectrum disorders. Accumulating evidence indicates a multifactorial etiology for these disorders, with social, physical, genetic susceptibility, nutritional factors, and chemical toxicants acting together to influence risk. Exposure to endocrine-disrupting chemicals during the early stages of life can disrupt normal patterns of development and thus alter brain function and disease susceptibility later in life. This article highlights research efforts and pinpoints approaches that could shed light on the possible associations between environmental chemicals that act on the endocrine system and compromised neurodevelopmental outcomes.

A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16–18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as “metabolic disruptors”, in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.

Obesity and diabetes have overtaken smoking as the number 1 preventable health determinate in the United States. In its basic form, obesity is due to disruptions of the endocrine systems that control food intake, satiety, and metabolic rate. Recent studies have identified a subclass of endocrine disrupting chemicals that interfere with hormonally regulated metabolic processes, especially during early development. These chemicals, called “obesogens,” may predispose individuals to gain weight despite efforts to limit caloric intake and increase physical activity. Evidence suggests that chemical exposures early in life can predispose individuals to weight gain through programming changes, which may enhance dysfunctional eating behaviors later in life. This review examines the latest research on the obesogen hypothesis and its underpinnings in the Developmental Origins of Heath and Disease model. We provide examples of known and suspected obesogens, and evidence of their general mechanisms of action. The research reviewed here provides a solid foundation of knowledge from which health scientists may draw from and build upon to inform their research and decision-making.

Sponsored by the New York Academy of Sciences and Cincinnati Children's Hospital Medical Center, with support from the National Institute of Environmental Health Sciences (NIEHS), the National Institute on Drug Abuse (NIDA), and Life Technologies, "Fetal Programming and Environmental Exposures: Implications for Prenatal Care and Preterm Birth" was held on June 11-12, 2012 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel discussions, highlighted basic, clinical, and translational research approaches, and highlighted the need for specialized testing of drugs, consumer products, and industrial chemicals, with a view to the unique impacts these can have during gestation. Speakers went on to discuss many other factors that affect prenatal development, from genetics to parental diet, revealing the extraordinary sensitivity of the developing fetus.

Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products– including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption.

Oxidative and hypertrophic stresses contribute to the pathogenesis of heart failure. Insulin-like growth factor-1 (IGF-1) is a peptide hormone with a complex post-transcriptional regulation, generating distinct isoforms. Locally acting IGF-1 isoform (mIGF-1) helps the heart to recover from toxic injury and from infarct. In the murine heart, moderate overexpression of the NAD(+)-dependent deacetylase SirT1 was reported to mitigate oxidative stress. SirT1 is known to promote lifespan extension and to protect from metabolic challenges. Circulating IGF-1 and SirT1 play antagonizing biological roles and share molecular targets in the heart, in turn affecting cardiomyocyte physiology. However, how different IGF-1 isoforms may impact SirT1 and affect cardiomyocyte function is unknown. Here we show that locally acting mIGF-1 increases SirT1 expression/activity, whereas circulating IGF-1 isoform does not affect it, in cultured HL-1 and neonatal cardiomyocytes. mIGF-1-induced SirT1 activity exerts protection against angiotensin II (Ang II)-triggered hypertrophy and against paraquat (PQ) and Ang II-induced oxidative stress. Conversely, circulating IGF-1 triggered itself oxidative stress and cardiomyocyte hypertrophy. Interestingly, potent cardio-protective genes (adiponectin, UCP-1 and MT-2) were increased specifically in mIGF-1-overexpressing cardiomyocytes, in a SirT1-dependent fashion. Thus, mIGF-1 protects cardiomyocytes from oxidative and hypertrophic stresses via SirT1 activity, and may represent a promising cardiac therapeutic.

Our recent study defined a new role for SIRT1 as a regulator of hepatic lipid metabolism. In the liver a major target of this sirtuin is the PPARalpha/PGC-1alpha signaling axis. Ablation of SIRT1 in the liver results in disrupted fatty acid oxidation, increased cellular stress, and elevations in proinflammatory cytokines. However, contrary to previous studies, we observed no changes in glucose production in the absence of SIRT1, despite impaired PGC-1alpha signaling. These findings point toward the involvement of other players in SIRT1-regulated hepatic metabolism. Here we discuss our findings, and comment on some of the controversy surrounding this protein in the current literature.

Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates lipid homeostasis by positively regulating peroxisome proliferators-activated receptor alpha (PPARalpha), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPARalpha signaling and decreases fatty acid beta-oxidation, whereas overexpression of SIRT1 induces the expression of PPARalpha targets. SIRT1 interacts with PPARalpha and is required to activate PPARalpha coactivator PGC-1alpha. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases.

Retinoic acid (RA) displays potent anticarcinogenic activities that are mediated by the nuclear retinoic acid receptors (RARs). However, use of RA in oncology is limited by RA resistance acquired during carcinogenesis. Moreover, in some cancers, RA facilitates rather than inhibits growth. A clue to this paradoxical behavior was recently suggested by the findings that RA also activates PPARβ/δ, a receptor involved in mitogenic and anti-apoptotic activities. The observations that partitioning of RA between its two receptors is regulated by two intracellular lipid-binding proteins—CRABP-II, which targets RA to RAR, and FABP5, which delivers it to PPARβ/δ—further suggest that RA resistance may stem from the deregulation of the binding proteins, resulting in activation of PPARβ/δ rather than RAR. Here, we show that, in the RA-resistant mouse model of breast cancer MMTV-neu , RA indeed activates the nonclassical RA receptor PPARβ/δ. This behavior was traced to an aberrantly high intratumor FABP5/CRABP-II ratio. Decreasing this ratio in mammary tissue diverted RA from PPARβ/δ to RAR and suppressed tumor growth. The data demonstrate the existence of a mechanism that underlies RA resistance in tumors, indicate that CRABP-II functions as a tumor suppressor, and suggest that the inhibition of FABP5 may comprise a therapeutic strategy for overcoming RA resistance in some tumors.

© 2015 Heindel et al. A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16-18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as "metabolic disruptors", in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.

Both the National Institute of Environmental Health Sciences (NIEHS) and the U.S. Food and Drug Administration (FDA) work to promote and protect public health. The NIEHS achieves this mission by conducting research, including toxicological studies, on agents of public health concern through its intramural laboratories, the National Toxicology Program (NTP), grants and contracts to research labs across the country, and interagency agreements. The FDA, in turn, reviews and uses information from these and other studies and, where needed, performs studies of its own to develop standards to ensure that the products it regulates meet its requirements, maximizing product benefits while protecting the public from unacceptable risks. The FDA and NIEHS have a long history of working together to generate and evaluate toxicological data necessary both for setting standards and for informing important regulatory decisions. For example, collaborative research projects between the NTP (itself a collaboration involving the National Institutes of Health, FDA, and Centers for Disease Control and Prevention) and the FDA National Center for Toxicological Research (NCTR) have contributed to safety determinations and regulation of a number of ingredients in dietary supplements, animal feed, and cosmetics and have been important for assessing potential risks of both human and veterinary pharmaceuticals (NTP 2013). For several years, the NIEHS and FDA have been working collaboratively to address potential health concerns about bisphenol A (BPA), a chemical used in manufacturing the packaging of some foods and beverages, in some medical devices, and in some thermal papers. In September 2008, the NTP completed a review of available research on BPA and concluded that there was “some concern for effects on the brain, behavior, and prostate gland in fetuses, infants, and children at current human exposures.” The NTP report also recognized the existence of substantial uncertainties, stating that “Overall, the current literature cannot yet be fully interpreted for biological or experimental consistency or for relevance to human health” [NTP-Center for the Evaluation of Risks to Human Reproduction (CERHR) 2008]. In 2008, the FDA, which has regulatory authority over many consumer and medical products containing BPA, issued a draft assessment of BPA (FDA 2008). In 2009, the FDA provided additional updates to the assessment and expressed its agreement with the the NTP’s perspective (FDA 2013). The FDA, like the NTP, also identified substantial uncertainties both in reported BPA research findings and in their implications for human health. Both agencies called for further research focused on key questions about BPA to help address and reduce these uncertainties. Since that time, the FDA and NIEHS have worked both independently and collaboratively to address areas of concern and to reduce uncertainties, including collaboration to enhance the relevance and usefulness of planned research in assessing potential risks to human health. These collaborative efforts have resulted in a number of important advances in our understanding of BPA. Both the focus and careful planning of the research, as well as the research findings themselves, are highly relevant for approaching other similar issues. Important accomplishments include technological and methodological advances in critical assays [e.g., determining levels of the active form of BPA in blood (Patterson et al. 2013)] and assuring strong study design, performance, and analysis, including carefully addressing considerations such as control groups and statistical analysis (Delclos 2013). The FDA/NCTR and the NIEHS Clinical Research Unit have incorporated these advances and perspectives in planning and carrying out a comprehensive investigation of BPA pharmacokinetics in human volunteers. The FDA/NIEHS collaboration has also more generally supported approaches to the design and conduct of studies that enhance study utility and reliability for supporting sound decision making. We have worked together to support both large-scale regulatory studies that examine multiple biological end points of concern, and new and unprecedented collaborations between academic and regulatory scientists that enable smaller-scale exploratory studies of mechanistic and other end points not traditionally evaluated in regulatory toxicological studies. The results of our collaborations to date have been especially important in improving the understanding of how BPA is metabolized and handled once in the body. This has greatly reduced key uncertainties concerning potential levels of internal exposure in humans. For example, we have learned that newborn and young rodents have significant age-dependent differences in metabolic capabilities, resulting in their not being able to metabolize BPA as well as adult rodents do and thus being exposed to higher levels internally; this is not the case for nonhuman primates (Doerge et al. 2010). Multiple pharmacokinetic studies in monkeys (supported by preliminary results in humans) have now demonstrated that newborn and young primates metabolize BPA at or very near the level of adult metabolism (Fisher et al. 2011; Patterson et al. 2013). Additional collaborative studies in pregnant primates have also shown both that potential fetal exposure is significantly reduced by the mother’s metabolic capabilities and that the fetus can effectively metabolize BPA (Doerge et al. 2010; Patterson et al. 2013). Through the combined and collaborative efforts of the NIEHS and FDA, many important questions surrounding BPA and risks to human health have been or will be addressed in the near future. The promise of this collaborative approach between FDA regulatory researchers and NIEHS academic researchers extends well beyond BPA. It represents a new model for filling knowledge gaps and enhancing the value of investments in research, developing and promoting best methods and practices, informing chemical risk assessment, and identifying new methods or end points with the potential to improve regulatory hazard assessments and enhance protection of humans. The goal of all our efforts is to support and perform the best science we can to inform the best possible decision making. Strong science is the common ground that can help us—particularly in situations of controversy where emotions and beliefs may become strong and positions polarized—to work together to accomplish what we all want to accomplish, keeping the public safe. Everyone involved in collaborative research has a role to play in building our understanding of the potential biological and/or health effects of substances and advancing technologies and methodologies, with the shared goal of protecting the public health.

Fetal and early postnatal development constitutes the most vulnerable time period of human life in regard to adverse effects of environmental hazards. Subtle effects during development can lead to functional deficits and increased disease risk later in life. The hypothesis stating that environmental exposures leads to altered programming and, thereby, to increased susceptibility to disease or dysfunction later in life has garnered much support from both experimental and epidemiological studies. Similar observations have been made on the long-term impact of nutritional unbalance during early development. In an effort to bridge the fields of nutritional and environmental developmental toxicity, the Society of Toxicology sponsored this work. This report summarizes novel findings in developmental toxicity as reported by select invited experts and meeting attendees. Recommendations for the application and improvement of current and future research efforts are also presented.

Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator-activated receptor α (PPARα) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism.

The prevalence of obesity and diabetes has risen dramatically in the United States and in other regions of the world over the past two decades. Perhaps even more important is that these metabolic diseases are rising dramatically in our children. There is considerable evidence that the risk factors for obesity and diabetes may begin early in life, during pregnancy, and in early childhood. Evidence shows that rapid weight gain in the first few months of life is associated with obesity later in life. Obesity and diabetes, like other complex diseases, are caused by a series of interactions between genetic, behavioral, and environmental factors. While there are certainly important genetic and lifestyle components contributing to obesity and diabetes, evidence also points to a contributing role of environmental influences, particularly exposure to endocrine disrupting chemicals during periods of development. Here we review current epidemiological and experimental relationships between these chemicals, their mechanisms of action, and the role of environmental exposures in the obesity and diabetes epidemic.

Sirtuin 1 (SIRT1), the mammalian ortholog of yeast Sir2, is a highly conserved NAD(+)-dependent protein deacetylase that has emerged as a key metabolic sensor that directly links environmental nutrient signals to animal metabolic homeostasis. SIRT1 is known to be involved in gluconeogenesis in the liver, fat mobilization in white adipose tissue, and insulin secretion in the pancreas. Recent studies have shown SIRT1 to regulate fatty acid oxidation in the liver, sense nutrient availability in the hypothalamus, influence obesity-induced inflammation in macrophages, and modulate the activity of the circadian clock in metabolic tissues. The activity of SIRT1 also appears to be under the control of AMPK and adiponectin. This review focuses on the involvement of SIRT1 in regulating metabolic diseases associated with obesity. It includes brief overviews of sirtuin signaling, with emphasis on SIRT1's role in the liver, macrophage, brain, and adipose tissue as it relates to obesity.

Obesity rates have risen steadily in the United States and around the world over the past century, with a marked escalation within the past two decades. Conventional wisdom within the medical community is that the burgeoning obesity epidemic is the product of poor nutrition and lack of exercise, but increasingly researchers are questioning whether those factors are wholly responsible. Emerging research about alternative factors is setting the stage for today’s “Perfect Storm” for obesity.