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Introduction Anthropogenic compounds, particularly endocrine disruption chemicals (EDCs), are being recognized for their unprecedented impact on the increasing worldwide prevalence of metabolic syndromes, (1) and the mechanisms underlying EDC-associated metabolic [...], BACKGROUND: Environmental chemical exposures have been associated with metabolic outcomes, and typically, their binding to nuclear hormone receptors is considered the molecular initiating event (MIE) for a number of outcomes. However, more studies are needed to understand the influence of such exposures on cell membrane-bound adiponectin receptors (AdipoRs), which are critical metabolic regulators. OBJECTIVE: We aimed to clarify the potential interactions between AdipoRs and environmental chemicals, specifically organophosphorus flame retardants (OPFRs), and the resultant effects. METHODS: Employing in silico simulation, cell thermal shift, and noncompetitive binding assays, we screened eight OPFRs for interactions with AdipoR1 and AdipoR2. We tested two key events underlying AdipoR modulation upon OPFR exposure in a liver cell model. The Toxicological Prioritization Index (ToxPi)scoring scheme was used to rank OPFRs according to their potential to disrupt AdipoR-associated metabolism. We further examined the inhibitory effect of OPFRs on AdipoR signaling activation in mouse models. RESULTS: Analyses identified pi-pi stacking and pi-sulfur interactions between the aryl-OPFRs 2-ethylhexyl diphenyl phosphate (EHDPP), triphenyl phosphate (TPhP), and tricresyl phosphate (TCP) and the transmembrane cavities of AdipoR1 and AdipoR2. Cell thermal shift assays showed a >3[degrees]C rightward shift in the AdipoR proteins' melting curves upon exposure to these three compounds. Although the binding sites differed from adiponectin, results suggest that aryl-OPFRs noncompetitively inhibited the binding of the endogenous peptide ligand ADP355 to the receptors. Analyses of key events underlying AdipoR modulation revealed that glucose uptake was notably lower, whereas lipid content was higher in cells exposed to aryl-OPFRs. EHDPP, TCP, and TPhP were ranked as the top three disruptors according to the ToxPi scores. A noncompetitive binding between these aryl-OPFRs and AdipoRs was also observed in wild-type (WT) mice. In db/db mice, the finding of lower blood glucose levels after ADP355 injection was diminished in the presence of a typical aryl-OPFR (TCP). WT mice exposed to TCP demonstrated lower AdipoR1 signaling, which was marked by lower phosphorylated AMP-activated protein kinase (pAMPK) and a higher expression of gluconeogenesis-related genes. Moreover, WT mice exposed to ADP355 demonstrated higher levels of pAMPK protein and peroxisome proliferator-activated receptor-a messenger RNA. This was accompanied by higher glucose disposal and by lower levels of long-chain fatty acids and hepatic triglycerides; these metabolic improvements were negated upon TCP co-treatment. CONCLUSIONS: In silico, in vitro, and in vivo assays suggest that aryl-OPFRs act as noncompetitive inhibitors of AdipoRs, preventing their activation by adiponectin, and thus function as antagonists to these receptors. Our study describes a novel MIE for chemical-induced metabolic disturbances and highlights a new pathway for environmental impact on metabolic health. https://doi.org/10.1289/EHP14634

Introduction In recent decades, declining male reproductive capacity has become a global concern, with decreasing semen quality and quantity evident. (1,2) Extensive evidence implicates environmental pollution rather than genetic factors [...], BACKGROUND: Legacy brominated flame retardants have been recognized as risky factors leading to declined sperm quality. The widespread utilization of decabromodiphenyl ethane (DBDPE) as a replacement for decabromodiphenyl ether has given rise to considerable concern over its potential risks to reproductive health. OBJECTIVES: The objectives were to quickly determine whether DBDPE affects sperm quality upon ex vivo exposure, to reveal the reproductive outcomes and underlying molecular mechanisms using an in vivo zebrafish model exposed to DBDPE, and to validate the potential impact on DNA damage and energy metabolism balance in vitro. METHODS: Zebrafish spermatozoa were treated with DBDPE (0.01, 0.1, 1, 10 [micro]M) for 3 h, and the spermatozoa motility and fertilization ability with normal eggs were evaluated. Then adult male zebrafish were treated with DBDPE (0.1, 1, 10, and 100 nM) for 2 months, and their reproductive performance was examined. Four-dimensional label-free proteome and phosphoproteome were performed in zebrafish testes, and the findings were validated by multiple indicators. Finally, mouse spermatogonial GC-1 cells were treated with DBDPE (0.1, 1 [micro]M) for 72 h, and DNA damage was examined, as well as the energy production of glycolysis and oxidative phosphorylation. RESULTS: Ex vivo exposure to DBDPE caused lower motility and fertilization rates of zebrafish spermatozoa. In vivo exposure to DBDPE caused lower sperm motility and abnormal spermatogenesis in male zebrafish testes. Integrated whole-proteome and phosphoproteome analysis revealed DNA damage responses and energy metabolic disorders in zebrafish testes. A dosage window characterized by higher mitochondrial membrane potential (MMP) in combination with unchanged reactive oxygen species and apoptosis rates was observed in both zebrafish testes and GC-1 cells. DISCUSSION: This study suggests that in zebrafish, DBDPE exposure could impair sperm quality and spermatogenesis, and the underlying mechanism could be related to DNA damage and energy metabolic reprogramming in testicular germ cells. https://doi.org/10.1289/EHP14426

Introduction Miscarriage has been recognized as the most noticeable complication during human pregnancy (1) and has sharply increased globally over the past decades. (2,3) About 23 million miscarriages occurred annually [...], Background: Amniogenesis is a key event in biochemical pregnancy, and its failure may result in human embryonic death. However, whether and how environmental chemicals affect amniogenesis remain largely unknown. OBJECTIVES: The objective of the present study was to screen chemicals that may disrupt amniogenesis in an amniotic sac embryoid model and to investigate the potential mechanism of amniogenesis failure, with a focus on organophosphate flame retardants (OPFRs). Methods: This study developed a high-throughput toxicity screening assay based on transcriptional activity of octamer- binding transcription factor 4 (Oct4). For the two positive OPFR hits with the strongest inhibitory activity, we used time-lapse and phase- contrast imaging to assess their effects on amniogenesis. Associated pathways were explored by RNA-sequencing and western blotting, and potential binding target protein was identified through a competitive binding experiment. Results: Eight positive hits exhibiting Oct4 expression were identified, with 2-ethylhexyl-diphenyl phosphate (EHDPP) and isodecyl diphenyl phosphate (IDDPP) showing the strongest inhibitory activity. EHDPP and IDDPP were found to disrupt the rosette-like structure of the amniotic sac or inhibit its development. Functional markers of squamous amniotic ectoderm and inner cell mass were also found disrupted in the EHDPP- and IDDPP-exposed embryoids. Mechanistically, embryoids exposed to each chemical exhibited abnormal accumulation of phosphorylated nonmuscle myosin (p-MLC-II) and were able to bind to integrin [beta]1 (ITG[beta]1). Conclusion: The amniotic sac embryoid models suggested that OPFRs disrupted amniogenesis likely by inhibiting the ITG[beta]1 pathway, thus providing direct in vitro evidence associating OPFRs with biochemical miscarriage. https://doi.org/10.1289/EHP11958

Flame retardant chemicals are commonly added to consumer products and raw materials to delay combustion and meet fire safety standards. Because many flame retardants are additive rather than chemically bonded [...]

BACKGROUND: Previous studies have indicated that cytochrome P450s (CYPs) are involved in the metabolism of polybrominated diphenyl ether (PBDE) flame retardants in humans, resulting in the formation of hydroxylated PBDEs [...]

Introduction One in six couples worldwide is affected by infertility, which is defined as the inability to get pregnant after 1 y or more of unprotected intercourse (Chandra et al. [...], Background: Evidence from animal studies suggests that exposure to organophosphate flame retardants (PFRs) can disrupt endocrine function and impair embryo development. However, no epidemiologic studies have been conducted to evaluate effects on fertility and pregnancy outcomes. Objectives: We evaluated associations between urinary concentrations of PFR metabolites and outcomes of in vitro fertilization (IVF) treatment among couples recruited from an academic fertility clinic. Methods: This analysis included 211 women enrolled in the Environment And Reproductive Health (EARTH) prospective cohort study (2005-2015) who provided one or two urine samples per IVF cycle. We measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP), and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). Molar concentrations of the urinary PFR metabolites were summed. We used multivariable generalized linear mixed models to evaluate the association of the PFR metabolites with IVF outcomes, accounting for multiple IVF cycles per woman. Results: Detection frequencies were high for BDCIPP (87%), DPHP (94%), and ip-PPP (80%), but low for tb-PPP (14%) and BCIPP (0%). We observed decreased success for several IVF outcomes across increasing quartiles of both summed and individual PFR metabolites (DPHP and ip-PPP) in our adjusted multivariable models. Significant declines in adjusted means from the lowest to highest quartile of [SIGMA]PFR were observed for the proportion of cycles resulting in successful fertilization (10% decrease), implantation (31%), clinical pregnancy (41%), and live birth (38%). Conclusions: Using IVF to investigate human reproduction and pregnancy outcomes, we found that concentrations of some urinary PFR metabolites were negatively associated with proportions of successful fertilization, implantation, clinical pregnancy, and live birth. https://doi.org/10.1289/EHP1021

Introduction Environmental health researchers and government scientists in the United States typically encounter a paucity of information on both toxicity and exposure for most chemicals in commerce (Judson et al. [...], Regulatory agencies face daunting challenges identifying emerging chemical hazards because of the large number of chemicals in commerce and limited data on exposure and toxicology. Evaluating one chemical at a time is inefficient and can lead to replacement with uncharacterized chemicals or chemicals with structural features already linked to toxicity. The Office of Environmental Health Hazard Assessment (OEHHA) has developed a process for constructing and assessing chemical groups for potential biomonitoring in California. We screen for chemicals with significant exposure potential and propose possible chemical groups, based on structure and function. To support formal consideration of these groups by Biomonitoring California's Scientific Guidance Panel, we conduct a detailed review of exposure and toxicity data and examine the likelihood of detection in biological samples. To date, 12 chemical groups have been constructed and added to the pool of chemicals that can be selected for Biomonitoring California studies, including p,p'-bisphenols, brominated and chlorinated organic compounds used as flame retardants, non-halogenated aromatic phosphates, and synthetic polycyclic musks. Evaluating chemical groups, rather than individual chemicals, is an efficient way to respond to shifts in chemical use and the emergence of new chemicals. This strategy can enable earlier identification of important chemicals for monitoring and intervention.

Introduction Dechlorane, or Mirex, is a chlorinated flame retardant that was widely used before concerns about its environmental effects prompted its replacement with analogs such as Dechlorane plus (DP), Dechlorane [...], BACKGROUND: Although the chlorinated flame retardant Dechlorane (Dec) 602 has been detected in food, human blood, and breast milk, there is limited information on potential health effects, including possible immunotoxicity. OBJECTIVES: We determined the immunotoxic potential of Dec 602 in mice by examining the expression of phenotypic markers on thymocyte and splenic lymphocyte subsets, Th1/Th2 transcription factors, and the production of cytokines and antibodies. METHODS: Adult male C57BL/6 mice were orally exposed to environmentally relevant doses of Dec 602 (1 and 10 µg/kg body weight per day) for 7 consecutive days. Thymocyte and splenic CD4 and CD8 subsets and splenocyte apoptosis were examined by flow cytometric analysis. Cytokine expression was measured at both the mRNA and the protein levels. Levels of the transcription factors Th1 (T-bet and STAT1) and Th2 (GATA3) were determined using quantitative real-time polymerase chain reaction (qPCR). Serum levels of immunoglobulins Ig[G.sub.1], Ig[G.sub.2a], Ig[G,syb.2b] and IgE were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Splenic [CD4.sup.+] and [CD8.sup.+] T cell subsets were decreased compared with vehicle controls, and apoptosis was significantly increased in splenic [CD4.sup.+] T cells. Expression (mRNA and protein) of Th2 cytokines [interleukin (IL)-4, IL-10, and IL-13] increased, and that of Th1 cytokines [IL-2, interferon (IFN)-γ and tumor necrosis factor (TNF)-α decreased. The Th2 transcriptional factor GATA3 increased, whereas the Th1 transcriptional factors T-bet and STAT1 decreased. As additional indicators of the Th2-Th1 imbalance, production of Ig[G.sub.1] was significantly increased, whereas Ig[G.sub.2a] was reduced. CONCLUSIONS: To our knowledge, we are the first to report evidence of the effects of Dec 602 on immune function in mice, with findings indicating that Dec 602 exposure favored Th2 responses and reduced Th1 function. http://dx.doi.org/10.1289/ehp.1510314

Introduction Flammability standards, such as California's Technical Bulletin 117 (Bureau of Home Furnishings and Thermal Insulation 2000), led to the addition of flame retardants at 2-5% levels in residential furniture, [...], Background: The use of alternative flame retardants has increased since the phase out of pentabromodiphenyl ethers (pentaBDEs). One alternative, Firemaster® 550 (FM550), induces obesity in rats. Triphenyl phosphate (TPP), a component of FM550, has a structure similar to that of organotins, which are obesogenic in rodents. OBJECTIVES: We tested the hypothesis that components of FM550 are biologically active peroxisome proliferator-activated receptor γ (PPARγ) ligands and estimated indoor exposure to TPP. METHODS: FM550 and its components were assessed for ligand binding to and activation of human PPARγ. Solvent mapping was used to model TPP in the PPARΓ binding site. Adipocyte and osteoblast differentiation were assessed in bone marrow multipotent mesenchymal stromal cell models. We estimated exposure of children to TPP using a screening-level indoor exposure model and house dust concentrations determined previously. RESULTS: FM550 bound human PPARγ, and binding appeared to be driven primarily by TPP. Solvent mapping revealed that TPP interacted with binding hot spots within the PPARγ ligand binding domain. FM550 and its organophosphate components increased human PPARγ1 transcriptional activity in a Cos7 reporter assay and induced lipid accumulation and perilipin protein expression in BMS2 cells. FM550 and TPP diverted osteogenic differentiation toward adipogenesis in primary mouse bone marrow cultures. Our estimates suggest that dust ingestion is the major route of exposure of children to TPP. CONCLUSIONS: Our findings suggest that FM550 components bind and activate PPARγ. In addition, in vitro exposure initiated adipocyte differentiation and antagonized osteogenesis. TPP likely is a major contributor to these biological actions. Given that TPP is ubiquitous in house dust, further studies are warranted to investigate the health effects of FM550. Environ Health Perspect 122:1225-1232; http://dx.doi.org/10.1289/ehp.1408111

Firemaster® 550 (FM550) was introduced in 2003 as an alternative to the toxic, persistent flame retardant pentabromodiphenyl ether, for use in mattresses, couches, and other items containing polyurethane foam. (1) [...]

Although no longer manufactured in the United States, polybrominated diphenyl ether (PBDE) flame retardants are still found in imported products as well as in older U.S.-made products; they also persist [...]

Introduction Flame retardant (FR) chemicals are commonly applied to raw materials and consumer products to reduce their flammability and meet fire safety standards. Until recently, polybrominated diphenyl ethers (PBDEs) accounted [...], Background: Firemaster® 550 (FM550) is commonly added to residential furniture to reduce its flammability. Recent toxicological evidence suggests that FM550 may be endocrine disrupting and obesogenic. Objectives: Our objectives were to develop methods to assess exposure to FM550 in human populations and to identify potential routes of exposure. Methods: Using mass spectrometry methods, we developed a method to measure 2,3,4,5-tetrabromobenzoic acid (TBBA), a urinary metabolite of the major brominated FM550 component 2-ethylhexyl-2,3,4,5'tetrabromobenzoate (TBB). The method was applied to a cohort of adult volunteers (n = 64). Participants completed questionnaires, provided urine and handwipe samples, and collected dust samples from their homes. We measured TBB and the other major brominated FM550 component, bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH), in paired dust and handwipe samples. Results: TBBA was detected in 72.4% of urine samples. Although TBBA is a rapidly formed metabolite, analyses indicated moderate temporal reliability (interclass correlation coefficient = 0.56; 95% confidence interval: 0.46, 0.66). TBB and TBPH were detected frequently in dust samples [geometric mean (GM) = 315.1 and 364.7 ng/g, respectively] and in handwipes (GM = 31.4 and 23.4 ng, respectively). Levels of TBB and TBPH in dust were positively correlated with levels in handwipes. In addition, levels of TBB in handwipes were positively correlated with urinary TBBA. Results suggest frequent hand washing may reduce the mass of TBB on participants' hands and reduce urinary TBBA levels. Conclusions: Cumulatively, our data indicate that exposures to FM550 are widespread and that the home environment may be an important source of exposure. Urinary TBBA provides a potentially useful biomarker of FM550 exposure for epidemiologic studies. http://dx.doi.org/10.1289/ehp.1308028

Introduction Hexabromocyclododecane (HBCD) (for chemical structure, see Supplemental Material, Figure S1) is a brominated flame retardant (BFR) that is incorporated into plastics, electrical and electronic products, textiles, and other materials [...], BACKGROUND: Hexabromocyclododecane (HBCD) is an additive flame retardant used in the textile industry and in polystyrene foam manufacturing. Because of its lipophilicity and persistency, HBCD accumulates in adipose tissue and thus has the potential of causing metabolic disorders through disruption of lipid and glucose homeostasis. However, the association between HBCD and obesity remains unclear. OBJECTIVES: We investigated whether exposure to HBCD contributes to initiation and progression of obesity and related metabolic dysfunction in mice fed a normal diet (ND) or a high-fat diet (HFD). METHODS: Male C57BL/6J mice were fed a HFD (62.2 kcal% fat) or a ND and treated orally with HBCD (0, 1.75, 35, or 700 µg/kg body weight) weekly from 6 to 20 weeks of age. We examined body weight, liver weight, blood biochemistry, histopathological changes, and gene expression profiles in the liver and adipose tissue. RESULTS: In HFD-fed mice, body and liver weight were markedly increased in mice treated with the high (700 µg/kg) and medium (35 µg/kg) doses of HBCD compared with vehicle. This effect was more prominent in the high-dose group. These increases were paralleled by increases in random blood glucose and insulin levels and enhancement of microvesicular steatosis and macrophage accumulation in adipose tissue. HBCD-treated HFD-fed mice also had increased mRNA levels of Pparg (peroxisome proliferator-activated receptor-γ) in the liver and decreased mRNA levels of Glut4 (glucose transporter 4) in adipose tissue compared with vehicle-treated HFD-fed mice. CONCLUSIONS: Our findings suggest that HBCD may contribute to enhancement of diet-induced body weight gain and metabolic dysfunction through disruption of lipid and glucose homeostasis, resulting in accelerated progression of obesity. 10.1289/ehp.1307421

Using X-ray crystallography to visualize the three-dimensional structure of an enzyme associated with regulating levels of estrogen, a team of National Institutes of Health scientists have discovered new information on [...]

Goodman et al. raise concerns regarding our study (Chevrier et al. 2010) in which we reported associations between serum levels of polybrominated diphenyl ethers (PBDEs) and lower thyroid-stimulating hormone (TSH) [...]

At a time of growing debate over the safety and usefulness of flame retardants added to consumer products, (1) new evidence is emerging about the breadth of human exposure to [...]

Polybrominated diphenyl ether (PBDE) flame retardants have been added to a wide variety of U.S. consumer goods including automobiles, airplanes, electronics, home furnishings, and furniture. Although two forms of PBDEs [...]

Human exposure to polybrominated diphenylether (PBDE) flame retardants has increased significantly over the last three decades. Animal and human studies suggest that PBDEs may disrupt thyroid function; although thyroid hormone [...]