Obesity and metabolic syndrome diseases have exploded into a global epidemic. Consumption of calorie-dense food and diminished physical activity are the generally accepted causes for obesity. But, could environmental factors expose preexisting genetic differences or exacerbate the root causes of diet and exercise? The environmental obesogen model proposes that chemical exposure during critical developmental stages influences subsequent adipogenesis, lipid balance and obesity. Obesogens are chemicals that stimulate adipogenesis and fat storage or alter the control of metabolism, appetite and satiety to promote weight gain. Tributyltin (TBT) is a high-affinity agonistic ligand for the retinoid X receptor (RXR) and peroxisome proliferator activated receptor gamma (PPARγ). RXR-PPARγ signaling is a key component in adipogenesis and the function of adipocytes; activation of this heterodimer increases adipose mass in rodents and humans. Thus, inappropriate activation of RXR-PPARγ can directly alter adipose tissue homeostasis. TBT exposure promoted adipocyte differentiation, modulated adipogenic genes and increased adiposity in mice after in utero exposure. These results suggest that organotin exposure is a previously unappreciated risk factor for the development of obesity and related disorders. Based on the observed effects of TBT on adipogenesis, we hypothesized that organotin exposure during prenatal adipose tissue development would create an environment that led to more adipocytes. We observed that the multipotent stromal cell compartment was altered by prenatal TBT exposure leading to an increased number of preadipocytes. This increase in the number of preadipocytes could correspondingly increase the steady state number of adipocytes in the adult, which could favor the development of obesity over time.

The discovery of a rare clear cell carcinoma of the vagina in young women gestationally exposed to the estrogen diethylstilbestrol (DES) lent empirical support to the hypothesis that prenatal exposure to xenoestrogens might cause cancer. This fact contradicted two well-accepted notions: (i) mammalian development was merely the unfolding of a genetic program and (ii) only mutagenic agents could cause cancer. The ecological developmental biology (eco–devo) movement revitalized the concept of developmental plasticity through the occurrence of polyphenisms whereby a single genotype produces diverse phenotypes which are determined by environmental cues. Based on the principles of eco–devo and the tissue organization field theory of carcinogenesis, we hypothesized that developmental exposure to xenoestrogens increased the propensity to develop mammary cancer during adulthood. Bisphenol-A (BPA), a ubiquitous xenoestrogen, was chosen as a model for environmental estrogen exposure. In mice, perinatal exposure to environmentally relevant BPA levels induced alterations of the mammary gland architecture which manifested during fetal morphogenesis and throughout life, including the development of pre-neoplastic lesions. In rats, gestational exposure to BPA induced pre-neoplastic lesions and carcinoma in situ that manifested in adulthood in the absence of any additional treatment. Emerging epidemiological data reveal an increased incidence of breast cancer in women exposed to DES during gestation. Hence, both animal experiments and epidemiological data strengthen the hypothesis that fetal exposure to xenoestrogens may be an underlying cause of the increased incidence of breast cancer observed over the past 50 years.

Advanced neuroimaging techniques offer unique insights into how childhood lead exposure impacts the brain. Volumetric magnetic resonance imaging affords anatomical information about the size of global, regional and subcomponent structures within the brain. Diffusion tensor imaging provides information about white matter architecture by quantitatively describing how water molecules diffuse within it. Proton magnetic resonance spectroscopy generates quantitative measures of neuronal, axonal and glial elements via concentration levels of select metabolites. Functional magnetic resonance imaging infers neuronal activity associated with a given task performed. Employing these techniques in the study of the Cincinnati Lead Study, a relatively homogeneous birth cohort longitudinally monitored for over 30 years, one can non-invasively and quantitatively explore how childhood lead exposure is associated with adult brain structure, organization and function. These studies yield important findings how environmental lead exposure impacts human health.

New thinking has arisen about the origin of adult onset diseases stemming from a collective body of evidence commonly referred to as the developmental origins of health and disease. This conceptual paradigm posits that certain adult onset diseases arise during critical or sensitive windows of human development or even transgenerationally. The testicular dysgenesis hypothesis (TDS) postulates an in utero origin for adverse male reproductive outcomes, and is an excellent example of the early origins of the paradigm. Despite similarities in the development of the male and female reproductive tracks, noticeably absent is a collective body of evidence focusing on the plausibility of an early origin for gynecologic outcomes and later onset of adult diseases. Using the TDS paradigm, we synthesized the available literature relative to the ovarian dysgenesis syndrome (ODS), which we define as alterations in ovarian structure or function that may manifest as fecundity impairments, gynecologic disorders, gravid diseases or later onset adult diseases. We evaluated environmental exposures, particularly the role of endocrine disrupting chemicals, in relation to these outcomes, and found evidence (although fragmented) consistent with an in utero origin of gynecologic outcomes, which in turn is associated with later onset of adult diseases. The findings are interpreted within the ODS paradigm while delineating methodological challenges and future research opportunities designed to answer critical data gaps regarding the origin of fecundity, gravid health and chronic diseases affecting the female population.

Exposure of fetuses to endocrine disrupting chemicals (EDCs), such as the estrogenic drug diethylstilbestrol (DES), disrupts development of the reproductive system and affects other aspects of adult phenotype including diseases, consistent with the developmental origins of health and disease hypothesis. To determine whether diet could influence the effects of DES, we compared mice fed a commonly used combination of soy-based Purina 5008 (breeding and lactation) and 5001 (post-weaning) with mice fed soy-based Purina 5002 throughout life. We exposed fetal CD-1 mice (F1) in utero on different feeds to a 0 (controls), low (0.1 μg/kg/day) or high (50 μg/kg/day) dose of DES via feeding the dam (F0) on gestation days 11–17. Compared to 5008, 5002 feed significantly increased serum estradiol in control fetuses. On 5008 (but not 5002) feed, DES significantly increased fetal serum estradiol at a low dose and reduced it at a high dose. Diet influenced the effects of in utero DES on F1 female onset of puberty and the uterine response to estradiol (an inverted-U dose–response relationship seen for DES on uterine weight with 5008/5001 feed was not observed with 5002). Both low- and high-dose DES reduced daily sperm production (DSP) in adult F1 males on 5008/5001 feed, whereas males fed 5002 showed no DES-induced reduction in DSP. Thus, we observed a number of low-dose effects of in utero DES exposure on Purina 5008/5001 feed that were not observed using Purina 5002, a feed commonly used in industry-funded toxicological studies conducted for regulatory purposes.

Exposure to environmental chemicals and other environmental stressors have health impacts on the fetus that may not be apparent until later in life. The concept of developmental origins of disease should be expanded to include these early life exposures in addition to the effects of nutrition and maternal factors. This paper will describe the toxicological, biological and epidemiological issues that are pertinent to conducting research on environmental exposures early in life and their health consequences over the life span.

Epidemiological studies suggest that glucocorticoid excess in the fetus may contribute to the pathophysiology of cardiovascular diseases in adulthood. However, the impact of maternal glucocorticoid on the cardiovascular system of the offspring has not been much explored in studies involving humans, especially in childhood. The objective of this study was to assess the influence of maternal cortisol concentrations on child arterial elasticity. One hundred and thirty pregnant women followed from 1997 to 2000, and respective children 5–7 years of age followed from 2004 to 2006 were included in the study. Maternal cortisol was determined in saliva by an enzyme immunoassay utilizing the mean concentration of nine samples of saliva. Arterial elasticity was assessed by the large artery elasticity index (LAEI; the capacitive elasticity of large arteries) by recording radial artery pulse wave, utilizing the equipment HDI/PulseWave CR-2000 Cardiovascular Profiling System®. The nutritional status of the children was determined by the body mass index (BMI). Insulin concentration was assessed by chemiluminescence, and insulin resistance by the homeostasis model assessment. Blood glucose, total cholesterol and fractions (LDL-c and HDL-c) and triglyceride concentrations were determined by automated enzymatic methods. The association between maternal cortisol and child arterial elasticity was assessed by multivariate linear regression analysis. There was a statistically significant association between maternal cortisol and LAEI (P = 0.02), controlling for birth weight, age, BMI and HDL-c of the children. This study suggests that exposure to higher glucocorticoid concentrations in the prenatal period is associated to lower arterial elasticity in childhood, an earlier cardiovascular risk marker.

Maternal obesity during pregnancy is often characterized by fetal macrosomia but it can also result in fetal growth restriction in a subset of pregnancies. We hypothesized that mechanisms of this growth restriction may include adverse effects of maternal high fat (HF) intake on placental growth and function. Female rats (100 days old) were time-mated and randomly assigned to either a control (Con) or HF diet ad libitum throughout gestation. At E21, dams were killed; litter size and fetal and placental weights were recorded and maternal and fetal samples collected for further analyses. The HF diet resulted in a 54% increase in maternal body weight gain during gestation. In contrast, male and female fetal weights were reduced in HF pregnancies (P < 0.05), as were the weights of the junctional zone of the placenta (P = 0.013), whereas labyrinth zone weights were unaffected. The HF diet increased maternal and fetal plasma leptin levels (P < 0.05), but maternal and fetal insulin and fetal glucose levels were unaffected. Labyrinthine expression of PPARγ and total VEGFa mRNA, both markers of placental vascular development, were unaffected by consumption of the HF diet in placentas of male and female fetuses. Furthermore, maternal HF nutrition did not alter phosphorylated protein levels of either mammalian target of rapamycin or its downstream signaling factor eIF4E binding protein 1 (4E-BP1). These data show that in the rat, maternal HF nutrition results in fetal and placental junctional zone growth restriction, maternal and fetal hyperleptinemia but did not alter gene expression of markers of placental vascular development.