Standardizing Extracted Data Using Automated Application of Controlled Vocabularies.

BACKGROUND: Extraction of toxicological end points from primary sources is a central component of systematic reviews and human health risk assessments. To ensure optimal use of these data, consistent language should be used for end point descriptions. However, primary source language describing treatment-related end points can vary greatly, resulting in large labor efforts to manually standardize extractions before data are fit for use. OBJECTIVES: To minimize these labor efforts, we applied an augmented intelligence approach and developed automated tools to support standardization of extracted information via application of preexisting controlled vocabularies. METHODS: We created and applied a harmonized controlled vocabulary crosswalk, consisting of Unified Medical Language System (UMLS) codes, German Federal Institute for Risk Assessment (BfR) DevTox harmonized terms, and The Organization for Economic Co-operation and Development (OECD) end point vocabularies, to roughly 34,000 extractions from prenatal developmental toxicology studies conducted by the National Toxicology Program (NTP) and 6,400 extractions from European Chemicals Agency (ECHA) prenatal developmental toxicology studies, all recorded based on the original study report language. RESULTS: We automatically applied standardized controlled vocabulary terms to 75% of the NTP extracted end points and 57% of the ECHA extracted end points. Of all the standardized extracted end points, about half (51%) required manual review for potential extraneous matches or inaccuracies. Extracted end points that were not mapped to standardized terms tended to be too general or required human logic to find a good match. We estimate that this augmented intelligence approach saved >350 hours of manual effort and yielded valuable resources including a controlled vocabulary crosswalk, organized related terms lists, code for implementing an automated mapping workflow, and a computationally accessible dataset. DISCUSSION: Augmenting manual efforts with automation tools increased the efficiency of producing a findable, accessible, interoperable, and reusable (FAIR) dataset of regulatory guideline studies. This open-source approach can be readily applied to other legacy developmental toxicology datasets, and the code design is customizable for other study types. https://doi.org/10.1289/EHP13215.

Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) has increased in prevalence in the past decade. Studies attempting to identify a specific genetic component have not been able to account for much of the heritability of ADHD, indicating there may be gene-environment interactions underlying the disorder, including early exposure to environmental chemicals. Based on several relevant studies, we chose to examine bisphenol A (BPA) as a possible contributor to ADHD in humans. BPA is a widespread environmental chemical that has been shown to disrupt neurodevelopment in rodents and humans. OBJECTIVES: Using the Office of Health Assessment and Translation (OHAT) framework, a systematic review and meta-analysis was designed to determine the relationship between early life exposure to BPA and hyperactivity, a key diagnostic criterion of ADHD. DATA SOURCES: Searches of PubMed, Web of Science, and Toxline were completed for all literature to January 1, 2017. STUDY ELIGIBILITY CRITERIA: For inclusion, the studies had to publish original data, be in the English language, include a measure of BPA exposure, and assess if BPA exposure affected hyperactive behaviors in mice, rats or humans. Exposure to BPA had to occur at <3 months of age for humans, up to postnatal day 35 for rats and up to postnatal day 40 for mice. Exposure could occur either gestationally (via maternal exposure) or directly to the offspring. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies were evaluated using the OHAT risk of bias tool. The effects in humans were assessed qualitatively. For rodents exposed to 20 µg/kg/day BPA, we evaluated the study findings in a random effects meta-analytical model. RESULTS: A review of the literature identified 29 rodent and 3 human studies. A random effects meta-analysis showed significantly increased hyperactivity in male rodents. In humans, early BPA exposure was associated with hyperactivity in boys and girls. LIMITATIONS, CONCLUSIONS, AND IMPLICATIONS OF KEY FINDINGS: We concluded that early life BPA exposure is a presumed human hazard for the development of hyperactivity. Possible limitations of this systematic review include deficiencies in author reporting, exclusion of some literature based on language, and insufficient similarity between human studies. SRs that result in hazard-based conclusions are the first step in assessing and mitigating risks. Given the widespread exposure of BPA and increasing diagnoses of ADHD, we recommend immediate actions to complete such risk analyses and take next steps for the protection of human health. In the meantime, precautionary measures should be taken to reduce exposure in pregnant women, infants and children. The present analysis also discusses potential mechanisms by which BPA affects hyperactivity, and the most effective avenues for future research. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not available.

Melamine, beyond the kidney: A ubiquitous endocrine disruptor and neurotoxicant?

Melamine is commonly used in a variety of consumer products such as furniture, dining ware, and food utensils. The chemical infamously gained worldwide attention by its illegal addition to a variety of foodstuffs in order to falsify protein content, which led to serious, sometimes fatal, health impacts in children and pets. This resulted in a large amount of published primary studies and reviews of the impacts of melamine exposure on kidney function. However, a growing body of literature suggests that melamine may have impacts beyond renal dysfunction. We conducted a scoping review of this literature which yielded more than 40 studies with human, animal, and in vitro findings. Neurological impacts, reproductive function, and anthropometric outcomes were identified as possible candidates for systematic review based on evidence stream and replication of endpoints. The results of this analysis provide a basis for prioritizing future research on health impacts associated with melamine exposure.

Polycyclic aromatic hydrocarbons and female reproductive health: A scoping review.

Polycyclic aromatic hydrocarbons (PAHs) are a class of common persistent environmental pollutants found in water, air, soil, and plants and can be released by natural sources. However, the majority of atmospheric PAHs are from vehicular emissions, coal-burning plants, and the production and use of petroleum-derived substances. Exposure to PAHs has been implicated in cancer and other diseases, including reproductive disorders. This scoping review is a preliminary step that explores the utility and feasibility of completing a systematic review evaluating the effect of PAHs on female reproduction. We performed literature searches in PubMed, Web of Science, and Scopus, then screened, identified, and categorized relevant studies. Our results identified fertility and pregnancy/fetal viability as outcomes with sufficient research for systematic review. In addition to presenting the relevant studies, the review identifies data gaps, and provides the groundwork to develop the most appropriate research questions for systematic review.

Systematic review of community health impacts of mountaintop removal mining.

BACKGROUND: The objective of this evaluation is to understand the human health impacts of mountaintop removal (MTR) mining, the major method of coal mining in and around Central Appalachia. MTR mining impacts the air, water, and soil and raises concerns about potential adverse health effects in neighboring communities; exposures associated with MTR mining include particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), metals, hydrogen sulfide, and other recognized harmful substances. METHODS: A systematic review was conducted of published studies of MTR mining and community health, occupational studies of MTR mining, and any available animal and in vitro experimental studies investigating the effects of exposures to MTR-mining-related chemical mixtures. Six databases (Embase, PsycINFO, PubMed, Scopus, Toxline, and Web of Science) were searched with customized terms, and no restrictions on publication year or language, through October 27, 2016. The eligibility criteria included all human population studies and animal models of human health, direct and indirect measures of MTR-mining exposure, any health-related effect or change in physiological response, and any study design type. Risk of bias was assessed for observational and experimental studies using an approach developed by the National Toxicology Program (NTP) Office of Health Assessment and Translation (OHAT). To provide context for these health effects, a summary of the exposure literature is included that focuses on describing findings for outdoor air, indoor air, and drinking water. RESULTS: From a literature search capturing 3088 studies, 33 human studies (29 community, four occupational), four experimental studies (two in rat, one in vitro and in mice, one in C. elegans), and 58 MTR mining exposure studies were identified. A number of health findings were reported in observational human studies, including cardiopulmonary effects, mortality, and birth defects. However, concerns for risk of bias were identified, especially with respect to exposure characterization, accounting for confounding variables (such as socioeconomic status), and methods used to assess health outcomes. Typically, exposure was assessed by proximity of residence or hospital to coal mining or production level at the county level. In addition, assessing the consistency of findings was challenging because separate publications likely included overlapping case and comparison groups. For example, 11 studies of mortality were conducted with most reporting higher rates associated with coal mining, but many of these relied on the same national datasets and were unable to consider individual-level contributors to mortality such as poor socioeconomic status or smoking. Two studies of adult rats reported impaired microvascular and cardiac mitochondrial function after intratracheal exposure to PM from MTR-mining sites. Exposures associated with MTR mining included reports of PM levels that sometimes exceeded Environmental Protection Agency (EPA) standards; higher levels of dust, trace metals, hydrogen sulfide gas; and a report of increased public drinking water violations. DISCUSSION: This systematic review could not reach conclusions on community health effects of MTR mining because of the strong potential for bias in the current body of human literature. Improved characterization of exposures by future community health studies and further study of the effects of MTR mining chemical mixtures in experimental models will be critical to determining health risks of MTR mining to communities. Without such work, uncertainty will remain regarding the impact of these practices on the health of the people who breathe the air and drink the water affected by MTR mining.

Potential Developmental and Reproductive Impacts of Triclocarban: A Scoping Review.

Triclocarban (TCC) is an antimicrobial agent used in personal care products. Although frequently studied with another antimicrobial, triclosan, it is not as well researched, and there are very few reviews of the biological activity of TCC. TCC has been shown to be a possible endocrine disruptor, acting by enhancing the activity of endogenous hormones. TCC has been banned in the US for certain applications; however, many human populations, in and outside the US, exhibit exposure to TCC. Because of the concern of the health effects of TCC, we conducted a scoping review in order to map the current body of literature on the endocrine, reproductive, and developmental effects of TCC. The aim of this scoping review was to identify possible endpoints for future systematic review and to make recommendations for future research. A search of the literature until August 2017 yielded 32 relevant studies in humans, rodents, fish, invertebrates, and in vitro. Based on the robustness of the literature in all three evidence streams (human, animal, and in vitro), we identified three endpoints for possible systematic review: estrogenic activity, androgenic activity, and offspring growth. In this review, we describe the body of evidence and make recommendations for future research.

Bisphenol S and F: A Systematic Review and Comparison of the Hormonal Activity of Bisphenol A Substitutes.

BACKGROUND: Increasing concern over bisphenol A (BPA) as an endocrine-disrupting chemical and its possible effects on human health have prompted the removal of BPA from consumer products, often labeled "BPA-free." Some of the chemical replacements, however, are also bisphenols and may have similar physiological effects in organisms. Bisphenol S (BPS) and bisphenol F (BPF) are two such BPA substitutes. OBJECTIVES: This review was carried out to evaluate the physiological effects and endocrine activities of the BPA substitutes BPS and BPF. Further, we compared the hormonal potency of BPS and BPF to that of BPA. METHODS: We conducted a systematic review based on the Office of Health Assessment and Translation (OHAT) protocol. RESULTS: We identified the body of literature to date, consisting of 32 studies (25 in vitro only, and 7 in vivo). The majority of these studies examined the hormonal activities of BPS and BPF and found their potency to be in the same order of magnitude and of similar action as BPA (estrogenic, antiestrogenic, androgenic, and antiandrogenic) in vitro and in vivo. BPS also has potencies similar to that of estradiol in membrane-mediated pathways, which are important for cellular actions such as proliferation, differentiation, and death. BPS and BPF also showed other effects in vitro and in vivo, such as altered organ weights, reproductive end points, and enzyme expression. CONCLUSIONS: Based on the current literature, BPS and BPF are as hormonally active as BPA, and they have endocrine-disrupting effects. CITATION: Rochester JR, Bolden AL. 2015. Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes.

Bisphenol A and human health: a review of the literature.

There is growing evidence that bisphenol A (BPA) may adversely affect humans. BPA is an endocrine disruptor that has been shown to be harmful in laboratory animal studies. Until recently, there were relatively few epidemiological studies examining the relationship between BPA and health effects in humans. However, in the last year, the number of these studies has more than doubled. A comprehensive literature search found 91 studies linking BPA to human health; 53 published within the last year. This review outlines this body of literature, showing associations between BPA exposure and adverse perinatal, childhood, and adult health outcomes, including reproductive and developmental effects, metabolic disease, and other health effects. These studies encompass both prenatal and postnatal exposures, and include several study designs and population types. While it is difficult to make causal links with epidemiological studies, the growing human literature correlating environmental BPA exposure to adverse effects in humans, along with laboratory studies in many species including primates, provides increasing support that environmental BPA exposure can be harmful to humans, especially in regards to behavioral and other effects in children.

Opposite-sex housing reactivates the declining GnRH system in aged transgenic male mice with FGF signaling deficiency.

The continued presence of gonadotropin-releasing hormone (GnRH) neurons is required for a healthy reproductive lifespan, but factors that maintain postnatal GnRH neurons have not been identified. To begin to understand these factors, we investigated whether 1) fibroblast growth factor (FGF) signaling and 2) interactions with the opposite sex are involved in the maintenance of the postnatal GnRH system. A transgenic mouse model (dnFGFR mouse) with the targeted expression of a dominant-negative FGF receptor (dnFGFR) in GnRH neurons was used to examine the consequence of FGF signaling deficiency on postnatal GnRH neurons. Male dnFGFR mice suffered a significant loss of postnatal GnRH neurons within the first 100 days of life. Interestingly, this loss was reversed after cohabitation with female, but not male, mice for 300-550 days. Along with a rescue in GnRH neuron numbers, opposite-sex housing in dnFGFR males also increased hypothalamic GnRH peptide levels, promoted a more mature GnRH neuronal morphology, facilitated litter production, and enhanced testicular morphology. Last, mice hypomorphic for FGFR3 exhibited a similar pattern of postnatal GnRH neuronal loss as dnFGFR males, suggesting FGF signaling acts, in part, through FGFR3 to enhance the maintenance of the postnatal GnRH system. In summary, we have shown that FGF signaling is required for the continued presence of postnatal GnRH neurons. However, this requirement is not absolute, since sexual interactions can compensate for defects in FGFR signaling, thereby rescuing the declining GnRH system. This suggests the postnatal GnRH system is highly plastic and capable of responding to environmental stimuli throughout adult life.

Fibroblast growth factor signaling in the developing neuroendocrine hypothalamus.

Fibroblast growth factor (FGF) signaling is pivotal to the formation of numerous central regions. Increasing evidence suggests FGF signaling also directs the development of the neuroendocrine hypothalamus, a collection of neuroendocrine neurons originating primarily within the nose and the ventricular zone of the diencephalon. This review outlines evidence for a role of FGF signaling in the prenatal and postnatal development of several hypothalamic neuroendocrine systems. The emphasis is placed on the nasally derived gonadotropin-releasing hormone neurons, which depend on neurotrophic cues from FGF signaling throughout the neurons' lifetime. Although less is known about neuroendocrine neurons derived from the diencephalon, recent studies suggest they also exhibit variable levels of dependence on FGF signaling. Overall, FGF signaling provides a broad spectrum of cues that ranges from genesis, cell survival/death, migration, morphological changes, to hormone synthesis in the neuroendocrine hypothalamus. Abnormal FGF signaling will deleteriously impact multiple hypothalamic neuroendocrine systems, resulting in the disruption of diverse physiological functions.

Post-hatch oral estrogen in zebra finches (Taeniopygia guttata): is infertility due to disrupted testes morphology or reduced copulatory behavior?

Previous studies show that post-hatch oral exposure of zebra finches to estradiol benzoate compromises male fertility, but the basis of the infertility is not clear. In this study, zebra finch nestlings were orally dosed with estradiol benzoate (at 1, 10, or 100 nmol/g BW per day, post-hatch days 5 to 11 [EB1, EB10, and EB100, respectively]). EB10 and EB100 males exhibited no significant differences in the frequency of mounting behavior (compared to canola oil [vehicle]-treated controls), when observed for six weeks as adults in communal breeding cages with similarly treated females; EB1 males showed reduced mounting behavior compared to controls (p<0.05). EB- and control-treated adult pairs were subsequently co-housed in a communal breeding trial to determine the extent of parentage outside the established pair-bond. Microsatellite analysis was consistent with EB-treated males having lower success than controls in obtaining paternity outside the established pair-bond. Histological examination of testes revealed dose-related disruption of normal morphology: disrupted basal-to-lumen laminarity of spermatogenesis stages, increased vacuolization within seminiferous tubules, decreased sperm aggregation and decreased spermatid density. Additionally, EB100 and control males were housed individually, implanted with testosterone propionate (TP) and presented with a female 3, 5, 9, and 11 days post-implantation for assessment of male sexual behavior. EB-treated, TP-implanted birds showed a slight decrease in mounting and singing behavior on day 5 after implantation; other male courtship behaviors (display, solicitation) were unaffected. Taken together, these results suggest that infertility in male zebra finches resulting from early oral estrogen exposure is more likely due to disrupted testicular morphology than altered sexual behavior.

Gonadotropin-releasing hormone-like molecule is not an acute reproductive activator in the gastropod, Aplysia californica.

Gonadotropin-releasing hormone (GnRH) is indispensable for reproductive activation in all vertebrates. Although several GnRH-like molecules have been isolated from non-chordates, the function of GnRH in these taxa remains unclear. We previously isolated the full-length cDNA sequence of a prohormone containing a GnRH-like molecule, termed ap-GnRH, from the gastropod mollusk, Aplysia californica. In this study, we characterized the distribution and quantity of ap-GnRH peptide in several central and peripheral tissues of A. californica. Further, we performed in vivo and in vitro studies to explore the function of ap-GnRH in these animals. Immunohistochemistry and radioimmunoassay using specific antisera against ap-GnRH showed that pedal ganglia contained the highest level of ap-GnRH peptide, followed by cerebral ganglia, abdominal ganglia, and then buccal ganglia. Ovotestis did not contain detectable levels of ap-GnRH peptide. Injection of sexually mature and immature animals with synthetic ap-GnRH over a course of 10-14 days had no effects on ovotestis mass, reproductive tract mass, egg-laying, and penile eversion. ap-GnRH also failed to alter oocyte growth and egg-laying hormone accumulation and secretion. Interestingly, ap-GnRH injection triggered acute behavioral responses including the stimulation of parapodial opening, inhibition of feeding, and promotion of substrate attachment. Our results showed that in A. californica, ap-GnRH could modulate a wide range of behavioral attributes. Most strikingly, ap-GnRH is not involved in the acute activation of reproduction in a fashion similar to vertebrate GnRH.

Phytoestrogens and avian reproduction: Exploring the evolution and function of phytoestrogens and possible role of plant compounds in the breeding ecology of wild birds.

Phytoestrogens are secondary plant compounds, which can act to mimic estrogen and cause the disruption of estrogenic responses in organisms. Although there is a substantial body of research studying phytoestrogens, including their mechanisms of estrogenic effects, evolution, and detection in biological systems, little is known about their ecological significance. There is evidence, however, that an ecological relationship involving phytoestrogens exists between plants and animals-plants may produce phytoestrogens to reduce fecundity of organisms that eat them. Birds and other vertebrates may also exploit phytoestrogens to regulate their own reproduction-there are well known examples of phytoestrogens inhibiting reproduction in higher vertebrates, including birds. Also, common plant stressors (e.g., high temperature) increase the production of secondary plant compounds, and, as evidence suggests, also induce phytoestrogen biosynthesis. These observations are consistent with the single study ever done on phytoestrogens and reproduction in wild birds [Leopold, A.S., Erwin, M., Oh, J., Browning, B., 1976. Phytoestrogens adverse effects on reproduction in California quail. Science 191, 98-100.], which found that drought stress correlated with increased levels of phytoestrogens in plants, and that increased phytoestrogen levels correlated with decreased young. This review discusses the hypothesis that plants may have an effect on the reproduction of avian species by producing phytoestrogens as a plant defense against herbivory, and that birds may "use" changing levels of phytoestrogens in the vegetation to ensure that food resources will support potential young produced. Evidence from our laboratory and others appear to support this hypothesis.

Dietary red clover (Trifolium pratense) induces oviduct growth and decreases ovary and testes growth in Japanese quail chicks.

To determine whether drought-stress alters phytoestrogens in red clover and whether red clover in the diet influences sexual development in Japanese quail, we fed chicks diets containing irrigated or non-irrigated clover. Irrigation altered phytoestrogenic activity of red clover (determined using an in vitro bioassay), with extracts of irrigated clover diet containing more estrogenic activity than extracts of non-irrigated clover diet. Chick growth was negatively correlated with the amount of irrigated or non-irrigated clover in the diet. Dietary red clover also depressed both absolute and relative gonad weights; however, relative oviduct weight was increased by the irrigated diet. Diets did not affect serum vitellogenin. These results reveal a negative influence of drought-stress on phytoestrogenic potency of clover, and that red clover in the diet can inhibit avian growth and development independent of irrigation state. Thus, phytoestrogens may affect reproductive development in wild birds, and environmental stressors may influence levels of phytoestrogens in the field.

Post-hatch oral estrogen exposure reduces oviduct and egg mass and alters nest-building behavior in adult zebra finches (Taeniopygia guttata).

In addition to well recognized effects on the zebra finch song system, we previously showed that post-hatch oral estrogen and xenoestrogen exposure disrupts reproduction by increasing eggshell breakage in females and decreasing fertility in males. Here we show that post-hatch exposure to estradiol benzoate (by oral gavage on days 5 to 11) at a 100 nmol EB per g body mass dose (EB100) also reduces adult oviduct mass. Further, EB100 and doses two orders of magnitude lower (EB10, EB1) reduce egg mass and length. Similar to the induction of song-control nuclei in females, dosing with EB10 and EB100 increased and masculinized another highly differentiated behavior: nest-building. Zebra finches orally exposed as chicks were observed during reproductive trials in communal breeding cages for 4 or 6weeks duration. EB100 males and females and EB10 males showed increased nest-building behaviors. Further, EB10 and EB100 birds had larger nests than canola oil-treated controls, and EB100 birds had faster rates of nest-building than controls, while EB1 birds had significantly slower rates of nest-building than controls. Additionally, EB100 males and females also showed an increased preference for a coarser male-typical nest-building material (jute) over a finer, female-typical material (wool), suggesting a masculinization of nest-building behavior at the higher doses. The change in zebra finch nest-building behavior induced by early EB exposure suggests that nest size and quality, in addition to egg mass and length, may provide new endpoints for assessing avian exposure to xeno- and phyto-estrogens in wild birds.