Epigenetic Transgenerational Inheritance of the Effects of Obesogen Exposure

Obesity and metabolic disorders have become a worldwide pandemic affecting millions of people. Although obesity is a multifaceted disease, there is growing evidence supporting the obesogen hypothesis, which proposes that exposure to a subset of endocrine disrupting chemicals (EDCs), known as obesogens, promotes obesity. While these effects can be observed in vitro using cell models, in vivo and human epidemiological studies have strengthened this hypothesis. Evidence from animal models showed that the effects of obesogen exposure can be inherited transgenerationally through at least the F4 generation. Transgenerational effects of EDC exposure predispose future generations to undesirable phenotypic traits and diseases, including obesity and related metabolic disorders. The exact mechanisms through which phenotypic traits are passed from an exposed organism to their offspring, without altering the primary DNA sequence, remain largely unknown. Recent research has provided strong evidence suggesting that a variety of epigenetic mechanisms may underlie transgenerational inheritance. These include differential DNA methylation, histone methylation, histone retention, the expression and/or deposition of non-coding RNAs and large-scale alterations in chromatin structure and organization. This review highlights the most recent advances in the field of epigenetics with respect to the transgenerational effects of environmental obesogens. We highlight throughout the paper the strengths and weaknesses of the evidence for proposed mechanisms underlying transgenerational inheritance and why none of these is sufficient to fully explain the phenomenon. We propose that changes in higher order chromatin organization and structure may be a plausible explanation for how some disease predispositions are heritable through multiple generations, including those that were not exposed. A solid understanding of these possible mechanisms is essential to fully understanding how environmental exposures can lead to inherited susceptibility to diseases such as obesity.

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Implications of environmental toxicants on ovarian follicles: how it can adversely affect the female fertility?

Environmental Science and Pollution Research ◽

10.1007/s11356-021-16489-4 ◽

2021 ◽

Author(s):

Keerthi Priya ◽

Manjunath Setty ◽

Uddagiri Venkanna Babu ◽

Karkala Sreedhara Ranganath Pai

Keyword(s):

Polycystic Ovary ◽

Endocrine Disrupting Chemicals ◽

Epidemiological Studies ◽

Female Fertility ◽

Environmental Toxicants ◽

Primordial Follicles ◽

Reproductive Life ◽

Sanitary Product

AbstractThe pool of primordial follicles formed in the ovaries during early development determines the span and quality of fertility in the reproductive life of a woman. As exposure to occupational and environmental toxicants (ETs) has become inevitable, consequences on female fertility need to be established. This review focuses on the ETs, especially well-studied prototypes of the classes endocrine disrupting chemicals (EDCs), heavy metals, agrochemicals, cigarette smoke, certain chemicals used in plastic, cosmetic and sanitary product industries etc that adversely affect the female fertility. Many in vitro, in vivo and epidemiological studies have indicated that these ETs have the potential to affect folliculogenesis and cause reduced fertility in women. Here, we emphasize on four main conditions: polycystic ovary syndrome, primary ovarian insufficiency, multioocytic follicles and meiotic defects including aneuploidies which can be precipitated by ETs. These are considered main causes for reduced female fertility by directly altering the follicular recruitment, development and oocytic meiosis. Although substantial experimental evidence is drawn with respect to the detrimental effects, it is clear that establishing the role of one ET as a risk factor in a single condition is difficult as multiple conditions have common risk factors. Therefore, it is important to consider this as a matter of public and wildlife health.

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Ultra-processed/Ultra-formulated foods: association with chronic disease risk

European Journal of Public Health ◽

10.1093/eurpub/ckaa165.1406 ◽

2020 ◽

Vol 30 (Supplement_5) ◽

Author(s):

M Touvier

Keyword(s):

Large Scale ◽

Disease Risk ◽

Heart Diseases ◽

Epidemiological Studies ◽

Processed Foods ◽

Breast Cancers ◽

Dietary Intakes ◽

Research Perspectives

Abstract During the past decades, diets have shifted towards an important increase in the degree of food processing and formulation. “Ultra-processed foods” (UPF) now represent more than 50% of energy intakes in several Western countries. In the very last years, an impressive accumulation of evidence from large-scale epidemiological studies linked regular UPF consumption to diverse adverse health outcomes. In this framework, our team of conducted pioneer studies within the prospective e-cohort NutriNet-Santé (n = 170 000) launched in 2009 in France. Dietary intakes were collected using repeated and validated 24-hour dietary records, covering >3,500 food items, which have been categorized using the NOVA classification according to their degree of processing. These analyses highlighted robust significant associations between the consumption of UPF and increased risks of overall and breast cancers, cardiovascular, cerebrovascular, and coronary heart diseases, mortality, type 2-diabetes, overweight, obesity and weight gain, depressive symptoms, and gastro-intestinal disorders. Research perspectives now consist in elucidating the potential mechanisms that underlie these associations. Our team is launching an Europe-funded project built as a combination of epidemiological studies and in-vitro/in-vivo experiments, in order to shed light on individual exposure to food additive 'cocktails' in relation to human health. Meanwhile and even if further studies are needed to better understand the relative contributions of these factors, public health authorities in several countries have recently started to promote unprocessed or minimally processed foods and to recommend limiting the consumption of ultra-processed foods.

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Toxic influence of organophosphate, carbamate, and organochlorine pesticides on cellular metabolism of lipids, proteins, and carbohydrates

Human & Experimental Toxicology ◽

10.1177/0960327110388959 ◽

2010 ◽

Vol 30 (9) ◽

pp. 1119-1140 ◽

Cited By ~ 197

Author(s):

Somayyeh Karami-Mohajeri ◽

Mohammad Abdollahi

Keyword(s):

Oxidative Stress ◽

Metabolic Disorders ◽

Epidemiological Studies ◽

The Body ◽

Bibliographic Databases ◽

Ache Inhibitors ◽

Central Nervous Systems ◽

Enzymatic Pathways

Pesticides, including organophosphate (OP), organochlorine (OC), and carbamate (CB) compounds, are widely used in agricultural and indoor purposes. OP and CB act as acetyl cholinesterase (AChE) inhibitors that affect lots of organs such as peripheral and central nervous systems, muscles, liver, pancreas, and brain, whereas OC are neurotoxic involved in alteration of ion channels. There are several reports about metabolic disorders, hyperglycemia, and also oxidative stress in acute and chronic exposures to pesticides that are linked with diabetes and other metabolic disorders. In this respect, there are several in vitro and in vivo but few clinical studies about mechanism underlying these effects. Bibliographic databases were searched for the years 1963–2010 and resulted in 1652 articles. After elimination of duplicates or irrelevant papers, 204 papers were included and reviewed. Results indicated that OP and CB impair the enzymatic pathways involved in metabolism of carbohydrates, fats and protein within cytoplasm, mitochondria, and proxisomes. It is believed that OP and CB show this effect through inhibition of AChE or affecting target organs directly. OC mostly affect lipid metabolism in the adipose tissues and change glucose pathway in other cells. As a shared mechanism, all OP, CB and OC induce cellular oxidative stress via affecting mitochondrial function and therefore disrupt neuronal and hormonal status of the body. Establishing proper epidemiological studies to explore exact relationships between exposure levels to these pesticides and rate of resulted metabolic disorders in human will be helpful.

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Normal mesothelial cell lines newly derived from human pleural biopsy explants

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00141.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. L652-L660

Author(s):

Nathanael Pruett ◽

Anand Singh ◽

Ahjeetha Shankar ◽

David S. Schrump ◽

Chuong D. Hoang

Keyword(s):

Cell Cultures ◽

Large Scale ◽

Mesothelial Cell ◽

Surgical Techniques ◽

Cell Surface Expression ◽

Patient Specific ◽

Phenotypic Traits ◽

Cancer Type

Mesothelial cells are arranged as a monolayer on covering membranes that invest surfaces of body cavities like the pleura and peritoneum. Primary human mesothelial cell (HMC) cultures are needed for studying mesothelial cell homeostasis and developing disease models, such as wound healing or cancers. Remarkably, there is a paucity of useable HMC lines that are currently available that faithfully recapitulate normal in vivo phenotypic characteristics. Here, we present a strategy to recover HMC from human pleural tissue and to immortalize them for extended in vitro culturing. Human pleural membrane was harvested by minimally invasive surgical techniques. HMC were isolated using a two-step process combining explant cellular outgrowth from biopsy tissue and flow cytometry based on cell surface expression of cadherin-1 and CD71. Cell cultures were generated after lentiviral transfection with human telomerase. The new HMC cultures retain the same phenotypic traits and physiologic features as their in vivo counterparts, yet they can be adapted for short-term or long-term culture in large-scale in vitro experimentation. In particular, we generated a new HMC line harboring a germline mutation in breast cancer type-1-associated protein-1 ( BAP1), a causal tumor suppressor gene, that could be instrumental to malignant mesothelioma research. Patient-specific, normal HMC may serve as novel discovery tools allowing more powerful research models of both normal physiology and disease processes. Our surgically driven approach leads to a limitless resource of novel mesothelial cell cultures.

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Purification of the Antihemophilic Factor by Gel Filtration on Agarose

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651394 ◽

1969 ◽

Vol 22 (03) ◽

pp. 577-583 ◽

Cited By ~ 3

Author(s):

M.M.P Paulssen ◽

A.C.M.G.B Wouterlood ◽

H.L.M.A Scheffers

Keyword(s):

Factor Viii ◽

Plasma Proteins ◽

Large Scale ◽

Gel Filtration ◽

Large Scale Preparation ◽

Scale Preparation ◽

Antihemophilic Factor

SummaryFactor VIII can be isolated from plasma proteins, including fibrinogen by chromatography on agarose. The best results were obtained with Sepharose 6B. Large scale preparation is also possible when cryoprecipitate is separated by chromatography. In most fractions containing factor VIII a turbidity is observed which may be due to the presence of chylomicrons.The purified factor VIII was active in vivo as well as in vitro.

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Naphthoquinones and derivatives for chemotherapy: perspectives and limitations of their anti-trypanosomatids activities

Current Pharmaceutical Design ◽

10.2174/1381612826666201109111802 ◽

2020 ◽

Vol 26 ◽

Author(s):

Luíza Dantas-Pereira ◽

Edézio F. Cunha-Junior ◽

Valter V. Andrade-Neto ◽

John F. Bower ◽

Guilherme A. M. Jardim ◽

...

Keyword(s):

Large Scale ◽

Neglected Tropical Diseases ◽

Folk Medicine ◽

Leishmania Species ◽

Parasitic Infections ◽

Mechanistic Analysis ◽

Leishmania Spp ◽

Nanomolar Range

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

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Lentiviral Vectors for Delivery of Gene-Editing Systems Based on CRISPR/Cas: Current State and Perspectives

Viruses ◽

10.3390/v13071288 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1288

Author(s):

Wendy Dong ◽

Boris Kantor

Keyword(s):

Large Scale ◽

Lentiviral Vector ◽

Clinical Applications ◽

Scale Production ◽

Base Editing ◽

Epigenome Editing ◽

Vector Systems ◽

Dividing Cells

CRISPR/Cas technology has revolutionized the fields of the genome- and epigenome-editing by supplying unparalleled control over genomic sequences and expression. Lentiviral vector (LV) systems are one of the main delivery vehicles for the CRISPR/Cas systems due to (i) its ability to carry bulky and complex transgenes and (ii) sustain robust and long-term expression in a broad range of dividing and non-dividing cells in vitro and in vivo. It is thus reasonable that substantial effort has been allocated towards the development of the improved and optimized LV systems for effective and accurate gene-to-cell transfer of CRISPR/Cas tools. The main effort on that end has been put towards the improvement and optimization of the vector’s expression, development of integrase-deficient lentiviral vector (IDLV), aiming to minimize the risk of oncogenicity, toxicity, and pathogenicity, and enhancing manufacturing protocols for clinical applications required large-scale production. In this review, we will devote attention to (i) the basic biology of lentiviruses, and (ii) recent advances in the development of safer and more efficient CRISPR/Cas vector systems towards their use in preclinical and clinical applications. In addition, we will discuss in detail the recent progress in the repurposing of CRISPR/Cas systems related to base-editing and prime-editing applications.

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Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma

Gut ◽

10.1136/gutjnl-2020-323276 ◽

2021 ◽

pp. gutjnl-2020-323276

Author(s):

Jin Zhou ◽

Zhong Wu ◽

Zhouwei Zhang ◽

Louisa Goss ◽

James McFarland ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Large Scale ◽

Cell Cancer ◽

Oesophageal Squamous Cell Carcinoma ◽

Squamous Cancer ◽

Striking Success

ObjectiveOesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.DesignWe combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.ResultsWe identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.ConclusionThese results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.

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A therapeutic vascular conduit to support in vivo cell-secreted therapy

npj Regenerative Medicine ◽

10.1038/s41536-021-00150-2 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Edward X. Han ◽

Hong Qian ◽

Bo Jiang ◽

Maria Figetakis ◽

Natalia Kosyakova ◽

...

Keyword(s):

Vascular Graft ◽

Large Scale ◽

Biological Effects ◽

Therapeutic Protein ◽

Close Proximity ◽

Delivery Platform ◽

Stage Renal Disease ◽

End Stage

AbstractA significant barrier to implementation of cell-based therapies is providing adequate vascularization to provide oxygen and nutrients. Here we describe an approach for cell transplantation termed the Therapeutic Vascular Conduit (TVC), which uses an acellular vessel as a scaffold for a hydrogel sheath containing cells designed to secrete a therapeutic protein. The TVC can be directly anastomosed as a vascular graft. Modeling supports the concept that the TVC allows oxygenated blood to flow in close proximity to the transplanted cells to prevent hypoxia. As a proof-of-principle study, we used erythropoietin (EPO) as a model therapeutic protein. If implanted as an arteriovenous vascular graft, such a construct could serve a dual role as an EPO delivery platform and hemodialysis access for patients with end-stage renal disease. When implanted into nude rats, TVCs containing EPO-secreting fibroblasts were able to increase serum EPO and hemoglobin levels for up to 4 weeks. However, constitutive EPO expression resulted in macrophage infiltration and luminal obstruction of the TVC, thus limiting longer-term efficacy. Follow-up in vitro studies support the hypothesis that EPO also functions to recruit macrophages. The TVC is a promising approach to cell-based therapeutic delivery that has the potential to overcome the oxygenation barrier to large-scale cellular implantation and could thus be used for a myriad of clinical disorders. However, a complete understanding of the biological effects of the selected therapeutic is absolutely essential.

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Antidiabetic Properties of Naringenin: A Citrus Fruit Polyphenol

Biomolecules ◽

10.3390/biom9030099 ◽

2019 ◽

Vol 9 (3) ◽

pp. 99 ◽

Cited By ~ 16

Author(s):

Danja J. Den Hartogh ◽

Evangelia Tsiani

Keyword(s):

Insulin Resistance ◽

Animal Studies ◽

Citrus Fruit ◽

Epidemiological Studies ◽

Personal Health ◽

Current Review ◽

Vegetables And Fruits

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by insulin resistance and hyperglycemia and is associated with personal health and global economic burdens. Current strategies/approaches of insulin resistance and T2DM prevention and treatment are lacking in efficacy resulting in the need for new preventative and targeted therapies. In recent years, epidemiological studies have suggested that diets rich in vegetables and fruits are associated with health benefits including protection against insulin resistance and T2DM. Naringenin, a citrus flavanone, has been reported to have antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, immunomodulatory and antidiabetic properties. The current review summarizes the existing in vitro and in vivo animal studies examining the anti-diabetic effects of naringenin.

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