Chemical Effects on Breast Development, Function, and Cancer Risk: Existing Knowledge and New Opportunities

Current environmental health reports

2022 Aug 19

Kay, JE;Cardona, B;Rudel, RA;Vandenberg, LN;Soto, AM;Christiansen, S;Birnbaum, LS;Fenton, SE;
PMID: 35984634 | DOI: 10.1007/s40572-022-00376-2

Population studies show worrisome trends towards earlier breast development, difficulty in breastfeeding, and increasing rates of breast cancer in young women. Multiple epidemiological studies have linked these outcomes with chemical exposures, and experimental studies have shown that many of these chemicals generate similar effects in rodents, often by disrupting hormonal regulation. These endocrine-disrupting chemicals (EDCs) can alter the progression of mammary gland (MG) development, impair the ability to nourish offspring via lactation, increase mammary tissue density, and increase the propensity to develop cancer. However, current toxicological approaches to measuring the effects of chemical exposures on the MG are often inadequate to detect these effects, impairing our ability to identify exposures harmful to the breast and limiting opportunities for prevention. This paper describes key adverse outcomes for the MG, including impaired lactation, altered pubertal development, altered morphology (such as increased mammographic density), and cancer. It also summarizes evidence from humans and rodent models for exposures associated with these effects. We also review current toxicological practices for evaluating MG effects, highlight limitations of current methods, summarize debates related to how effects are interpreted in risk assessment, and make recommendations to strengthen assessment approaches. Increasing the rigor of MG assessment would improve our ability to identify chemicals of concern, regulate those chemicals based on their effects, and prevent exposures and associated adverse health effects.

Pathophysiology of Nociception and Rare Genetic Disorders with Increased Pain Threshold or Pain Insensitivity

Pathophysiology : the official journal of the International Society for Pathophysiology

2022 Aug 02

Cascella, M;Muzio, MR;Monaco, F;Nocerino, D;Ottaiano, A;Perri, F;Innamorato, MA;
PMID: 35997391 | DOI: 10.3390/pathophysiology29030035

Pain and nociception are different phenomena. Nociception is the result of complex activity in sensory pathways. On the other hand, pain is the effect of interactions between nociceptive processes, and cognition, emotions, as well as the social context of the individual. Alterations in the nociceptive route can have different genesis and affect the entire sensorial process. Genetic problems in nociception, clinically characterized by reduced or absent pain sensitivity, compose an important chapter within pain medicine. This chapter encompasses a wide range of very rare diseases. Several genes have been identified. These genes encode the Nav channels 1.7 and 1.9 (SCN9A, and SCN11A genes, respectively), NGFβ and its receptor tyrosine receptor kinase A, as well as the transcription factor PRDM12, and autophagy controllers (TECPR2). Monogenic disorders provoke hereditary sensory and autonomic neuropathies. Their clinical pictures are extremely variable, and a precise classification has yet to be established. Additionally, pain insensitivity is described in diverse numerical and structural chromosomal abnormalities, such as Angelman syndrome, Prader Willy syndrome, Chromosome 15q duplication syndrome, and Chromosome 4 interstitial deletion. Studying these conditions could be a practical strategy to better understand the mechanisms of nociception and investigate potential therapeutic targets against pain.

Primary Cutaneous Lymphoma: Recommendations for Clinical Trial Design and Staging Update from the ISCL, USCLC, and EORTC

Blood

2021 Nov 10

Olsen, EA;Whittaker, S;Willemze, R;Pinter-Brown, L;Foss, FM;Geskin, LJ;Schwartz, LH;Horwitz, SM;Guitart, J;Zic, J;Kim, YH;Wood, GS;Duvic, M;Ai, WZ;Girardi, M;Gru, A;Guenova, E;Hodak, E;Hoppe, RT;Kempf, W;Kim, EJ;Lechowicz, MJ;Ortiz-Romero, PL;Papadavid, E;Quaglino, P;Pittelkow, MR;Prince, HM;Sanches, JA;Sugaya, M;Vermeer, MH;Zain, J;Knobler, R;Stadler, R;Bagot, M;Scarisbrick, JJ;
PMID: 34758074 | DOI: 10.1182/blood.2021012057

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome (MF/SS), the most common type of PCL, none exist for the other PCLs. In addition, staging in the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

An introduction to spatial transcriptomics for biomedical research

Genome medicine

2022 Jun 27

Williams, CG;Lee, HJ;Asatsuma, T;Vento-Tormo, R;Haque, A;
PMID: 35761361 | DOI: 10.1186/s13073-022-01075-1

Single-cell transcriptomics (scRNA-seq) has become essential for biomedical research over the past decade, particularly in developmental biology, cancer, immunology, and neuroscience. Most commercially available scRNA-seq protocols require cells to be recovered intact and viable from tissue. This has precluded many cell types from study and largely destroys the spatial context that could otherwise inform analyses of cell identity and function. An increasing number of commercially available platforms now facilitate spatially resolved, high-dimensional assessment of gene transcription, known as 'spatial transcriptomics'. Here, we introduce different classes of method, which either record the locations of hybridized mRNA molecules in tissue, image the positions of cells themselves prior to assessment, or employ spatial arrays of mRNA probes of pre-determined location. We review sizes of tissue area that can be assessed, their spatial resolution, and the number and types of genes that can be profiled. We discuss if tissue preservation influences choice of platform, and provide guidance on whether specific platforms may be better suited to discovery screens or hypothesis testing. Finally, we introduce bioinformatic methods for analysing spatial transcriptomic data, including pre-processing, integration with existing scRNA-seq data, and inference of cell-cell interactions. Spatial -omics methods are already improving our understanding of human tissues in research, diagnostic, and therapeutic settings. To build upon these recent advancements, we provide entry-level guidance for those seeking to employ spatial transcriptomics in their own biomedical research.

LB981 Pandemic associated chilblain-like lesions result from an inducible type 1 interferon response to SARS-CoV-2

Journal of Investigative Dermatology

2022 Aug 01

Arkin, L;Costa da Silva, A;Mays, J;
| DOI: 10.1016/j.jid.2022.05.1004

Chilblain-like lesions (CLL), known in the lay press as “COVID toes,” increased significantly during the COVID-19 pandemic. The phenotypic similarity of chilblains in the monogenic type 1 interferonopathies, coupled with the consistent clinical phenotype across multiple countries and temporospatial association with COVID-19 spread, suggest a SARS-CoV-2 triggered immune phenomenon. Yet direct evidence of this relationship has been limited due to low rates of SARS-CoV-2 positivity utilizing conventional testing. We prospectively enrolled a cohort of 79 patients with CLL across 4 waves of the SARS-CoV-2 pandemic in Wisconsin collecting serial blood samples and lesional skin biopsies. Immunophenotyping including the type 1 interferon (IFN-1) signature was investigated utilizing multiplex immunohistochemistry in affected tissue. Proteomics and RNA sequencing were performed on the peripheral blood at serial time points. RNAscope for S gene and depositional immunohistochemistry for evidence of SARS-CoV-2 were performed on tissue. Antibody responses and T-cell specific responses to SARS-CoV-2 were performed and an animal model (golden hamster) provided mechanistic evidence of dissemination of viral RNA to acral sites with local IFN-1 activation. Our results support an inducible local and peripheral IFN-1 signature, which abrogates within weeks, with evidence of viral SARS-CoV-2 RNA as the trigger.

Genetics at the Cell Level

Handbook of Genetic Diagnostic Technologies in Reproductive Medicine

2022 May 10

Lorenzi, V;Vento-Tormo, R;
| DOI: 10.1201/9781003024941-2

The Human Cell Atlas (HCA) is an international consortium established at the end of 2016 with the mission of mapping and characterizing all cells in the human body in terms of their distinctive patterns of gene expression, physiological states, and location (Rozenblatt-Rosen et al., 2017); (Regev et al., 2017) (http://www.humancellatlas.org" xmlns:xlink="http://www.w3.org/1999/xlink">www.humancellatlas.org). It is an open and collaborative initiative, bringing together experts across multiple disciplines, and is meant to progress in phases. Recently, the first maps focused on specific organs and tissues (Ordovas-Montanes et al., 2018; Vento-Tormo et al., 2018; Popescu et al., 2019; Ramachandran et al., 2019; Smillie et al., 2019; Stewart et al., 2019; Vieira Braga et al., 2019) have laid the foundations for further work aimed at completing the atlas to include at least ten billion cells that fully represent the world's diversity.

Deprenyl Reduces Inflammation During Acute SIV Infection

SSRN Electronic Journal

2021 Nov 17

Emanuel, K;Runner, K;Brodnik, Z;Morsey, B;Lamberty, B;Johnson, H;Acharya, A;Byrareddy, S;Espana, R;Fox, H;Gaskill, P;
| DOI: 10.2139/ssrn.3961038

In the era of antiretroviral therapy, inflammation is currently a central factor in a growing number of HIV-associated comorbidities, such as cardiovascular disease, cognitive impairment, and neuropsychiatric disorders. This highlights the value of developing therapeutics that both reduce HIV-associated inflammation and treat associated co-morbidities. Previous research on monoamine oxidase inhibitors (MAOIs) suggests that this class of drugs has anti-inflammatory properties in addition to neuropsychiatric effects. Therefore, we examined the impact of the deprenyl, an MAOI, on SIV-associated inflammation during acute SIV infection using the rhesus macaque model of HIV infection. Our results show that deprenyl decreased both peripheral and CNS inflammation but had no effect on viral load in either the periphery or CNS. These data show that the MAOI deprenyl has broad anti-inflammatory effects when given during the acute stage of SIV infection, suggesting that repurposing this drug could provide a beneficial adjuvant for antiretroviral therapy.

Rabies anterograde monosynaptic tracing allows identification of postsynaptic circuits receiving distinct somatosensory input

Neuroscience

2022 Mar 16

Pimpinella, S;Sauve, I;Dietrich, S;Zampieri, N;
PMID: 35306143 | DOI: 10.1016/j.neuroscience.2022.03.011

Somatosensory neurons detect vital information about the environment and internal status of the body, such as temperature, touch, itch, and proprioception. The circuit mechanisms controlling the coding of somatosensory information and the generation of appropriate behavioral responses are not clear yet. In order to address this issue, it is important to define the precise connectivity patterns between primary sensory afferents dedicated to the detection of different stimuli and recipient neurons in the central nervous system. In this study we describe and validate a rabies tracing approach for mapping mouse spinal circuits receiving sensory input from distinct, genetically defined, modalities. We analyzed the anatomical organization of spinal circuits involved in coding of thermal and mechanical stimuli and showed that somatosensory information from distinct modalities is relayed to partially overlapping ensembles of interneurons displaying stereotyped laminar organization, thus highlighting the importance of positional features and population coding for the processing and integration of somatosensory information.

Sensory representation and detection mechanisms of gut osmolality change

Nature

2022 Feb 01

Ichiki, T;Wang, T;Kennedy, A;Pool, AH;Ebisu, H;Anderson, DJ;Oka, Y;
PMID: 35082448 | DOI: 10.1038/s41586-021-04359-5

Ingested food and water stimulate sensory systems in the oropharyngeal and gastrointestinal areas before absorption1,2. These sensory signals modulate brain appetite circuits in a feed-forward manner3-5. Emerging evidence suggests that osmolality sensing in the gut rapidly inhibits thirst neurons upon water intake. Nevertheless, it remains unclear how peripheral sensory neurons detect visceral osmolality changes, and how they modulate thirst. Here we use optical and electrical recording combined with genetic approaches to visualize osmolality responses from sensory ganglion neurons. Gut hypotonic stimuli activate a dedicated vagal population distinct from mechanical-, hypertonic- or nutrient-sensitive neurons. We demonstrate that hypotonic responses are mediated by vagal afferents innervating the hepatic portal area (HPA), through which most water and nutrients are absorbed. Eliminating sensory inputs from this area selectively abolished hypotonic but not mechanical responses in vagal neurons. Recording from forebrain thirst neurons and behavioural analyses show that HPA-derived osmolality signals are required for feed-forward thirst satiation and drinking termination. Notably, HPA-innervating vagal afferents do not sense osmolality itself. Instead, these responses are mediated partly by vasoactive intestinal peptide secreted after water ingestion. Together, our results reveal visceral hypoosmolality as an important vagal sensory modality, and that intestinal osmolality change is translated into hormonal signals to regulate thirst circuit activity through the HPA pathway.

Primary cilia direct murine articular cartilage tidemark patterning through Hedgehog signaling and ambulatory load

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

2022 Jan 21

Rux, D;Helbig, K;Han, B;Cortese, C;Koyama, E;Han, L;Pacifici, M;
PMID: 35060644 | DOI: 10.1002/jbmr.4506

Articular cartilage (AC) is essential for body movement but is highly susceptible to degenerative diseases and has poor self-repair capacity. To improve current subpar regenerative treatments, developmental mechanisms of AC should be clarified and, specifically, how its postnatal multi-zone organization is acquired. Primary cilia are cell surface organelles crucial for mammalian tissue morphogenesis. While their importance for chondrocyte functioning is appreciated, their specific roles in postnatal AC morphogenesis remain unclear. To explore these mechanisms, we used a murine conditional loss-of-function approach (Ift88-flox) targeting joint-lineage progenitors (Gdf5Cre) and monitored postnatal knee AC development. Joint formation and growth up to juvenile stages were largely unaffected. However, mature AC (aged 2 months) exhibited disorganized extracellular matrix, decreased aggrecan and collagen II due to reduced gene expression (not increased catabolism), and marked reduction of AC modulus by 30-50%. In addition, and unexpectedly, we discovered that tidemark patterning was severely disrupted, as was hedgehog signaling, and exhibited specificity based on regional load-bearing functions of AC. Interestingly, Prg4 expression was markedly increased in highly loaded sites in mutants. Together, our data provide evidence that primary cilia orchestrate postnatal AC morphogenesis including tidemark topography, zonal matrix composition and ambulation load responses. This article is protected by

Glial Modulation of Energy Balance: The Dorsal Vagal Complex Is No Exception

International journal of molecular sciences

2022 Jan 16

Troadec, JD;Gaigé, S;Barbot, M;Lebrun, B;Barbouche, R;Abysique, A;
PMID: 35055143 | DOI: 10.3390/ijms23020960

The avoidance of being overweight or obese is a daily challenge for a growing number of people. The growing proportion of people suffering from a nutritional imbalance in many parts of the world exemplifies this challenge and emphasizes the need for a better understanding of the mechanisms that regulate nutritional balance. Until recently, research on the central regulation of food intake primarily focused on neuronal signaling, with little attention paid to the role of glial cells. Over the last few decades, our understanding of glial cells has changed dramatically. These cells are increasingly regarded as important neuronal partners, contributing not just to cerebral homeostasis, but also to cerebral signaling. Our understanding of the central regulation of energy balance is part of this (r)evolution. Evidence is accumulating that glial cells play a dynamic role in the modulation of energy balance. In the present review, we summarize recent data indicating that the multifaceted glial compartment of the brainstem dorsal vagal complex (DVC) should be considered in research aimed at identifying feeding-related processes operating at this level.

Identification of Lung Innervating Sensory Neurons and Their Target Specificity

American journal of physiology. Lung cellular and molecular physiology

2021 Nov 10

Su, Y;Barr, J;Jaquish, A;Xu, J;Verheyden, JM;Sun, X;
PMID: 34755535 | DOI: 10.1152/ajplung.00376.2021

Known as the gas exchange organ, the lung is also critical for responding to the aerosol environment in part through interaction with the nervous system. The diversity and specificity of lung innervating neurons remains poorly understood. Here, we interrogated the cell body location, molecular signature and projection pattern of lung innervating sensory neurons. Retrograde tracing from the lung coupled with whole tissue clearing highlighted neurons primarily in the vagal ganglia. Centrally, they project specifically to the nucleus of the solitary tract in the brainstem. Peripherally, they enter the lung alongside branching airways. Labeling of nociceptor Trpv1+ versus peptidergic Tac1+ vagal neurons showed shared and distinct terminal morphology and targeting to airway smooth muscles, vasculature including lymphatics, and alveoli. Notably, a small population of vagal neurons that are Calb1+ preferentially innervate pulmonary neuroendocrine cells, a demonstrated airway sensor population. This atlas of lung innervating neurons serves as a foundation for understanding their function in lung.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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