bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Claims for Discovery of Elements 110, 111, 112, 114, 116, and 118 (IUPAC Technical Report)
Authors: Karol P. J. , Nakahara H. , Petley B. W. , Vogt E.
Published: October 2007

The IUPAC/IUPAP Joint Working Party on the priority of claims to the discovery of new elements has reviewed the relevant literature pertaining to several claims. In accordance with the criteria for the discovery of elements, previously established by the 1992 IUPAC/IUPAP Transfermium Working Group, and reinforced by the 1999 IUPAC/IUPAP Joint Working Party, it was determined that the claim by the Hofmann et al. research collaboration for the discovery of element 111 at Gesellschaft für Schwerionenforschung (GSI) has fulfilled those criteria. For elements 112, 114, and 116, the collaborations of Hofmann et al. and of Oganessian et al. produced high-quality data with plausible interpretations. However, confirmation by further results is needed to assign priority of discovery for these elements. The working party was not persuaded that other collaborations have satisfied the discovery criteria.
Name and Symbol of the Element with Atomic Number 110 (IUPAC Recommendations 2003)
Authors: Corish John , Rosenblatt G. M.
Published: October 2007

A joint IUPAC–IUPAP Working Party (JWP) confirmed the discovery of the element with atomic number 110. In accord with IUPAC procedures, the discoverers proposed a name and symbol for the element. The Inorganic Chemistry Division recommended this proposal for acceptance, and it was adopted by the IUPAC Council at Ottawa, 16 August 2003. The recommended name is darmstadtium with symbol Ds.
Nuclear receptor superfamily: Principles of signaling
Authors: Germain Pierre , Altucci Lucia , Bourguet William , Rochette-Egly C. , Gronemeyer Hinrich
Published: October 2007

Nuclear receptors (NRs) comprise a family of 49 members that share a common structural organization and act as ligand-inducible transcription factors with major (patho)physiological impact. For some NRs (“orphan receptors”), cognate ligands have not yet been identified or may not exist. The principles of DNA recognition and ligand binding are well understood from both biochemical and crystal structure analyses. The 3D structures of several DNA-binding domains (DBDs),in complexes with a variety of cognate response elements, and multiple ligand-binding domains (LBDs), in the absence (apoLBD)and presence (holoLBD) of agonist, have been established and reveal canonical structural organization. Agonist binding induces a structural transition in the LBD whose most striking feature is the relocation of helix H12, which is required for establishing a coactivator complex, through interaction with members of the p160 family (SRC1, TIF2, AIB1) and/or the TRAP/DRIP complex. The p160-dependent coactivator complex is a multiprotein complex that comprises histone acetyltransferases (HATs), such as CBP,methyltransferases, such as CARM1, and other enzymes (SUMO ligase,etc.). The agonist-dependent recruitment of the HAT complex results in chromatin modification in the environment of the target gene promoters, which is requisite to, or may in some cases be sufficient for, transcription activation. In the absence of ligands, or in the presence of some antagonists, certain NRs are bound to distinct multiprotein complexes through the interaction with corepressors, such as NCoR and SMRT. Corepressor complexes comprise histone deacetylases (HDACs) that have the capacity to condense chromatin over target gene promoters. Ligands have been designed that selectively modulate the interaction between NRs and their coregulators. Both HATs and HDACs can also modify the acetylation status of nonhistone proteins, but the significance in the context of NR signaling is unclear. NRs communicate with other intracellular signaling pathways on a mutual basis, and their functionality may be altered, positively or negatively, by post-translational modification. The majority of NRs act as retinoid X receptor (RXR) heterodimers in which RXR cannot a priori respond autonomously to its cognate ligand to activate target gene transcription. This RXR subordination allows signaling pathway identity for the RXR partner. The corresponding mechanism is understood and reveals cell and NR selectivity, indicating that RXR can, under certain conditions, act autonomously. NRs are regulators of cell life and death,and NR malfunction can be at the basis of both disease and therapy, as is impressively documented in the case of acute promyelocytic leukemia. Recently, several pathways have been uncovered that link NR action with cell proliferation and apoptosis.
Nuclear receptor coregulators
Authors: McKenna N. J. , O'Malley B. W.
Published: October 2007

It has been postulated that nuclear receptors (NRs) regulate transcription via interactions with chromatin and the basal transcription machinery at the promoters of genes. Coregulators (coactivators or corepressors) are important in mediating these interactions and thereby modulating positive or negative receptor activity. A large number of putative coactivators have been isolated, several of which will be reviewed with respect to certain "criteria" initially proposed for coactivators. We will discuss, with reference to in vitro and in vivo experiments, the main steps in initiation that are influenced by coactivators: (1) initiation (e.g., SRC-1 family, CBP); (2) repetitive transcription (e.g., TRAPs/DRIPs); (3) RNA processing (PGC-1, etc); and (4) termination/turnover (E6-AP, etc). A variety of enzyme functions have been implicated in the coactivator complex including acetylase, methylase, ubiquitin ligase, kinase, and phosphatase activities. Moreover, coactivators and corepressors appear to exist in the steady-state cell as a series of multiprotein complexes referred to collectively as the "coregulatorsome". Different subcomplexes within the coregulatorsome may have different levels of preference for individual receptors or promoters, likely contributing to context-specific functions of NRs in target tissues.
Function and mode of action of nuclear receptors: Estrogen, progesterone, and vitamin D
Authors: Kimbrel E. A. , McDonnell D. P.
Published: October 2007

Estrogens and progestins play important roles in regulating growth and differentiation of a wide range of cell types, in both reproductive and nonreproductive tissues. Not surprisingly, therefore, endocrine active substances that mimic the actions of these steroid hormones have been demonstrated to have untoward effects on the reproductive function of a variety of animals. Although direct links between exposure to endocrine active substances of this class and reproductive abnormalities in humans have been difficult to establish, the potential for harm by this class of chemicals warrants further investigation. This chapter summarizes our current understanding of the molecular pharmacology of the estrogen and progesterone receptors, ER and PR, beginning with a historical perspective of ER pharmacology and ending with a comparison of these receptors to the vitamin D receptor (VDR), a nonsteroid hormone nuclear receptor involved in regulating growth and development in nonreproductive tissues. Major topics discussed include receptor subtypes (or isoforms), receptor functional domains, ligand-binding characteristics, receptor structure, cofactor binding, effects of phosphorylation, and nonclassical modes of action. This discussion will demonstrate the need for developing novel screens for potential endocrine disruptors that incorporate our current understanding of nuclear receptor pharmacology.
Biological function and mode of action of the androgen receptor
Authors: Wilson E. M.
Published: October 2007

Chemical contaminants with antiandrogen or androgen activity have been identified in the environment. The mode of action of these endocrine disruptors derives from their ability to bind to the androgen receptor (AR), a member of the steroid receptor family of nuclear receptors. The AR is a ligand-activated transcription factor with properties unique among members of the steroid receptor family. Binding of endocrine disruptors to the AR impacts its ability to activate or inhibit AR-regulated genes. Most notable of these are the agonist-induced and antagonist-inhibited interdomain interactions that influence AR stability and function. Environmental antiandrogens identified thus far are metabolites of pesticides and herbicides, exerting androgen antagonist effects by blocking AR-induced gene transcription required for male sexual development. Environmental androgens can be precursors of the naturally occurring biologically active androgens testosterone and dihydrotestosterone or result from anabolic steroid use in the livestock industry. They have agonist activity by their ability to bind the AR and mimic the natural hormone, increasing AR-mediated transcription of androgen-responsive genes. The presence of masculinized female fish in polluted rivers indicates the presence of androgen-like pollutants in the environment.
Genetic dissection of gluco- and mineralocorticoid receptor function in mice
Authors: Greiner E. F. , Berger S. , Schütz G.
Published: October 2007

Nuclear hormone receptors function to transduce hormonal signals into transcriptional responses by controlling the activity of specific target genes. These target genes comprise a genetic network whose coordinate activity defines the physiological responses to hormonal signals. Dissecting nuclear hormone receptor functions in vivo by gene inactivation and transgenic strategies represents an invaluable and powerful approach to increase our knowledge of these genetic networks and their physiological functions. Glucocorticoids and mineralocorticoids are involved in numerous physiological processes important to maintain metabolic, cardiovascular, central nervous, and immune system homeostasis. Germline and somatic gene targeting as well as an increased dosage of the glucocorticoid receptor (GR) allows the characterization of the various functions and molecular modes of action of this receptor. Most of the effects of the GR are mediated via activation and repression of gene expression. To separate activating from repressing functions of the GR, a point mutation was introduced which allowed us to characterize and distinguish functions dependent on GR binding to DNA from those mediated by protein/protein interaction. Cell/tissue-specific mutations of the gluco- and mineralocorticoid receptor is the basis for the evaluation of their cell-specific functions, including the characterization of target genes of the receptors in order to describe their specific effects on different targets.
Functions of RARs and RXRs in vivo: Genetic dissection of the retinoid signaling pathway
Authors: Mark Manuel , Chambon Pierre
Published: October 2007

Retinoids, the active metabolites of vitamin A, regulate complex gene networks involved in vertebrate morphogenesis, growth, cellular differentiation, and homeostasis. They are used for the treatment of skin disorders and as chemopreventive agents for certain cancers. Molecular biology and genetic studies performed during the last 15 years in vitro, using either acellular systems or transfected cells, have shown that retinoid actions are mediated through heterodimers between the 8 major RARα, β, and γ; isoforms and the 6 major RXRα, β and γ isoforms that belong to the nuclear receptor (NR) superfamily, and act as ligand-dependent transcriptional regulators. Furthermore, RXRs not only heterodimerize with RARs, but also with numerous other members of the NR superfamily. As in vitro studies are carried out under nonphysiological conditions, they only indicate what is possible, but not necessarily what is actually occurring in vivo. Therefore, mutations have been introduced by homologous recombination (HR) in F9 embryonal carcinoma (EC) cells, a cell-autonomous system that differentiates in the presence of RA, in order to disrupt RAR and RXR genes and establish their cellular and molecular functions in RA-induced differentiation. However, genetic approaches in the animal should be used to determine the function of retinoid receptors under truly physiological conditions. HR in embryonic stem (ES) cells, has therefore been used to generate null mutations of the various RARs and RXRs in the mouse germline. As reviewed here, the generation of such RAR and RXR germline mutations, combined with pharmacological approaches to block the RA signaling pathway, has provided many valuable insights on the developmental functions of RA receptors. However, due to (i) the complexity in "hormonal" signaling through transduction by the multiple RARs and RXRs, (ii) the functional redundancies (possibly artefactually generated by the mutations) within receptor isotypes belonging to a given gene family, and (iii) in utero or postnatal lethality of certain germline null mutations, these genetic studies through germline mutagenesis have failed to reveal many of the physiological functions of RARs and RXRs, notably in adults. We conclude that spatio-temporally controlled somatic mutations generated in animal models in given cell-types/tissues and at chosen times during pre- and postnatal life, are required to reveal the physiological and pathophysiological functions of the receptor genes involved in the retinoid signaling pathway throughout the life of the mouse.
Biological function and mode of action of nuclear xenobiotic receptors
Authors: Sonoda J. , Evans R. M.
Published: October 2007

Two related nuclear receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), act as xenobiotic sensors that protect the body from a multitude of foreign chemicals (xenobiotics) and play a central role in the metabolism and clearance of steroids and toxic endogenous lipids (endobiotics). A structurally diverse array of chemicals including pharmaceutical drugs, steroids, herbal extracts, and pesticides activate PXR or CAR. This activation results in induction of overlapping, but yet distinct drug clearance pathways consisting of cytochrome P450 enzymes, conjugating enzymes, drug transporters, and other related proteins. Similar pathways are also utilized to protect the body from toxic compounds of endogenous origin. Thus, the xenobiotic regulatory circuit contributes both to drug-drug and food-drug interactions as well as endocrine disruption. Consistent with the notion that xenobiotic receptors regulate drug clearance, single nucleotide polymorphisms (SNPs) in either the receptors themselves or receptor-binding sites in the regulatory region of genes encoding metabolic enzymes appear to contribute to the polymorphic expression of components of drug clearance pathways. Together, the xenobiotic receptors PXR and CAR confer metabolic immunity via the ability to control an integrated array of target genes.
Molecular mechanisms of cross-talk between growth factors and nuclear receptor signaling
Authors: Picard D.
Published: October 2007

Signaling pathways can be linear, but more complex patterns are common. Growth factors and many other extracellular signals cannot directly enter cells and transduce their information via membrane-bound receptors. In contrast, steroid receptors are members of the nuclear receptor superfamily and await their cognate hormones inside the cells. These two types of signaling pathways are extensively intertwined and crosstalk at many different levels. A wide range of extra- and intracellular signals, including a variety of growth factors, can activate the transcriptional activity of steroid receptors in the absence of their cognate hormones. Conversely, steroid receptors lead a double life. By coupling to signaling molecules that mediate signal transduction of extracellular factors, they can elicit very rapid nongenomic responses. The signaling pathways of steroid-independent activation of steroid receptors, on the one hand, and of nongenomic signaling by steroid receptors, on the other, display a remarkable reciprocal relationship suggesting that these two modes of signaling crosstalk may be two faces of the same coin.
Nuclear receptor action involved with sex differentiation
Authors: Hughes I. A. , Martin Howard , Jääskeläinen Jarmo , Acerini C. L.
Published: October 2007

Sex determination and differentiation in the male is an orderly sequence of events coordinated by genetic and hormonal factors operating in a time- and concentration-dependent manner. The constitutive sex in mammals is female. Disorders of fetal sex development have provided the means to identify testis-determining genes and the molecular mechanisms of hormone action. Thus, the androgen receptor, a nuclear hormone receptor critical for androgen-induced male sex differentiation, displays unique intra-receptor and protein-protein interactions which, when disturbed, can result in extreme forms of sex reversal. Polymorphic variants are associated with milder disorders of sex development. Against this genetic background, endocrine active substances may further contribute to the underlying causes of an increase in male reproductive tract disorders.
Human disorders caused by nuclear receptor gene mutations
Authors: Achermann J. C. , Jameson J. L.
Published: October 2007

The identification of naturally occurring nuclear receptor mutations highlights the critical role that many of these transcription factors play in human endocrine development and function. Inactivating mutations in the ligand-dependent nuclear receptors (TRβ, VDR, ERα, GR, MR, AR) are well characterized in patients with conditions such as androgen insensitivity syndrome (AIS) and vitamin D resistance. On the other hand, mutations in TRβ act in a dominant negative manner to cause hormone resistance. Inactivating mutations in orphan nuclear receptors have also been identified (PPARγ2, HNF4α, PNR, NURR1, SF1, DAX1, SHP) and reveal important developmental and metabolic functions for this group of receptors with previously elusive physiologic roles. In addition to loss of function mutations, receptor activation can result from mutations that confer constitutive activity or altered ligand responsiveness to the receptor (MR, AR), or from genetic duplication (DAX1) or the expression of fusion proteins (RARA, PPARγ1). Together, these naturally occurring mutations provide fascinating insight into key structural and functional receptor domains to reveal the diverse role nuclear receptors play in human biology.
Interactions of exogenous endocrine active substances with nuclear receptors
Authors: Katzenellenbogen J. A. , Muthyala R.
Published: October 2007

Nuclear receptors function as ligand-regulated transcription factors and modulate the expression of sets of genes in response to varying concentrations of ligands. The ligand modulators can be endogenous metabolites that function as hormones, or they can be exogenous substances, such as pharmaceutical agents or environmental substances of natural or man-made origin, which in some cases can cause endocrine disruption. Ligands modulate nuclear receptor activity by binding to their ligand-binding domains and stabilizing conformations that lead either to transcriptional activation or repression. The ligand-binding pocket is somewhat flexible, and binding affinities can be measured over a 10-million-fold range (i.e., with equilibrium dissociation constant values ranging from ca. 0.01 nM to 100 μM). Thus, it is not surprising that by binding a large variety of structures, some nuclear receptors can appear to be promiscuous; however, when affinity is considered, the binding patterns are more restricted. The spectrum of ligands that bind to the estrogen receptor has been most thoroughly investigated. Those from natural sources include natural products in food, such as soy isoflavones and whole grain lignans, as well as microbial products and components from wood. Aside from pharmaceuticals, man-made estrogen ligands can be found in industrial products, such as alkyl phenols from nonionic detergents, bisphenols from plastics, indicator dye impurities, polymer chemicals, and chlorinated aromatics and pesticides. Exogenous ligands are also known for the androgen and progesterone receptors. While it is possible that endocrine disruption can result from exogenous chemicals acting directly as ligands for the nuclear receptors, endocrine disruption needs to be considered in the broader context; thus, compounds also need to be assessed for their effects at other levels, such as on endogenous hormone production, transport, metabolism, and clearance, and at points in signal transduction cascades that are beyond the ligand-receptor interaction.
Transcriptional roles of AhR in expression of biological effects induced by endocrine disruptors
Authors: Fujii-Kuriyama Yoshiaki , Mimura J.
Published: October 2007

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), one of most toxic man-made chemicals, binds arylhydrocarbon receptor (AhR or dioxin receptor), whose endogenous ligand remains unknown, with an extremely high affinity and expresses pleiotropic biological effects.

From analysis of the primary structures, AhR belongs to a distinct group of a super-gene family from that of nuclear receptors. PCB, 3-methylcholanthrene, and benzo(a)pyrene are also ligands to the AhR, and these polycyclic aromatic chemicals are considered to display pleiotropic biological effects such as induction of a variety of drug-metabolizing enzymes, teratogenesis, tumor promotion, immunodeficiency due to thymic involution, and liver damage. Generation of the AhR-deficient mice by gene knock-out technology revealed that these biological effects described are mediated by AhR, because AhR(-/-) mice lost susceptibility to these effects by TCDD and benzo(a) pyrene. It has recently been revealed that AhR is also involved in reproduction of female mice. Although the detailed mechanisms of involvement of AhR in exerting these effects are not always clarified, AhR is generally considered to function as a transcription factor, which activates the expression of genes by binding directly the XRE sequence in their promoter in a heterodimer form with Arnt. From analysis of DNA transfection and GST pull-down assays, it is revealed that AhR and Arnt interact with various coactivators such as RIP140, SRC-1/NcoA, and CBP/p300 to transmit their transactivation activity to general transcription factors (GTFs). AhR has also been shown to interact with various regulatory factors including Rb, NF-κB, and SP1, resulting in mutual inhibition or synergistic enhancement of their activities depending on the mode of localization of their cognate binding sequences in the target genes. Agonistic and antagonistic properties of various ligands to AhR also are discussed.
Nonmammalian nuclear receptors: Evolution and endocrine disruption
Authors: Thornton J. W.
Published: October 2007

Most research to identify endocrine-disrupting chemicals and their impacts has relied on mammalian models or in vitro systems derived from them. But nuclear receptors (NRs), the proteins that transduce hydrophobic hormonal signals and are major mediators of endocrine disruption, emerged early in animal evolution and now play biologically essential roles throughout the Metazoa. Nonmammalian vertebrates and invertebrates, many of which are of considerable ecological, economic, and cultural importance, are therefore potentially subject to endocrine disruption by synthetic environmental pollutants.

Are methods that rely solely on mammalian models adequate to predict or detect all chemicals that may disrupt NR signaling? Regulation of NRs by small hydrophobic molecules is ancient and evolutionarily labile. Within and across genomes, the NR superfamily is very diverse, due to many lineage-specific gene and genome duplications followed by independent divergence. Receptors in nonmammalian species have in many cases evolved unique molecular and organismal functions that cannot be predicted from those of their mammalian orthologs. Endocrine disruption is therefore likely to occur throughout the metazoan kingdom, and a significant number of the thousands of synthetic chemicals now in production may disrupt NR signaling in one or more nonmammalian taxa. Many of these endocrine disruptors will not be detected by current regulatory/scientific protocols, which should be reformulated to take account of the diversity and complexity of the NR gene family.
Analysis of endocrine active substances in food and the environment
Authors: Holland P. T.
Published: October 2007

A critical review is made of techniques for analysis of residues of endocrine active substances (EASs) including sampling, extraction cleanup and determination based on GC/MS, LC/MS, ELISA, and bioassays. The growing importance of receptor-based in vitro bioassays is highlighted for integrated monitoring of environmental levels of certain classes of EASs and for establishing exposures. Some recent advances in methods of analysis for each of the key classes of EASs are summarized including for organochlorines, PCBs, dioxins and dioxin-like substances, polybrominated diphenyl ethers, phenolic xenoestrogens, phthalates, organotin compounds, steroidal hormones, and phytoestrogens. The issues raised in interpreting complementary chemical and bioassay data at an effects level are briefly discussed.
Naturally produced steroid hormones and their release into the environment
Authors: Shore L. S. , Shemesh M.
Published: October 2007

Steroidal hormones produced by humans and animals are constantly excreted into the environment in their active forms. The primary steroid hormones are progesterone, estrone, estradiol, testosterone, and cortisol, all of which are lipophilic and poorly soluble in water. The steroids of major concern are estrone and estradiol-17β, since they exert their physiological effects at a lower concentration than other steroids and can be found in the environment in concentrations above their LOEL for fish and plants (10 ng/l). The steroid hormones can be readily measured in run-off, soil, and groundwater, but each steroid has its distinct pathway of transport. Since the major source of steroids in the environment appears to be cattle and chickens, the hormonal steroid input into the environment could be drastically reduced by well-established techniques such as buffer strips and composting.
Concentration of phytohormones in food and feed and their impact on the human exposure
Authors: Verger Ph. , LeBlanc J. C.
Published: October 2007

Phytohormones, which naturally occur in plants, must be taken into consideration for their contribution to the total human exposure to potential endocrine active substances (EASs). Phytohormones are usually divided into two families: phytoestrogens that are mainly occur from soybeans and soy derivatives and phytosterols that occur from vegetables and vegetable oils. The present paper compiles different sources of information about the concentration of phytohormones in foodstuffs in order to assess the current human exposure to those substances via food. A particular attention is given to most exposed groups of consumers, on the one hand, infants and young children fed with soy-based infant formulas for their exposure to phytoestrogens and on the other hand, consumers of fortified foods for their exposure to phytosterols.

Available literature shows that the total dietary intake of isoflavones could reach 20 to 25 mg/day/person for the Japanese adult population. For infants and young children, the quantity of phytoestrogen ingested is likely to be 35-50 mg/day/person corresponding on a body weight basis to an exposure 7 to 11 times higher. Regarding phytosterols, an assessment of the exposure via food was done, considering both their natural occurrence and their potential concentration in fortified foods. Results shows that the "natural" exposure is estimated at 340 ± 440 mg/day/person at the mean and at 1040 mg/day/person at the 95th percentile. Considering the potential exposure via fortified foods, it is estimated at 2700 ± 1200 mg/day/person at the mean and at 4700 mg/day/person at the 95th percentile.

After their ingestion, isoflavones are absorbed from the intestinal tract before being excreted in the urine and feces. The increasing use of phytohormones in human foodstuffs could increase locally their release into the environment. Nevertheless, considering the weak estrogenic potential of phytohormones in relation to synthetic or endogenous steroids, any introduction of these substances into aquatic ecosystems would probably have comparatively minor effects on aquatic organisms.
Pharmaceuticals and personal care products - A source of endocrine disruption in the environment?
Authors: Ingerslev F. , Vaclavik E. , Halling-Sørensen B.
Published: October 2007

A wide variety of chemicals are used in pharmaceuticals. Most of these are already under thorough control for endocrine activity. The main causal agents recognized for endocrine disruption from sewage are substances used in medicine (sex hormones, glucocorticoids, and others), natural substances (estrone and 17β-estradiol), and synthetic estrogens (e.g., 17α-ethinylestradiol). Similar substances are used in anabolic agents (growth hormones) in livestock production in some countries. Although the estimated use of anabolic agents in livestock production is approximately one order of magnitude below the natural release of estrogens from farm animals, their possible significance remains unanswered.

At present, no other medical substances are recognized as endocrine disruptors in the environment. However, candidates may be identified on the basis of simple assumptions regarding their use and activity: (1) Nonestrogenic steroids may react with environmental endocrine receptors or metabolize on their way to the environment and thus form endocrine disruptors. (2) Many high-volume drugs released to the environment have not yet been tested for their endocrine properties, and some of these are known to interact with the human endocrine system. (3) Compared to medicinal substances, personal care products and additives in drugs are used in high amounts; from this group, parabens, siloxanes, and other substances are suspected of causing endocrine disruption in the environment.
Endocrine active industrial chemicals: Release and occurrence in the environment
Authors: Johnson A. , Jürgens M.
Published: October 2007

Of the xenobiotic endocrine active substances (EASs), tributyltin (TBT) has had the clearest link to an impact on aquatic ecology. Its release from marine antifouling paints had a drastic impact on dogwhelk populations in polluted harbors due to a masculization effect. 4-tert-nonylphenol is seen as the most significant of the industrial xenobiotic estrogen mimics, being implicated as the dominant endocrine disruptor in certain industrialized river reaches. Apart from hot spots associated with particular industries, the estrogenic alkylphenols, phthalates, and bisphenol A are present in effluent and receiving water at concentrations below that which would give cause for concern. Other more bioaccumulative compounds such as polybrominated flame retardants, dioxins, furans may possess some endocrine active properties. The possibility of additivity effects may yet mean that low concentrations of xenobiotic EASs will need careful consideration. It is noted that considerable quantities of many of these compounds are often found in sewage sludge and sediments.
Release of pesticides into the environment and initial concentrations in soil, water, and plants
Authors: Racke K. D.
Published: October 2007

Considerable information exists as to the initial concentrations of pesticide residues to be expected in soils, plants, and water. Empirical or theoretical models have been developed for incorporating this data into exposure assessments for humans as well as terrestrial and aquatic wildlife. In addition, monitoring data exists for many older products, especially with respect to typical concentrations observed in food commodities for human consumption and in surface and ground waters. Estimated and observed concentrations of pesticides in these matrices have been routinely employed for more than 30 years in assessing the potential impacts of pesticides on a variety of biologically relevant endpoints. The same data will also prove useful for exposure assessments of endocrine active substances. There are some additional research needs, however. First, further research and development is needed to ensure that estimation and monitoring methods for pesticide concentrations in soil, water, and food are applicable and utilized for all important and relevant cultural, agronomic, and environmental conditions. This is especially true with respect to developing countries and tropical climates, which are often disproportionately ignored in favor of developing countries and temperate climates. Second, methodologies for collection of monitoring data and generation of modeled estimates for pesticide residues in soil, water, and food need to be carefully designed with the requirements of higher-tier, probabilistic exposure assessments in view. Although worst-case, point estimates or analyses may be useful for screening-level assessments, advanced assessments targeted at addressing the likelihood of biologically relevant exposures are urgently required by scientists and regulatory authorities for reaching sound risk assessment and risk management decisions.
Role of metabolism in the endocrine-disrupting effects of chemicals in aquatic and terrestrial systems
Authors: van den Berg M. , Sanderson T. , Kurihara N. , Katayama A.
Published: October 2007

This review describes the role of metabolism with endocrine active substances. Many modern synthetic compounds are readily metabolized to more polar forms that often contain hydroxy groups. This presence of polar groups and aromatic moieties in the parent compound or metabolite can play an important role in the mechanism of endocrine disruption. In addition, phase II metabolism (e.g., glucuronidation) can also lead to deactivation of the endocrine properties. In the case of bisphenol A and alkylphenols, metabolism can be considered as a detoxification mechanism as glucuronides decrease of inhibit binding to the estrogen receptors. In the case of phthalate esters, the primary metabolites, the monoesters, and further degraded metabolites do not interact with the estrogen receptor either. In contrast, the demethylation of methoxychlor in fish and other vertebrate species leads to metabolites with an increased affinity for the estrogen receptor. Certain PCB metabolites with hydroxy groups on the para position without vicinal chlorines have estrogenic activity, but these metabolites are not relevant for the environment. PCB metabolites with methylsulfonyl groups are commonly found in environmental biota and have been associated with several endocrine, developmental, and reproductive effects. Some DDT metabolites bind weakly to the estrogen receptor, but the major biotransformation product p,p-DDE is an androgen receptor (AR) antagonist. Vinclozolin is an anti-androgen and this effect appears to caused by two of its more water-soluble metabolites. The chloro-s-triazines exhibit an in vitro induction of aromatase, but their dealkylated metabolites show a decrease or lack of this effect.

It is recognized that common metabolic processes can differ strongly among species that complicates ecotoxicological risk assessment of endocrine active substances. In conclusion, the testing of metabolites for endocrine-disrupting properties should be encouraged in the future to establish a better risk assessment process.

An appendix containing levels and half-lives of various endocrine-disrupting chemicals in the environment and in wildlife is included at the end of this article.
Critical factors in exposure modeling of endocrine active substances
Authors: de Voogt P. , van Hattum B.
Published: October 2007

Multimedia transport, partitioning, and degradation pathways are key processes in the probability of a substance to interact with target organisms. Biotic factors such as toxicokinetics, biotransformation capacity, and behavioral and life-cycle aspects of the organisms are determinants for final concentrations at target organs. The role of metabolites in endocrine disruption can be quite different from those of the parent compounds, and often this requires separate toxicokinetic evaluation.

The exposure assessment of endocrine active substances (EASs) suffers from a huge lack of reliable data, of both values that are used as input parameters in exposure models, and field data that are needed for validation purposes. In general, for the more classic EASs, such as PCBs, p,p'-DDE, chlorinated dioxins, some pesticides, and organotins, reliable data are sufficiently available, but careful evaluation of the quality of databases is necessary. Several data quality evaluation systems have been proposed. For the "newer" compounds, only few data have been gathered so far. The latter compounds include alkylphenols, bisphenol A, brominated flame retardants, phytoestrogens, and in particular natural and synthetic hormones, which in view of their high estrogenic potency could be the most important compounds in terms of risk.

The suitability of current exposure assessment models for EASs at this moment seems to be restricted to the persistent compounds such as PCBs, PCDDs, and PCDFs. Especially for the compounds subject to biodegradation and biotransformation, the lack of experimental data to derive model-input parameters and perform validation studies at this moment is one of the main obstacles for the further application of generic exposure models to other EASs. Most of the current models do not allow life stage-specific predictions.

Although the mechanisms of endocrine disruption involve different types of action, the principle of additivity, based on the equivalent toxicity approach (using estrogen equivalent potencies relative to 17β-estradiol) seems promising for the design of integrated exposure and effect models for EASs.

Research programs aimed at the endocrine disruption issue must focus on promoting experimental studies for generation of reliable, high-quality parameter data on the one hand, and surveys or monitoring campaigns for collection of representative field data on the other. The non-specificity of possible effects caused through endocrine mechanisms implies that in order to reveal dose-response relationships all potentially active agents, or at least as many as feasible, need be included in the risk assessments. Current regulatory monitoring programs should further be evaluated and harmonized with validation requirements of models used in exposure assessment.
Environmental fate and metabolism: Issues and recommendations
Authors: de Voogt P. , Halling-Sørensen B. , van Hattum B. , Holland P. T. , Ingerslev F. , Johnson A. , Jürgens M. , Katayama A. , Klein W. , Kurihara N. , Leblanc J. C. , Racke K. D. , Sanderson T. , Shemesh M. , Shore L. S.
Published: October 2007

This main topic of the project and symposium includes the issue of releases of EASs and their monitoring in the environment, food, and feed in order to provide the full set of criteria, relevant for exposure assessment. Much less research has been devoted to these areas as compared to investigations on the effects. Issues of special importance regarding exposure to EASs, both from a research and risk management point of view, predominantly result from the fact that high-potency natural products are released as well as anthropogenic substances.

In order to provide reliable information for risk assessment and risk management, substantial research, methodological improvements, and improvements in data interpretation are needed regarding the following: releases and technologies for their mitigation; monitoring; establishment of background levels; transport, partitioning, persistence, degradation, and metabolism of EASs; dealing with "joint toxicity"; and providing reliable analytical methodology conforming to the principles of quality assurance.

Phytohormones play a special role in this whole area since they may be used as food amendments.
Interactions of xenobiotics with the steroid hormone biosynthesis pathway
Authors: Sanderson T. , van den Berg M.
Published: October 2007

Environmental contaminants can potentially disrupt endocrine processes by interfering with the function of enzymes involved in steroid synthesis and metabolism. Such interferences may result in reproductive problems, cancers, and toxicities related to (sexual) differentiation, growth, and development. Various known or suspected endocrine disrupters interfere with steroidogenic enzymes. Particular attention has been given to aromatase, the enzyme responsible for the conversion of androgens to estrogens. Studies of the potential for xenobiotics to interfere with steroidogenic enzymes have often involved microsomal fractions of steroidogenic tissues from animals exposed in vivo, or in vitro exposures of steroidogenic cells in primary culture. Increasingly, immortalized cell lines, such as the H295R human adrenocortical carcinoma cell line are used in the screening of effects of chemicals on steroid synthesis and metabolism. Such bioassay systems are expected to play an increasingly important role in the screening of complex environmental mixtures and individual contaminants for potential interference with steroidogenic enzymes. However, given the complexities in the steroid synthesis pathways and the biological activities of the hormones, together with the unknown biokinetic properties of these complex mixtures, extrapolation of in vitro effects to in vivo toxicities will not be straightforward and will require further, often in vivo, investigations.
Prevention of ambiguous genitalia by prenatal treatment with dexamethasone in pregnancies at risk for congenital adrenal hyperplasia
Authors: New M. I.
Published: October 2007

Congenital adrenal hyperplasia (CAH) refers to a family of monogenic inherited disorders of adrenal steroidogenesis most often caused by a deficiency of the 21-hydroxylase enzyme. In the classic forms of CAH (simple virilizing and salt-wasting), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Prenatal treatment of CAH with dexamethasone has been successfully utilized for over a decade. This article reports on 595 pregnancies prenatally diagnosed using amniocentesis or chorionic villus sampling between 1978 and 2002 at the New York Presbyterian Hospital-Weill Medical College of Cornell University. No significant or enduring side effects were noted in the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight from untreated, unaffected newborns. Based on our experience, prenatal diagnosis and treatment of 21-hydroxylase deficiency is effective in significantly reducing or eliminating virilization in the newborn female. Prevention of genital virilization in female newborns with classic CAH avoids the risk of sex misassignment and diminishes the need for corrective surgery and the resulting psychological impact that may extend into adulthood.
Male reproductive disorders and the role of endocrine disruption: Advances in understanding and identification of areas for future research
Authors: Sharpe R. M. , Skakkebaek N. E.
Published: October 2007

This review addresses whether there is a secular increasing trend in male reproductive developmental disorders (cryptorchidism, hypospadias, testis cancer, low sperm counts), and highlights the limitations of available data and how these issues are being addressed. These disorders are considered to represent a syndrome of disorders [testicular dysgenesis syndrome (TDS)] with a common origin in fetal life, and in which "endocrine disruption" plays a central role. The potential involvement of environmental estrogens in the etiology of these disorders is reviewed in light of new understanding about the pathways and dose-effect relationships of estrogen action on male reproductive development. Several new pathways of estrogen action have been identified, including suppression of the production of testosterone and insulin-like factor-3 by fetal/neonatal Leydig cells and suppression of androgen receptor expression in androgen target tissues. It is tentatively concluded that identified environmental chemicals are unlikely to activate these pathways because of their intrinsically weak estrogenicity. However, chemicals that may alter endogenous estrogen production, bioavailability, or inactivation represent a new focus of concern. Additionally, environmental chemicals that alter endogenous levels of androgens in the rat fetus (certain phthalates) induce a similar collection of disorders to TDS. Whether human exposure to such compounds might contribute to TDS remains to be shown, but studies in animals should help to define susceptible pathways for induction of TDS.
Brominated flame retardants and endocrine disruption
Authors: Vos J. G. , Becher Georg , van den Berg M. , de Boer J. , Leonards P. E. G.
Published: October 2007

From an environmental point of view, an increasing important group of organohalogen compounds are the brominated flame retardants (BFRs), which are widely used in polymers and textiles and applied in construction materials, furniture, and electronic equipment. BFRs with the highest production volume are the polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A (TBBP-A), and hexabromocyclododecane (HBCD). Because of their persistence and low biodegradation profile, several of the PBDE congeners accumulate in biota and are widely found in the aquatic food chain. Their levels in the environment and in humans have increased during the last decades, in contrast to compounds such as polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT), for example. Humans may be exposed to PBDEs mainly through consumption of fatty food of animal origin (e.g., fish), but exposure through skin contact with textiles protected with flame retardants or through inhalation of BFRs volatilized from electronic and electric equipment may also occur. The levels of PBDEs in Swedish human milk showed a doubling in concentration every five years over the period 1972 to 1997 (2,2',4,4'-tetraBDE being the predominant congener). The levels of penta- and hexa-BDEs increased at the same rate in ringed seals collected in the Canadian Arctic from 1981 to 2000. PBDEs exhibit a great variety of biological effects, depending on the bromine substitution pattern. PBDEs are potential endocrine disrupters, based on shared toxicity with the structurally related PCBs, polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo-p-dioxins (PCDDs) (partial aryl hydrocarbon- [Ah-] receptor agonist and antagonist activity in vitro, thyroid toxicity, and immune effects), including developmental toxicity. The potency of TBBP-A to interact with thyroid hormone homeostasis is indicated from in vitro studies in which the compound competes with thyroxin (T4) for binding to transthyretin (TTR). So far, the toxicological profile of many BFRs is too incomplete and insufficient to perform an adequate risk assessment, and further information is required regarding the potential for endocrine disruption of these compounds that are of increasing environmental concern.