A Global Assessment of Gold, Titanium, Strontium and Barium Pollution Using Sperm Whales (Physeter Macrocephalus) As an Indicator Species

This study provides a global baseline for barium, gold, titanium and strontium as marine pollutants using the sperm whale (Physeter macrocephalus) as an indicator species. Barium, gold, titanium and strontium are metals that are little studied in marine environments. However, their recent emergence as nanomaterials will likely increase their presence in the marine environment. Moreover, nanosized particles are likely to exhibit toxic outcomes not seen in macrosized particles. Biopsies from free ranging sperm whales were collected from around the globe. Total barium levels were measured in 275 of 298 sperm whales tested for barium and collected from 16 regions around the globe. The global mean for barium was 0.93 +/- 0.2ug/g with a detectable range from 0.1 to 27.9ug. Total strontium levels were measurable in all 298 sperm whales producing a global mean level of 2.2 +/- 0.1ug/g and a range from 0.2 to 11.5ug/g. Total titanium levels were also measured in all 298 sperm whales producing a global mean level of 4.5 +/- 0.25ug/g with a range from 0.1 to 29.8ug/g. Total gold levels were detected in 50 of the 194 sperm whales collected from 16 regions around the globe. Detectable levels ranged from 0.1 to 2.3ug/g tissue with a global mean level equal to 0.2 +/- 0.02ug/g. Previous reports of these metals were much lower than the mean levels reported here. The likely explanation is location differences and consistent with this explanation, we found statistically significant variation among regions. These data provide an important global baseline for barium, gold, titanium and strontium pollution and will allow for important comparisons to be made over time to assess the impact of nanomaterials on whales and the marine environment

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue

In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Optineurin-mediated Autophagy in Environmental Models of Parkinson’s Disease

Parkinson’s disease is a complex, progressive neurodegenerative disease that has a poorly understood etiology and no known cure. Epidemiological studies suggest the vast majority of cases are likely due to interactions between genetic susceptibilities and exposure to external factors (e.g. environmental chemicals) synergistically contributing to disease development. Pesticides are the strongest environmental link and have been utilized in vivo and in vitro to robustly replicate behavior, pathology, and cellular and molecular impairments observed in patients. Decades of research has revealed a variety of impaired cellular and molecular mechanisms, though it is still unclear which are the most critical or in what order they occur. Intriguingly, the protein optineurin, which is genetically linked to amyotrophic lateral sclerosis and glaucoma, is known to be involved in many of these impaired mechanisms. Moreover, a recent genome-wide association study found the M98K mutation is a risk factor for development of Parkinson’s disease. Increasing evidence suggests a link between Parkinson’s disease and glaucoma, with Parkinson’s patients exhibiting an increased likelihood of developing glaucoma, thinned retinal nerve fiber layers, and a variety of other visual impairments. Hence, we proposed that optineurin participates in Parkinson’s disease pathology and may exhibit polymorphisms that increase susceptibility of developing the disease. To investigate this, we used a rat rotenone model of Parkinson’s disease and evaluated changes in optineurin activity in various brain regions implicated in Parkinson’s disease pathogenesis and considered the contribution of optineurin mutation or depletion to Parkinson’s-like brain pathology. We initially determined that optineurin is expressed in the dopaminergic neurons of the substantia nigra pars compacta, and its expression here appears to be more robust than many other regions by qualitative analysis. Then we considered how optineurin expression changes after rotenone exposure. Across all time points considered (24 h, 5 d, or end-stage parkinsonian phenotype), optineurin expression was significantly elevated. We also found optineurin colocalized with LC3, a critical autophagy-related protein, and the number of colocalized puncta was significantly increased after 5 d rotenone exposure. Such an accumulation of mature autophagosomes has been repeatedly observed in Parkinson’s disease models, and is believed to derive from impaired lysosomal fusion. Finally, in our initial investigation we demonstrated a shift in alpha-synuclein expression from a dispersed, cytosolic expression to a more punctate expression and these puncta were colocalized with optineurin. We believe optineurin colocalizes with alpha-synuclein to target aggregates for degradation by autophagy, but this will need to be verified by further investigation. In the third chapter, we proposed autophagic dysfunction occurs ahead of alpha-synuclein aggregation, and expanded our investigation of optineurin and autophagic dysfunction into four other brainstem regions implicated in preclinical Parkinson’s disease: the dorsal motor vagal nucleus, raphe, locus coeruleus, and pontine tegmental nucleus. Again, we measured optineurin and LC3 expression, mean number of puncta per cell, and colocalized puncta. Furthermore, we considered the percent of optineurin and LC3 puncta that were colocalized (i.e. of the total number of optineurin or LC3 puncta, what percent are colocalized). Collectively, these data suggested impaired lysosomal fusion across multiple regions and multiple time points, as well as impaired binding between optineurin and LC3. We found significantly decreased percent of colocalized puncta for both LC3 and optineurin in most regions and time points considered after rotenone exposure when compared to control. Finally, when we considered the mean number of LC3 puncta per cell in control animals across all regions analyzed, our data show significantly fewer puncta in dopaminergic neurons of the substantia nigra pars compacta and locus coeruleus. These data suggest autophagic capacity may be another limiting factor for dopaminergic neurons ability to cope with cellular stress. Chapter 4 investigates the potential role of optineurin in Golgi fragmentation, which has been observed as an early event in multiple neurodegenerative diseases. Our data showed presence of Golgi fragmentation after rotenone exposure with optineurin colocalizing to fragments, but quantitative analyses were inconclusive regarding the amount of Golgi fragmentation present. Chapter 5 begins to consider the potential for the E50K optineurin mutation or optineurin knock-out contributing to development of Parkinson’s disease. To address this, we considered the signal intensity of tyrosine hydroxylase in the striatum of optineurin transgenic or wild type mice. These preliminary results show decreased intensity of striatal tyrosine hydroxylase in optineurin transgenic mice when compared to control, suggesting optineurin expression is important for nigral dopaminergic neuron survival. In sum, our data is the first to present optineurin as a potentially important protein in the pathogenesis of Parkinson’s disease. Further investigations of optineurin’s role in gene-environment interactions of Parkinson’s disease are warranted and will likely reveal novel mechanisms of pathogenesis and disease progression

One Environmental Health: an emerging perspective in toxicology [version 1; referees: 2 approved]

The One Environmental Health research approach, a subspecialty of the One Health initiative, focuses on toxic chemicals. Distinct disciplines work together to give a holistic perspective of a health concern through discrete disciplines, including, but not limited to, public health and the medical and veterinary sciences. In this article, we illustrate the concept of One Environmental Health with two case studies. One case study focuses on alligators and contributions to the field of endocrine disruption. The other case study focuses on whales and contributions to understanding carcinogenic metals. Both studies illustrate how the health of sentinel organisms has the potential to inform about the health of humans and the ecosystem

Excision repair is required for genotoxin-induced mutagenesis in mammalian cells

Certain hexavalent chromium [Cr(VI)] compounds are human lung carcinogens. Although much is known about Cr-induced DNA damage, very little is known about mechanisms of Cr(VI) mutagenesis and the role that DNA repair plays in this process. Our goal was to investigate the role of excision repair (ER) pathways in Cr(VI)-mediated mutagenesis in mammalian cells. Repair-proficient Chinese hamster ovary cells (AA8), nucleotide excision repair (NER)-deficient (UV-5) and base excision repair (BER)-inhibited cells were treated with Cr(VI) and monitored for forward mutation frequency at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus. BER was inhibited using methoxyamine hydrochloride (Mx), which binds to apurinic/apyrimidinic sites generated during BER. Notably, we found that both NER-deficient (UV-5 and UV-41) and BER-inhibited (AA8 + Mx) cells displayed attenuated Cr(VI) mutagenesis. To determine whether this was unique to Cr(VI), we included the alkylating agent, methylmethane sulfonate (MMS) and ultraviolet (UV) radiation (260 nm) in our studies. Similar to Cr(VI), UV-5 cells exhibited a marked attenuation of MMS mutagenesis, but were hypermutagenic following UV exposure. Moreover, UV-5 cells expressing human xeroderma pigmentosum complementation group D displayed similar sensitivity to Cr(VI) and MMS-induced mutagenesis as AA8 controls, indicating that the genetic loss of NER was responsible for attenuated mutagenesis. Interestingly, Cr(VI)-induced clastogenesis was also attenuated in NER-deficient and BER-inhibited cells. Taken together, our results suggest that NER and BER are required for Cr(VI) and MMS-induced genomic instability. We postulate that, in the absence of ER, DNA damage is channeled into an error-free system of DNA repair or damage tolerance. © The Author 2008. Published by Oxford University Press. All rights reserved