This report is an overview of the current state of the science relative to environmental endocrine disruption in humans, laboratory testing, and wildlife species. Background information is presented on the field of endocrinology, the nature of hormones, and potential sites for endocrine disruption, with specific examples of chemicals affecting these sites. An attempt is made to present objectively the issue of endocrine disruption, consider working hypotheses, offer opposing viewpoints, analyze the available information, and provide a reasonable assessment of the problem. Emphasis is placed on disruption of central nervous system--pituitary integration of hormonal and sexual behavioral activity, female and male reproductive system development and function, and thyroid function. In addition, the potential role of environmental endocrine disruption in the induction of breast, testicular, and prostate cancers, as well as endometriosis, is evaluated. The interrelationship of the endocrine and immune system is documented. With respect to endocrine-related ecological effects, specific case examples from the peer-reviewed literature of marine invertebrates and representatives of the five classes of vertebrates are presented and discussed. The report identifies some data gaps in our understanding of the environmental endocrine disruption issue and recommends a few research needs. Finally, the report states the U.S. Environmental Protection Agency Science Policy Council's interim position on endocrine disruption and lists some of the ongoing activities to deal with this matter.

Recent work indicates that oxidative stress is a factor in Parkinson's disease (PD); however, it is unknown how this condition causes selective dopaminergic cell death. The neurotransmitter dopamine (DA) has been implicated as an endogenous neurotoxin to explain the selective neurodegeneration. DA undergoes catabolism by monoamine oxidase (MAO) to the reactive intermediate 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is further oxidized to 3,4-dihydroxyphenylacetic (DOPAC) acid via mitochondrial aldehyde dehydrogenase (ALDH). Previous studies found DOPAL to be more toxic than DA, and the major lipid peroxidation products, that is, 4-hydroxynonenal (4HNE) and malondialdehyde (MDA), potently inhibit ALDH. The hypothesis of this work is that lipid peroxidation products inhibit DOPAL oxidation, yielding aberrant levels of the reactive aldehyde intermediate. Treatment of striatal synaptosomes with 2-100 microM 4HNE or 2-50 microM MDA impaired DOPAL oxidation, resulting in elevated [DOPAL]. The aberrant concentration of DOPAL yielded an increase in protein modification by the DA-derived aldehyde, evident via staining of proteins with nitroblue tetrazolium (NBT). Pretreatment of synaptosomes with an MAO inhibitor significantly decreased NBT staining. On the basis of NBT staining, the order of protein reactivity for DA and metabolites was found to be DOPAL>>DOPAC>DA. Mass spectrometric analysis of a model peptide reacted with DOPAL revealed the adduct to be a Schiff base product. In summary, these data demonstrate the sensitivity of DA catabolism to the lipid peroxidation products 4HNE and MDA even at low, physiologic levels and suggest a mechanistic link between oxidative stress and generation of aberrant levels of an endogenous and protein reactive dopaminergic toxin relevant to PD.

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Dopamine (DA) has been implicated as an endogenous neurotoxin to explain the selective neurodegeneration as observed for Parkinson’s disease (PD). In addition, oxidative stress and lipid peroxidation are hypothesized culprits in PD pathogenesis. DA undergoes catabolism by monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is further oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH). As a minor and compensatory metabolic pathway, DOPAL can be reduced to 3,4-dihydroxyphenylethanol (DOPET) via cytosolic aldehyde or aldose reductase (AR). Previous studies have found DOPAL to be significantly more toxic to DA cells than DA and that the major lipid peroxidation products, i.e. 4-hydroxynonenal (4HNE) and malondialdehyde (MDA), potently inhibit DOPAL oxidation via ALDH. The hypothesis of this work is that lipid peroxidation products inhibit DOPAL oxidation, yielding aberrant levels of the toxic aldehyde intermediate. To test this hypothesis, nerve-growth factor differentiated PC6-3 cells were used as a model for DA neurons. Cell viability in the presence of 4HNE and MDA (2-100 μM) was measured by MTT assay and it was found that only 100 μM 4HNE exhibited significant cytotoxicity. Treatment of cells with varying concentrations of 4HNE and MDA resulted in reduced DOPAC production and significant elevation of DOPAL levels, suggesting inhibition of ALDH. In cells treated with 4HNE that exhibited elevated DOPAL, there was a significant increase in DOPET. However, elevated DOPET was not observed for the cells treated with MDA, suggesting MDA to be an inhibitor of AR. Using isolated cytosolic AR, it was found that MDA but not 4HNE inhibited reductase activity toward DOPAL, surprisingly. These data demonstrate that the oxidative stress products 4HNE and MDA inhibit the aldehyde biotransformation step of DA catabolism yielding elevated levels of the endogenous neurotoxin DOPAL, which may link oxidative stress to selective neurodegeneration as seen in PD.

The oxidation and toxicity of dopamine is believed to contribute to the selective neurodegeneration associated with Parkinson disease. The formation of reactive radicals and quinones greatly contributes to dopaminergic toxicity through a variety of mechanisms. The physiological metabolism of dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL) via monoamine oxidase significantly increases its toxicity. To more adequately explain this enhanced toxicity, we hypothesized that DOPAL is capable of forming radical and quinone species upon oxidation. Here, two unique oxidation products of DOPAL are identified. Several different oxidation methods gave rise to a transient DOPAL semiquinone radical, which was characterized by electron paramagnetic resonance spectroscopy. NMR identified the second oxidation product of DOPAL as the ortho-quinone. Also, carbonyl hydration of DOPAL in aqueous media was evident via NMR. Interestingly, the DOPAL quinone exists exclusively in the hydrated form. Furthermore, the enzymatic and chemical oxidation of DOPAL greatly enhance protein cross-linking, whereas auto-oxidation results in the production of superoxide. Also, DOPAL was shown to be susceptible to oxidation by cyclooxygenase-2 (COX-2). The involvement of this physiologically relevant enzyme in both oxidative stress and Parkinson disease underscores the potential importance of DOPAL in the pathogenesis of this condition. Parkinson disease (PD)2 involves specific loss of dopaminergic nuclei in the substantia nigra of the brain (1). Although the exact causes of this selective degeneration are unknown (2), the role of affected cells as centers of dopamine (DA) synthesis, storage, and metabolism suggests that DA may be an endogenous neurotoxin (3, 4) that contributes to the pathogenesis of PD. DA may act as a source of cellular oxidative stress and is known to undergo oxidation (Scheme 1) to cytotoxic radicals and quinones (5-8). Such oxidations can occur spontaneously or via metal-or enzyme-catalyzed mechanisms (9). One-electron oxidation of DA produces a radical capable of interfering with DA storage and causing oxidative protein and DNA modifications (5, 6, 10). Similarly, two-electron oxidation of DA to an ortho-quinone results in reactivity with cellular nucleophiles such as thiols and proteins (8, 11). Both species are capable of redox cycling, which could deplete cellular oxidative defenses. Also, in the presence of transition metals and/or O 2 , such oxidations could result in the production of ROS capable of inducing lipid peroxidation and damage to other cellular macromolecules (12). Another potential mechanism of toxicity for DA is its physiological metabolism to 3,4-dihydroxyphenylacetaldehyde (DOPAL) (13).DOPAL is a very reactive aldehyde that is 100 -1000-fold more toxic than DA both in vivo and in vitro (14,15). Physiological levels of DOPAL in the substantia nigra are ϳ2 M; levels as low as 6 M can exert significant toxicity (16). Reactivity with proteins, presumably via Schiff base formation, is an important mechanism o...

The goal of this paper concerns the development of photoinitiating systems usable in industrial processes for coating applications and the production of thick epoxy/glass fibre composites.

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ObjectivesWe aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes.MethodsA systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group.ResultsFive FND-specific measures were identified—three clinician-rated and two patient-rated—but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost–utility (eg, healthcare resource use and quality-adjusted life years).ConclusionsThere are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population.