An AIE-based fluorescent probe to detect peroxynitrite levels in human serum and its cellular imaging.

An AIE-based fluorescent probe was designed to evaluate peroxynitrite levels in complex biological samples. The newly synthesized hydrazone-conjugated probe fluoresces strongly in the presence of peroxynitrite. Clinically, the peroxynitrite levels can be measured in human serum and cellular mitochondria with an LOD of 6.5 nM by fluorescence imaging in vitro.

Theranostic Fluorescent Probes.

The ability to gain spatiotemporal information, and in some cases achieve spatiotemporal control, in the context of drug delivery makes theranostic fluorescent probes an attractive and intensely investigated research topic. This interest is reflected in the steep rise in publications on the topic that have appeared over the past decade. Theranostic fluorescent probes, in their various incarnations, generally comprise a fluorophore linked to a masked drug, in which the drug is released as the result of certain stimuli, with both intrinsic and extrinsic stimuli being reported. This release is then signaled by the emergence of a fluorescent signal. Importantly, the use of appropriate fluorophores has enabled not only this emerging fluorescence as a spatiotemporal marker for drug delivery but also has provided modalities useful in photodynamic, photothermal, and sonodynamic therapeutic applications. In this review we highlight recent work on theranostic fluorescent probes with a particular focus on probes that are activated in tumor microenvironments. We also summarize efforts to develop probes for other applications, such as neurodegenerative diseases and antibacterials. This review celebrates the diversity of designs reported to date, from discrete small-molecule systems to nanomaterials. Our aim is to provide insights into the potential clinical impact of this still-emerging research direction.

Multiple low-dose radiation-induced neuronal cysteine transporter expression and oxidative stress are rescued by N-acetylcysteine in neuronal SH-SY5Y cells.

Recently, several studies have demonstrated that low-dose radiation (LDR) therapy has positively impacts on the treatment of Alzheimer's disease (AD). LDR suppresses the production of pro-neuroinflammation molecules and improves cognitive function in AD. However, it is unclear whether direct exposure to LDR causes beneficial effects and what mechanism is involved in neuronal cells. In this study, we first determined the effect of high-dose radiation (HDR) alone on C6 cells and SH-SY5Y cells. We found that SH-SY5Y cells were more vulnerable than C6 cells to HDR. Moreover, in neuronal SH-SY5Y cells exposed to single or multiple LDR, N-type cells showed decreased cell viability with increasing radiation exposure time and frequency, but S-type cells were unaffected. Multiple LDR increased proapoptotic molecules such as p53, Bax and cleaved caspase-3, and decreased anti-apoptotic molecule (Bcl2). Multiple LDR also generated free radicals in neuronal SH-SY5Y cells. We detected a change in the expression of the neuronal cysteine transporter EAAC1. Pretreatment with N-acetylcysteine (NAC) rescued the increased in EAAC1 expression and the generation of ROS in neuronal SH-SY5Y cells after multiple LDR. Furthermore, we verified whether the increased in EAAC1 expression induces cell defense or cell death promotion signaling. We showed that transient overexpression of EAAC1 reduced the multiple LDR-induced p53 overexpression in neuronal SH-SY5Y cells. Our results indicate that neuronal cells can be injured by increased production of ROS not only by HDR but also by multiple LDR, which suggests that combination treatment with anti-free radical agents such as NAC may be useful in multiple LDR therapy.

Neuregulin-1 reverses anxiety-like behavior and social behavior deficits induced by unilateral micro-injection of CoCl2 into the ventral hippocampus (vHPC).

Neuregulin-1 (NRG1) is an epidermal growth factor family member with essential roles in the developing and adult nervous systems. In recent years, establishing evidence has collectively suggested that NRG1 is a new modulator of central nervous system (CNS) injury and disease, with multifaceted roles in neuroprotection, remyelination, neuroinflammation, and other repair mechanisms. NRG1 signaling exerts its effects via the tyrosine kinase receptors ErbB2-ErbB4. The NRG1/ErbB network in CNS pathology and repair has evolved, primarily in recent years. In the present study, we demonstrated that a unilateral microinjection of CoCl2 into the ventral hippocampus (vHPC) induced hypoxic insult and led to anxiety-related behaviors and deficit sociability in mice. NRG1 treatment significantly alleviated the CoCl2-induced increase of hypoxic-related molecules and behavioral abnormalities. Furthermore, NRG1 reduced the CoCl2-induced neuroinflammation and neuronal deficits in the vHPC or primary hippocampal neurons in mice. Collectively, these results suggest that NRG1 ameliorates hypoxia by alleviating synaptic deficits and behavioral abnormalities of the CoCl2-induced vHPC hypoxic model.

Inhibiting peripheral and central MAO-B ameliorates joint inflammation and cognitive impairment in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation and the destruction of joints and systemic organs. RA is commonly accompanied by neuropsychiatric complications, such as cognitive impairment and depression. However, the role of monoamine oxidase (MAO) and its inhibitors in controlling neurotransmitters associated with these complications in RA have not been clearly identified. Here, we report that peripheral and central MAO-B are highly associated with joint inflammation and cognitive impairment in RA, respectively. Ribonucleic acid (RNA) sequencing and protein expression quantification were used to show that MAO-B and related molecules, such as gamma aminobutyric acid (GABA), were elevated in the inflamed synovium of RA patients. In primary cultured fibroblast-like synoviocytes in the RA synovium, MAO-B expression was significantly increased by tumor necrosis factor (TNF)-α-induced autophagy, which produces putrescine, the polyamine substrate for GABA synthesis. We also observed that MAO-B-mediated aberrant astrocytic production of GABA was augmented by interleukin (IL)-1ß and inhibited CA1-hippocampal pyramidal neurons, which are responsible for memory storage, in an animal model of RA. Moreover, a newly developed reversible inhibitor of MAO-B ameliorated joint inflammation by inhibiting cyclooxygenase (Cox)-2. Therefore, MAO-B can be an effective therapeutic target for joint inflammation and cognitive impairment in patients with RA.

Sex, menopause, and age differences in the associations of persistent organic pollutants with thyroid hormones, thyroxine-binding globulin, and peripheral deiodinase activity: A cross-sectional study of the general Korean adult population.

Persistent organic pollutants (POPs) can disrupt the thyroid hormone system in humans. We assessed the associations of several POPs with serum thyroid hormones (T3 and T4) and thyroid-stimulating hormone, and investigated the modulating effects of sex, menopausal status, and age on these associations, in a subgroup of the adult population (n = 1250) from the Korean National Environmental Health Survey. PCB105 and PCB118 were negatively associated with total T4 in premenopausal females and males aged <50, whereas the associations were insignificant in other groups. PCB180, p,p'-DDE, and p,p'-DDT showed positive associations with total T3 in postmenopausal females; however, among males aged ≥50, PCB118, PCB138, and p,p'-DDE showed negative associations with total T3. The effects of exposure to multiple POPs were examined in multi-factor analyses. Factor 2 comprised PCB52, hexachlorobenzene, and BDE-47 was associated with an increase in free T4 in premenopausal females (ß = 0.015, p = 0.024), while Factor 1, which contained most POPs, was associated with a change in total T3 in postmenopausal females (ß = 0.032, p = 0.040) and males aged ≥50 (ß = -0.039, p = 0.023). Changes in total T4 or total T3 could be explained by differences in thyroxine-binding globulin (TBG) and peripheral deiodinase activity (GD). Negative associations of TBG with PCB105 in premenopausal females and PCB153 in males aged <50 may mediate the effect of decreasing total T4. PCB180, p,p'-DDE, p,p'-DDT, and Factor 1 were positively associated with GD, which is consistent with an increased total T3 in postmenopausal females. PCB118 was negatively associated with GD and total T3 in males aged ≥50. BDE-47 and ß-hexachlorocyclohexane were associated with thyroid autoantibodies in premenopausal females and males aged <50. Our observations suggest that the thyroid-disrupting effects of POPs may differ by sex, sex hormonal status, and age, and may be mediated by TBG and GD.

Profile of Environmental Chemicals in the Korean Population-Results of the Korean National Environmental Health Survey (KoNEHS) Cycle 3, 2015-2017.

The Korean National Environmental Health Survey (KoNEHS) program provides useful information on chemical exposure, serves as the basis for environmental health policies, and suggests appropriate measures to protect public health. Initiated on a three-year cycle in 2009, it reports the concentrations of major environmental chemicals among the representative Korean population. KoNEHS Cycle 3 introduced children and adolescents into the analysis, where the blood and urine samples of 6167 participants were measured for major metals, phthalates, phenolics, and other organic compounds. Lead, mercury, cadmium, metabolites of DEHP and DnBP, and 3-phenoxybenzoic acid levels of the Korean adult population tended to decrease compared to previous survey cycles but remained higher than those observed in the US or Canada. Both bisphenol A (BPA) and trans,trans-muconic acid concentrations have increased over time. Heavy metal concentrations (blood lead, and cadmium) in children and adolescents were approximately half that of adults, while some organic substances (e.g., phthalates and BPA) were high. BPA showed higher levels than in the US or Canada, whereas BPF and BPS showed lower detection rates in this cycle; however, as these are increasingly used as a substitute for BPA, further research is necessary. As environmental chemicals may affect childhood health and development, additional analyses should assess exposure sources and routes through continuous observations.

Lead, mercury, and cadmium exposures are associated with obesity but not with diabetes mellitus: Korean National Environmental Health Survey (KoNEHS) 2015-2017.

BACKGROUND: Associations of heavy metal exposures with obesity and obesity-related traits have been suggested, while those with nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM) are often inconsistent. METHODS: This study included 3787 adults aged ≥19 years who participated in the Korean National Environmental Health Survey 2015-2017, and investigated the association of toxic heavy metals with metabolic diseases. Lead (Pb), mercury (Hg), and cadmium (Cd) were measured either in urine (uHg, uCd) or total blood (bPb, bHg). Body mass index (BMI) was calculated, and DM cases were identified through a self-answered medication history. Hepatic Steatosis Index (HSI) as a surrogating index of NAFLD, was calculated using hepatic enzyme measurements, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). RESULTS: Adults in the highest quartile of bPb, bHg, and uHg showed significantly elevated odds of obesity (BMI ≥25 kg/m2), compared to the lowest quartile (OR 1.58 for bPb, 1.92 for bHg, and 1.81 for uHg). HSI was positively correlated with bHg, uHg, and uCd concentrations. The odds of NAFLD (HSI ≥36) were also increased with increasing quartile of bHg, uHg, and uCd concentrations. For DM, bPb showed a significant negative association, while bHg and uCd exhibited non-monotonic and inconclusive associations. CONCLUSIONS: Among the general adult population of Korea, both Pb and Hg exposures were associated with an increased risk of obesity. In addition, both Hg and Cd exposures were associated with increased odds of NAFLD. These metals, however, were not associated with an increased risk of DM.

Exposure to polycyclic aromatic hydrocarbons and volatile organic compounds is associated with a risk of obesity and diabetes mellitus among Korean adults: Korean National Environmental Health Survey (KoNEHS) 2015-2017.

Environmental pollutants have been known to increase the risks of not only respiratory and cardiovascular disease but also metabolic diseases such as obesity and diabetes mellitus (DM). Polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs) such as benzene and toluene are major constituents of environmental pollution. In the present study, we employed the population of the Korean National Environmental Health Survey (KoNEHS) Cycle 3 conducted between 2015 and 2017, and assessed the associations of urinary biomarkers for PAHs and VOCs exposure with obesity and DM. A total of 3787 adult participants were included and the urinary concentrations of four PAH metabolites and two VOC metabolites were measured. For correcting urine dilution, a covariate-adjusted standardization method was used. The highest quartiles of urinary 2-hydroxynaphthalene (2-NAP) [OR (95% confidence interval (CI)) = 1.46 (1.13, 1.87)] and sum of PAH metabolites [OR (95% CI) = 1.45 (1.13, 1.87)] concentrations were associated with a higher risk of obesity [body mass index (BMI)≥25 kg/m2]. BMI was positively associated with urinary 2-NAP [ß (95% CI) = 0.25 (0.09, 0.41), p = 0.003] and sum of PAH metabolites [ß (95% CI) = 0.29 (0.08, 0.49), p = 0.006] concentrations. The risk of DM was increased with increasing quartile of 2-hydroxyfluorene (2-OHFlu) and trans, trans-muconic acid (t,t-MA) (p for trend<0.05 and < 0.001, respectively). The highest quartile of t,t-MA showed a significantly higher risk of DM [OR (95% CI) = 2.77 (1.74, 4.42)] and obesity [OR (95% CI) = 1.42 (1.06, 1.90)]. Urinary t,t,-MA level was positively associated with BMI [(ß (95% CI) = 0.51 (0.31, 0.71), p < 0.001] and non-alcoholic fatty liver disease index [(ß (95% CI) = 0.09 (0.06, 0.12), p < 0.001]. In conclusion, the benzene metabolites t,t-MA and PAH metabolite 2-OHFlu were associated with an increased risk of DM. Urinary biomarkers for PAHs and VOCs were positively associated with BMI in the Korean adult population. Further studies to validate these observations in other populations are warranted.

Enpp2 Expression by Dendritic Cells Is a Key Regulator in Migration.

Enpp2 is an enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which exhibits a wide variety of biological functions. Here, we examined the biological effects of Enpp2 on dendritic cells (DCs), which are specialized antigen-presenting cells (APCs) characterized by their ability to migrate into secondary lymphoid organs and activate naïve T-cells. DCs were generated from bone marrow progenitors obtained from C57BL/6 mice. Enpp2 levels in DCs were regulated using small interfering (si)RNA or recombinant Enpp2. Expression of Enpp2 in LPS-stimulated mature (m)DCs was high, however, knocking down Enpp2 inhibited mDC function. In addition, the migratory capacity of mDCs increased after treatment with rmEnpp2; this phenomenon was mediated via the RhoA-mediated signaling pathway. Enpp2-treated mDCs showed a markedly increased capacity to migrate to lymph nodes in vivo. These findings strongly suggest that Enpp2 is necessary for mDC migration capacity, thereby increasing our understanding of DC biology. We postulate that regulating Enpp2 improves DC migration to lymph nodes, thus improving the effectiveness of cancer vaccines based on DC.

MicroRNA-138 Increases Chemo-Sensitivity of Glioblastoma through Downregulation of Survivin.

Glioblastoma (GBM) is one of the most deadly cancers and poorly responses to chemotherapies, such as temozolomide (TMZ). Dysregulation of intrinsic signaling pathways in cancer cells are often resulted by dysregulated tumor suppressive microRNAs (miRNAs). Previously, we found miR-138 as one of tumor suppressive miRNAs that were significantly down-regulated in GBM. In this study, we demonstrated that ectopic over-expression of miR-138 sensitizes GBM cells to the treatment of TMZ and increased apoptotic cell death. Mechanistically, miR-138 directly repressed the expression of Survivin, an anti-apoptotic protein, to enhance caspase-induced apoptosis upon TMZ treatment. Using an intracranial GBM xenograft mice model, we also showed that combination of miR-138 with TMZ increases survival rates of the mice compared to the control mice treated with TMZ alone. This study provides strong preclinical evidence of the therapeutic benefit from restoration of miR-138 to sensitize the GBM tumor to conventional chemotherapy.

Urinary parabens and their potential sources of exposure among Korean children and adolescents: Korean National Environmental Health Survey 2015-2017.

Parabens are used as a preservative in several consumer products including cosmetics, personal care products, and medicinal products. These chemicals have been suspected for estrogenicity and potential adverse endocrine outcomes in humans. For the first time, exposure profiles and potential sources of major parabens are investigated for a nationally representative population of children and adolescents of Korea. In addition, major determinants of urinary paraben levels were identified. For this purpose, the children, and adolescents (n = 2355, 3-18 years of age) who participated in the Korean National Environmental Health Survey cycle 3 (2015-2017) were studied. Adjusted multiple linear regression models were employed to investigate the relationships of several potential demographic and behavioral determinants of exposure, with the urinary levels of three parabens; methyl, ethyl, and propyl paraben. Methyl and propyl paraben levels of the Korean children and adolescents were comparable to those of the US, but the high exposure group (95th percentile) showed much higher levels of exposure. Moreover, urinary ethyl paraben levels are always higher than those of other countries. The uses of personal care products including liquid soaps, fragrance products, nail polish, or antiseptic products were significantly associated with urinary paraben levels. In addition, dietary sources such as fast food and canned food consumption were identified as major contributors to ethyl paraben levels. For methyl and propyl parabens, the use of fever medications and ointments were identified as major determinants of the exposure, especially among the younger children of 3-5 years of age. These observations are related to the Korean regulations that permit the use of the parabens as preservatives in foods and medications. The findings demonstrate that the exposure profile of parabens among Korean children are unique, and mitigation efforts for some parabens are required in Korea. Further studies are warranted to confirm the exposure sources of parabens and to develop mitigation measures among Korean children and adolescents.

First nationwide exposure profile of major persistent organic pollutants among Korean adults and their determinants: Korean National Environmental Health Survey Cycle 3 (2015-2017).

Since 2009, Korea has measured the exposure levels of major environmental chemicals and heavy metals among representative adult populations through the Korean National Environmental Health Survey (KoNEHS). However, exposure to persistent organic pollutants (POPs) has never been assessed. This study reports the serum concentrations of twenty-four POPs and their influencing factors for Korean adults (n = 1295) who participated in the KoNEHS Cycle 3 (2015-2017). The POPs included seven organochlorine pesticides (OCPs), eleven polychlorinated biphenyls (PCBs), and six polybrominated diphenyl ethers (PBDEs). Among them, three OCPs (i.e., hexachlorobenzene (HCB), p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE)) and five PCBs (i.e., PCB52, PCB118, PCB138, PCB153, and PCB180) were detected in over 60% of the samples. PBDEs were not detected at a detection frequency of 60% or above. The most frequently detected POPs were p,p'-DDE (99.8%, geometric mean of 128.47 ng/g lipid), followed by PCB180 (98.8%, 8.49 ng/g lipid), PCB153 (98.8%, 13.14 ng/g lipid), HCB (96.2%, 67.08 ng/g lipid), PCB138 (95.2%, 8.84 ng/g lipid), PCB118 (89.6%, 2.66 ng/g lipid), p,p'-DDT (80.5%, 6.68 ng/g lipid), and PCB52 (71.2%, 1.57 ng/g lipid). The concentrations of most POPs were lower than or similar to concentrations reported in national-scale biomonitoring surveys. The only exception was HCB, whose concentration was up to seven-fold higher than the concentration reported by the Canadian Health Measures Survey. Excluding HCB and PCB52, most POPs showed increasing serum levels among older adults, adults with higher body mass index, adults living in coastal areas, and more frequent fish consumption. Relatively higher POP concentrations were observed in menopausal women. This study provides the first data on POP exposure levels among the representative adult population in Korea, and the results highlight the need to integrate POPs in the national biomonitoring program.

Neuregulin 1/ErbB4/Akt signaling attenuates cytotoxicity mediated by the APP-CT31 fragment of amyloid precursor protein.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by neuronal and synaptic loss. The cytoplasmic tail of amyloid precursor protein (APP) undergoes sequential cleavage at a specific intracellular caspase site to generate the cytoplasmic terminal 31 (CT31) fragment. The APP-CT31 fragment is a potent inducer of apoptosis. The cytotoxicity of APP-CT31 in SH-SY5Y cells was evaluated by the lactate dehydrogenase (LDH) assay. TUNEL staining was used to detect apoptotic signals in SH-SY5Y cells and primary cortical neurons. The expression of apoptosis-related proteins, such as p53, PUMA (p53 up-regulated modulator of apoptosis), and cleaved was investigated by immunofluorescence analysis and Western blotting. In this study, we investigated the neuroprotective effect of neuregulin 1 (NRG1) against cytotoxicity induced by APP-CT31. Our data showed that CT31 induced cytotoxicity and apoptosis in SH-SY5Y cells and primary cortical neurons. NRG1 attenuated the neurotoxicity induced by the expression of APP-CT31. We also showed that APP-CT31 altered the expression of p53 and cleaved caspase 3. However, treatment with NRG1 rescued the APP-CT31-induced upregulation of p53 and cleaved caspase 3 expression. The protective effect of NRG1 was abrogated by inhibition of the ErbB4 receptor and Akt. These results indicate an important role of ErbB4/Akt signaling in NRG1-mediated neuroprotection, suggesting that endogenous NRG1/ErbB4 signaling represents a valuable therapeutic target in AD.

Association of exposure to polycyclic aromatic hydrocarbons and heavy metals with thyroid hormones in general adult population and potential mechanisms.

Air pollution and fuel emissions are the common sources of human exposure to polycyclic aromatic hydrocarbons (PAHs) and heavy metals. Several studies have suggested potential associations between PAHs/heavy metals and thyroid hormones, however, reports have been inconsistent. In this study, we employed a subpopulation of the adults (n = 1254) who participated in the Korean National Environmental Health Survey 2015-2017, and investigated the association of PAHs and major heavy metals with thyroid hormones, and explored the underlying mechanisms of thyroid disruption. Four PAH metabolites and three heavy metals of lead (Pb), mercury (Hg), and cadmium (Cd) were measured either in urine or in total blood. In addition, thyroid hormones (T3 and T4), TSH, thyroxine-binding globulin (TBG), and thyroid autoantibodies were measured, and peripheral deiodinase activity (GD) and thyroid's secretory capacity (GT) were calculated. Urinary Hg was negatively associated with total T3 in both males and females, while it was positively associated with total T4 among females only. Urinary Hg was related to decreased GD and increased GT in both sexes. In contrast, urinary Cd was positively associated with total T3 and GD in both male and female populations. Urinary Cd also showed a positive association with thyroid autoantibodies, but only in males. A multi-factor model considering co-exposure to multiple chemicals also resulted in similar associations. Among the measured PAH metabolites, only urinary 1-hydroxypyrene showed a negative association with total T3 in males. However, this association was marginal, and disappeared in a multi-chemical model. The present observations are suggestive that exposures to Hg and Cd might disrupt thyroid hormones, possibly through an alteration of deiodinase activity. Association of PAH exposure with thyroid hormone appears to be insignificant.

Associations of urinary concentrations of phthalate metabolites, bisphenol A, and parabens with obesity and diabetes mellitus in a Korean adult population: Korean National Environmental Health Survey (KoNEHS) 2015-2017.

Phthalates and bisphenol A (BPA) have been suspected as risk factors for obesity and diabetes mellitus (DM) among humans. However, associations between phthalates and environmental phenols are often inconsistent across different populations. In this study, we recruited the adult population (n = 3782) of the Korean National Environmental Health Survey (KoNEHS) 2015-2017 (Cycle 3) and assessed the associations between urinary biomarkers of phthalate, BPA, and paraben exposure with obesity and DM. A potential collider issue with the use of urinary creatinine (Cr) or specific gravity (SG) exists when adjusting urinary dilution; therefore, a covariate-adjusted standardization (CAS) was employed for adjustment, and the results were compared. In the present population, the direction of the association often varied depending on the choices made to adjust urinary dilution. When using CAS, the direction of association resembled those of previously reported experimental observations. With Cr or SG adjustment, ORs for obesity decreased in the highest quartiles of monocarboxyoctyl phthalate (MCOP) [OR (95% CI) = Cr: 0.71 (0.54, 0.93); SG: 0.68 (0.52, 0.90)], monocarboxy-isononyl phthalate (MCNP) [OR (95% CI) = Cr: 0.67 (0.52, 0.87); SG: 0.68 (0.52, 0.89)], and mono(3-carboxylpropyl) phthalate (MCPP) in the urine [OR (95% CI) = Cr: 0.60 (0.47, 0.76); SG: 0.61 (0.48, 0.77)]; however, with CAS, these negative associations disappeared. Instead, mono-benzyl phthalate (MBzP) [OR (95% CI) = 1.31 (1.03, 1.66)], BPA [OR (95% CI) = 1.62 (1.27, 2.06)], or ethyl paraben (EtP) [OR (95% CI) = 1.51 (1.19, 1.91)] concentrations in the highest quartile showed positive associations with a higher risk of obesity. On the other hand, for DM, an overall decrease in ORs was observed for phthalate metabolites and BPA following SG adjustment and disappeared with CAS adjustment. In addition, the highest quartiles of BPA, methyl paraben (MeP), and ethyl paraben (EtP) showed a significantly higher risk of DM than those in the lowest quartiles following CAS [OR (95% CI) = BPA: 1.65 (1.06, 2.59); MeP: 1.68 (1.08, 2.60); and EtP: 2.74 (1.77, 4.24), respectively]. The present observations outline the importance of using an appropriate adjustment method for urinary dilution in association studies on obesity and DM. In addition, several phthalates, BPA, and parabens were identified as potential chemical risk factors for these outcomes. Further studies are warranted in other populations to confirm these observations.

Neuregulin-1 inhibits CoCl2-induced upregulation of excitatory amino acid carrier 1 expression and oxidative stress in SH-SY5Y cells and the hippocampus of mice.

Excitatory amino acid carrier 1 (EAAC1) is an important subtype of excitatory amino acid transporters (EAATs) and is the route for neuronal cysteine uptake. CoCl2 is not only a hypoxia-mimetic reagent but also an oxidative stress inducer. Here, we found that CoCl2 induced significant EAAC1 overexpression in SH-SY5Y cells and the hippocampus of mice. Transient transfection of EAAC1 reduced CoCl2-induced cytotoxicity in SH-SY5Y cells. Based on this result, upregulation of EAAC1 expression by CoCl2 is thought to represent a compensatory response against oxidative stress in an acute hypoxic state. We further demonstrated that pretreatment with Neuregulin-1 (NRG1) rescued CoCl2-induced upregulation of EAAC1 and tau expression. NRG1 plays a protective role in the CoCl2-induced accumulation of reactive oxygen species (ROS) and reduction in antioxidative enzyme (SOD and GPx) activity. Moreover, NRG1 attenuated CoCl2-induced apoptosis and cell death. NRG1 inhibited the CoCl2-induced release of cleaved caspase-3 and reduction in Bcl-XL levels. Our novel finding suggests that NRG1 may play a protective role in hypoxia through the inhibition of oxidative stress and thereby maintain normal EAAC1 expression levels.

Early-life stress induces EAAC1 expression reduction and attention-deficit and depressive behaviors in adolescent rats.

Neonatal maternal separation (NMS), as an early-life stress (ELS), is a risk factor to develop emotional disorders. However, the exact mechanisms remain to be defined. In the present study, we investigated the mechanisms involved in developing emotional disorders caused by NMS. First, we confirmed that NMS provoked impulsive behavior, orienting and nonselective attention-deficit, abnormal grooming, and depressive-like behaviors in adolescence. Excitatory amino acid carrier 1 (EAAC1) is an excitatory amino acid transporter expressed specifically by neurons and is the route for the neuronal uptake of glutamate/aspartate/cysteine. Compared with that in the normal control group, EAAC1 expression was remarkably reduced in the ventral hippocampus and cerebral cortex in the NMS group. Additionally, EAAC1 expression was reduced in parvalbumin-positive hippocampal GABAergic neurons in the NMS group. We also found that EAAC1-knockout (EAAC1-/-) mice exhibited impulsive-like, nonselective attention-deficit, and depressive-like behaviors compared with WT mice in adolescence, characteristics similar to those of the NMS behavior phenotype. Taken together, our results revealed that ELS induced a reduction in EAAC1 expression, suggesting that reduced EAAC1 expression is involved in the pathophysiology of attention-deficit and depressive behaviors in adolescence caused by NMS.

Thyroxine-binding globulin, peripheral deiodinase activity, and thyroid autoantibody status in association of phthalates and phenolic compounds with thyroid hormones in adult population.

Exposure to consumer chemicals such as phthalates and phenolic compounds has been associated with thyroid hormone disruption in humans. However, information related to factors that may influence such associations, e.g., transport and activation of the hormones, and autoimmunity status, is limited. In the present study, we employed a subpopulation of adults (n = 1,254) who participated in the Korean National Environmental Health Survey (KoNEHS) 2015-2017, and associated urinary concentrations of major phthalate metabolites, bisphenol A (BPA), and parabens, with thyroid hormone-related measures, including free and total T3 and T4, TSH, thyroxine-binding globulin (TBG), calculated peripheral deiodinase (DIO) activity, and thyroid autoantibodies of thyroperoxidase (TPO) and thyroglobulin (Tg). Phthalate metabolites were negatively associated with total T4 and free T3, and positively associated with total T3. These observations could be explained by TBG levels and calculated peripheral DIO activity that were positively associated with phthalates exposure. In contrast, BPA was positively associated with total T4 and negatively associated with total T3, without any changes in TBG concentration. Serum TPO and Tg antibodies were not associated with urinary phthalate metabolites and BPA. However, thyroid autoantibody status appeared to modulate the association of some phthalates with thyroid hormones. For parabens, little to negligible association was observed. The results of our observation show potential underlying mechanisms of phthalates-induced thyroid hormone disruption, and suggests the importance of consideration of thyroid autoimmunity status in association studies for thyroid disrupting chemicals.