Thea M. Edwards

Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing

OBJECTIVE To evaluate the possible role of endocrine-disrupting compounds (EDCs) on female reproductive disorders emphasizing developmental plasticity and the complexity of endocrine-dependent ontogeny of reproductive organs. Declining conception rates and the high incidence of female reproductive disruptions warrant evaluation of the impact of EDCs on female reproductive health. DESIGN Publications related to the contribution of EDCs to disorders of the ovary (aneuploidy, polycystic ovary syndrome, and altered cyclicity), uterus (endometriosis, uterine fibroids, fetal growth restriction, and pregnancy loss), breast (breast cancer, reduced duration of lactation), and pubertal timing were identified, reviewed, and summarized at a workshop. CONCLUSION(S) The data reviewed illustrate that EDCs contribute to numerous human female reproductive disorders and emphasize the sensitivity of early life-stage exposures. Many research gaps are identified that limit full understanding of the contribution of EDCs to female reproductive problems. Moreover, there is an urgent need to reduce the incidence of these reproductive disorders, which can be addressed by correlative studies on early life exposure and adult reproductive dysfunction together with tools to assess the specific exposures and methods to block their effects. This review of the EDC literature as it relates to female health provides an important platform on which womens health can be improved.

Is Nitrate an Ecologically Relevant Endocrine Disruptor in Vertebrates

Abstract The last three decades have brought clear recognition that many populations of animals are experiencing severe declines or local and global extinctions. Many examples have become common knowledge to the general public, such as worldwide declines in amphibian populations and extensive loss of coral reefs. The mechanisms underlying these and other changes are poorly understood. However, a growing literature indicates that a wide array of chemical contaminants have the potential to disrupt normal cell-to-cell signaling mechanisms. A global pollutant of most aquatic systems, nitrate has the potential to be an endocrine disrupting contaminant. This paper reviews studies performed on vertebrates demonstrating that nitrate and/or nitrite have the potential to alter endocrine function. Further, a retrospective study of our work on alligators from various lakes in Florida suggests that nitrate could contribute to some of the altered endocrine parameters previously reported in juvenile animals. We propose hypotheses suggesting that nitrate could alter steroidogenesis by 1) conversion to nitrite and nitric oxide in the mitochondria, the site of initial steroid synthesis, 2) altering Cl− ion concentrations in the cell by substituting for Cl− in the membrane transport pump or 3) binding to the heme region of various P450 enzymes associated with steroidogenesis and altering enzymatic action. Future studies are needed to examine the endocrine disruptive action of this ubiquitous pollutant. A growing literature indicates that all biologists studying natural systems, whether they choose to or not, must now consider contaminant exposure as a direct influence on their studies. That is, ubiquitous global contamination has the potential to alter the endocrine, nervous and immune systems of all organisms with resulting changes in gene expression and phenotypes.

Water quality influences reproduction in female mosquitofish (Gambusia holbrooki) from eight Florida springs

Contamination of freshwater ecosystems with nitrate is a growing global concern. Although nitrate pollution is recognized as a cause of aquatic eutrophication, few studies have examined the possible physiological impacts of nitrate exposure. In this study, we surveyed several reproductive variables of viviparous female Gambusia holbrooki (Poeciliidae) captured from eight springs in Florida. The eight springs represent a gradient of nitrate contamination (1–5 mg/L nitrate–nitrogen). We had two objectives in this study: to describe reproductive biology of female mosquitofish in the springs and to understand reproductive variation in the context of water quality, particularly the nitrate concentration. Our data show a significant negative association between nitrate and both dry weight of developing embryos and rate of reproductive activity among mature females. In addition, variation in Gambusia condition index and embryo number and dry weight was related to temperature variation, and hepatic weight was negatively related to dissolved oxygen concentration. Finally, we observed that many of the measured reproductive variables were interrelated and changeable, depending on gestational stage. Specifically, we provide evidence that maternal support of the embryo occurs at least during the first two thirds of gestation and that female fecundity is affected by an apparent tradeoff between embryo size and embryo number.

Environmental exposures and gene regulation in disease etiology

OBJECTIVE Health or disease is shaped for all individuals by interactions between their genes and environment. Exactly how the environment changes gene expression and how this can lead to disease are being explored in a fruitful new approach to environmental health research, representative studies of which are reviewed here. DATA SOURCES We searched Web of Science and references of relevant publications to understand the diversity of gene regulatory mechanisms affected by environmental exposures with disease implications. DATA SYNTHESIS Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms. Mechanisms include regulation of gene translocation, histone modifications, DNA methylation, DNA repair, transcription, RNA stability, alternative RNA splicing, protein degradation, gene copy number, and transposon activation. Furthermore, chemically induced changes in gene regulation are associated with serious and complex human diseases, including cancer, diabetes and obesity, infertility, respiratory diseases, allergies, and neurodegenerative disorders such as Parkinson and Alzheimer diseases. One of the best-studied areas of gene regulation is epigenetics, especially DNA methylation. Our examples of environmentally induced changes in DNA methylation are presented in the context of early development, when methylation patterns are initially laid down. This approach highlights the potential role for altered DNA methylation in fetal origins of adult disease and inheritance of acquired genetic change. CONCLUSIONS The reviewed studies indicate that genetic predisposition for disease is best predicted in the context of environmental exposures. Second, the genetic mechanisms investigated in these studies offer new avenues for risk assessment research. Finally, we are likely to witness dramatic improvements in human health, and reductions in medical costs, if environmental pollution is decreased.

Environmental influences on fertility: can we learn lessons from studies of wildlife?

Wildlife are good models for understanding the impacts of environmental contamination on fertility because [1] exposure doses are representative of actual contaminant mixtures and concentrations in the environment, [2] wildlife populations are more genetically diverse than laboratory animal populations, and [3] both individual and population level effects of fertility compromise can be observed.

Reproductive physiology of free-living White Ibises (Eudocimus albus) in the Florida Everglades

We measured plasma concentrations of testosterone, estradiol, progesterone, and corticosterone; and recorded changes in gonad size, body condition, molt, and brood patch development of free-living adult White Ibises (Eudocimus albus) during the breeding season in the Florida Everglades. White Ibises are colonially breeding, long-legged wading birds that inhabit freshwater and estuarine wetlands. They have flexible breeding schedules (nest initiation dates can range from January to September) and onset of nesting is usually associated with increased prey availability caused by concentration of small fish in pools during periods of wetland drying. In this paper, we present the hormonal and physical characteristics of White Ibis reproductive physiology. We classified White Ibis breeding into five stages: pre-breeding, display, copulation/egg production, incubation, and chick rearing. White Ibises showed cyclic gonadal development which corresponded to reproductive stage. Male and female testosterone concentrations increased during the display stage and decreased during copulation, incubation, and chick rearing. Female estradiol concentrations were highest during display and chick rearing and male estradiol concentrations were lowest during copulation. Female progesterone concentrations increased during display and remained high throughout the breeding season. Female ibises had low corticosterone concentrations that increased during incubation and were highest during chick rearing, concomitant with lower body condition and flight muscle-mass scores. Male ibis progesterone and corticosterone concentrations did not show seasonal changes and were more variable than concentrations in female ibises at similar stages. Males and females had elevated body condition scores during the display stage, which were depleted by the onset of incubation. Increased energy stores during display may be used later for fasting in male birds that do not eat during the 10-day copulation/egg production stage, and for egg production in female birds. During incubation, male and female ibises developed brood patches. Ibises molted in all stages of reproduction, indicating that ibis molt and reproductive physiology may not inhibit each other as in most temperate bird species. White Ibises showed similar patterns in reproductive physiology to other monogamous, seasonally breeding bird species in which both sexes incubate and care for the young.

Group-Advantaged Training of Research (GATOR): A Metamorphosis of Mentorship

We describe Group-Advantaged Training of Research (GATOR), a yearlong structured program at the University of Florida that guided graduate student mentors and their undergraduate mentees through the mentored research process. Using the national Survey of Undergraduate Research Experiences for an academic year, we found that outcomes for our mentees were similar to those for other programs. We also used an internal survey, combined with qualitative observations, to develop a road map of the mentoring process, which we call the “Metamorphosis of Mentorship.” This model provides tangible steps on the road to becoming a scientist, incorporates reasons mentees stall in research, and suggests ways to overcome mentoring challenges and prevent attrition. The structure and outcomes of this program will be useful to researchers and administrators working to engage undergraduates in scientific research, particularly at large universities where undergraduates are often mentored by graduate students.

Environmentally relevant concentrations of nitrate increase plasma testosterone concentrations in female American alligators (Alligator mississippiensis)

Anthropogenic nitrogen is a ubiquitous environmental contaminant that is contributing to the degradation of freshwater, estuarine, and coastal ecosystems worldwide. The effects of environmental nitrate, a principal form of nitrogen, on the health of aquatic life is of increasing concern. We exposed female American alligators to three concentrations of nitrate (0.7, 10 and 100mg/L NO3-N) for a duration of five weeks and five months from hatch. We assessed growth, plasma sex steroid and thyroid hormone concentrations, and transcription levels of key genes involved in steroidogenesis (StAR, 3β-HSD, and P450scc) and hepatic clearance (Cyp1a, Cyp3a). Exposure to 100mg/L NO3-N for both five weeks and five months resulted in significantly increased plasma testosterone (T) concentrations compared with alligators in the reference treatment. No differences in 17β-estradiol, progesterone, or thyroid hormones were observed, nor were there differences in alligator weight or the mRNA abundance of steroidogenic or hepatic genes. Plasma and urinary nitrate concentrations increased with increasing nitrate treatment levels, although relative plasma concentrations of nitrate were significantly lower in five month, versus five week old animals, possibly due to improved kidney function in older animals. These results indicate that environmentally relevant concentrations of nitrate can increase circulating concentrations of T in young female alligators.

Hormonally-active phytochemicals and vertebrate evolution

Living plants produce a diversity of chemicals that share structural and functional properties with vertebrate hormones. Wildlife species interact with these chemicals either through consumption of plant materials or aquatic exposure. Accumulating evidence shows that exposure to these hormonally active phytochemicals (HAPs) often has consequences for behavior, physiology, and fecundity. These fitness effects suggest there is potential for an evolutionary response by vertebrates to HAPs. Here, we explore the toxicological HAP–vertebrate relationship in an evolutionary framework and discuss the potential for vertebrates to adapt to or even co‐opt the effects of plant‐derived chemicals that influence fitness. We lay out several hypotheses about HAPs and provide a path forward to test whether plant‐derived chemicals influence vertebrate reproduction and evolution. Studies of phytochemicals with direct impacts on vertebrate reproduction provide an obvious and compelling system for studying evolutionary toxicology. Furthermore, an understanding of whether animal populations evolve in response to HAPs could provide insightful context for the study of rapid evolution and how animals cope with chemical agents in the environment.

Taste and physiological responses to glucosinolates: seed predator versus seed disperser.

In contrast to most other plant tissues, fleshy fruits are meant to be eaten in order to facilitate seed dispersal. Although fleshy fruits attract consumers, they may also contain toxic secondary metabolites. However, studies that link the effect of fruit toxins with seed dispersal and predation are scarce. Glucosinolates (GLSs) are a family of bitter-tasting compounds. The fleshy fruit pulp of Ochradenus baccatus was previously found to harbor high concentrations of GLSs, whereas the myrosinase enzyme, which breaks down GLSs to produce foul tasting chemicals, was found only in the seeds. Here we show the differential behavioral and physiological responses of three rodent species to high dose (80%) Ochradenus’ fruits diets. Acomys russatus, a predator of Ochradenus’ seeds, was the least sensitive to the taste of the fruit and the only rodent to exhibit taste-related physiological adaptations to deal with the fruits’ toxins. In contrast, Acomys cahirinus, an Ochradenus seed disperser, was more sensitive to a diet containing the hydrolyzed products of the GLSs. A third rodent (Mus musculus) was deterred from Ochradenus fruits consumption by the GLSs and their hydrolyzed products. We were able to alter M. musculus avoidance of whole fruit consumption by soaking Ochradenus fruits in a water solution containing 1% adenosine monophosphate, which blocks the bitter taste receptor in mice. The observed differential responses of these three rodent species may be due to evolutionary pressures that have enhanced or reduced their sensitivity to the taste of GLSs.