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Genome Editing and Gene Therapies: Complex and Expensive Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Intellia Therapeutics in collaborations with researchers at Regeneron Pharmaceuticals, Inc., and the University of Porto in Portugal work on an in vivo CRISPR/Cas9-mediated cure of hereditary transthyretin amyloidosis (ATTR). ATTR is an autosomal dominant, adult-onset systemic disease, characterized by slowly progressive neuropathy affecting the peripheral and autonomic nervous systems, and caused by point mutations in the gene encoding transthyretin (TTR) leading to its misfolding associated with amyloid deposits in the bodies organs (Adams et al., 2019). More than 100 TTR mutations are known of which V30M and V122I occur most frequently. In the NTLA-1001 therapy a modular lipid nanoparticle (LNP) formulation contains encapsulated a single guide RNA, and mRNA encoding S. pyrogenes Cas9 for delivery into the cell’s nucleus. The strategy is to disrupt the expression of a mutated transthyretin-encoding allele via non homologous end joining (Subsection 10.3). So far, the results are promising. For instance, TTR knock-down persist in mice over a period of 12 month, and in primary human hepatocytes a reduction of TTR mRNA and protein was demonstrated in vitro with lead human TTR CRISPR/Cas9 LNPs. A submission of an IND application is planned for end of 2019.
Association between polychlorinated biphenyl exposure and thyroid hormones: a systematic review and meta-analysis
Published in Journal of Environmental Science and Health, Part C, 2022
Christine C. Little, Joshua Barlow, Mathilda Alsen, Maaike van Gerwen
PCBs are metabolized to hydroxylated metabolites (OH-PCBs) by cytochrome P450 enzymes in vivo. Hydroxylated PCBs share a similar molecular structure to thyroid hormones and have been demonstrated to competitively bind the thyroid hormone transport protein transthyretin with high affinity, thereby displacing the natural ligand T4.41,42 Furthermore, shared structural properties have been shown to enable interaction of both PCBs and their hydroxylated metabolites with thyroid hormone receptors, producing both agonistic and antagonistic effects.40,43 A recent study using computational analysis found that the difference in receptor effects may stem from the degree of PCB chlorination, with higher chlorinated PCBs tending to produce antagonistic effects and lower chlorinated PCBs tending to produce agonistic effects at thyroid hormone receptors.43 PCB 105, 153 and 180 are all considered to be high-chlorination PCB congeners.
Toward an integrated framework for assessing micropollutants in marine mammals: Challenges, progress, and opportunities
Published in Critical Reviews in Environmental Science and Technology, 2021
Edmond Sanganyado, Ran Bi, Charles Teta, Lucas Buruaem Moreira, Xiaoxuan Yu, Sun Yajing, Tatenda Dalu, Imran Rashid Rajput, Wenhua Liu
Effect-directed analysis integrates differential extraction, bioassay and chemical analysis to to determine the biological effect of a group of compounds using a simple, sensitive, and reproducible endpoint. Biological responses at molecular to cellular level can be used as endpoints in effect-directed analysis. For example, in-vitro bioassays such as marine mammalian cell cultures can be used in effect-directed analysis of marine mammals. The chemical-activated luciferase gene expression (CALUX) reporter gene bioassay is widely used in effect-directed analysis of potentially endocrine disrupting micropollutants and their transformation products in mammals (Simon et al., 2013). It measures exogenous activation of different receptors such as androgen, dioxin, and progesterone receptors as well as estrogen receptor α and peroxisome proliferator-activated receptor γ2 (Bletsou et al., 2015). Care should be taken when using androgenic and estrogenic receptors since they have a broad ligand specificity which complicates identification of the causative toxicants. Current studies on effect-directed analysis in marine mammals are not limited to bioassays monitoring disruption of estrogenic and androgenic activities but also include the disruption of thyroid hormones in blood plasma and nonspecific modes of action (Jin et al., 2015). Micropollutants such as PBDEs, PFAS, and hydroxylated PCB metabolites can mimic thyroid hormones such as thyroxine and triiodothyronine by binding to transport proteins resulting in an adverse effect on the transport of thyroid hormones. Thyroid hormonal system plays a critical role in metabolism as well as development of nervous systems in fetuses. For example, screening of polar bear blood plasma using a radioligand 125I- thyroxine- transthyretin binding assay found high thyroid hormone transport protein binding activity which was attributed to branched nonylphenol, mono- and dihydroxylated-octachlorinated biphenyls (Simon et al., 2013).
Dietary exposure to thyroid disrupting chemicals: a community-based study in Canada
Published in Journal of Environmental Science and Health, Part C, 2023
Nicole Babichuk, Atanu Sarkar, Shree Mulay, John Knight, Edward Randell
Most endocrine disrupting chemicals are manufactured intentionally or as by-products of human industrial activities; they can be found in personal care products, food items, and the household environment (shedding from consumer products into dust).4,5 Ultimately, endocrine disrupting chemicals escape into the local environment, where they can disperse over long distances.5,6 Research has pointed to polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), and dichloro-diphenyl-dichloro-ethylene (DDE) as being thyroid disruptors, and their ubiquitous presence in the environment makes them an ideal candidate to study population-level exposure and health effects. There are five PBDE congeners (PBDE-47, -99, -100, -153, -154) used commercially, and they are most commonly found in the environment and are known to bioaccumulate.7 In studies measuring the accumulation of PBDEs in serum and tissues, PBDE-47, -99, and -153 predominate.8,9 All three of these chemicals are associated with TH disruption in humans and marine species, the effects of which may lead to detrimental developmental, physical, and cognitive functioning due to the important role of THs in these processes. PBDEs may compete with THs for binding to the transport protein transthyretin (TTR) in the serum and suppress TH receptor transcription in tissues,10,11 while PCBs have been shown to decrease total T4 and T3 levels in dogs.12 This trend persists at the population level in humans, where PCB concentrations have been negatively associated with FT3 and TSH in pregnant women.13 Hydroxylated PCBs (OH-PCBs) have also been shown to alter the activity of microsomal enzymes such as sulfotransferases, and to competitively bind to TTR.14 PBB-153 has been associated with metabolic alterations.15 PBB levels are associated with higher free T3 (FT3) but lower FT4,16 and at the population level, PBB-153 is associated with thyroid disease.17 A negative association has been found between DDE and both FT3 and TSH.13 Exposure to DDE is associated with a decline in serum TTR, elevated TH receptor mRNA expression, and upregulated hepatic enzymes.18