Ph. D. Candidate, Rutgers University
Endocrine disrupting compounds (EDCs) are ubiquitous in the environment and accumulate in human tissues causing concerns for exposures during sensitive developmental periods including gestation and lactation. One of common type of EDC are flame-retardants. Polybrominated diphenyl ethers (PBDE) have previously been shown to have neurological effects in rodent models, but have been banned since 2004. Their replacement compounds, organophosphate flame retardants (OPFR), are currently found in many household products with little existing data on their effects on fetal or neonatal development and offspring neurological behavior. This study explored these potential effects of OPFR on feeding and exploratory behaviors. Wild-type dams were mated and dosed with either oil or an OPFR mixture (triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl) phosphate, 1 mg/kg/day) in peanut butter from gestational day 7 to postnatal day 14. Litter were either fed a low-fat or a high-fat diet for 16 weeks after weaning before exploratory behaviors (open field test and elevated plus maze) followed by meal pattern analysis and locomotor behavior (activity). This study will be an initial characterization of OPFR on rodent behavior at concentrations relevant to human environments.
Abstract: As brominated flame retardants are being banned or phased out worldwide, organophosphate flame retardants (OPFRs) have been used as alternatives on a large scale and have thus become ubiquitous environmental contaminants; this raises great concerns about their environmental health risk and toxicity. Considering that previous research has identified the nervous system as a sensitive target, Japanese medaka were used as an aquatic organism model to evaluate the developmental neurotoxicity of four OPFRs, including triphenyl phosphate (TPHP), tri-n-butyl phosphate (TNBP), tris(2-butoxyethyl) phosphate (TBOEP) and tris(2-chloroethyl) phosphate (TCEP). The embryo toxicity test showed that OPFR exposure could decrease hatchability, delay time to hatching, increase the occurrence of malformations, reduce body length, and slow heart rate. Regarding locomotor behavior, exposure to the tested OPFRs (except TCEP) for 96 h resulted in hypoactivity for medaka larvae in both the free-swimming and the dark-to-light photoperiod stimulation test. The changes of acetylcholinesterase (AChE) activity and transcriptional responses of genes related to the nervous system likely provide a reasonable explanation for the neurobehavioral disruption. Overall, the present study clearly demonstrated the developmental neurotoxicity of various OPFRs with very different potency and contributed to the determination of which OPFRs are appropriate substitutes, as well as the consideration of whether regulations are reasonable and required. This article is protected by copyright. All rights reserved.
Pub.: 06 May '16, Pinned: 29 Jun '17
Abstract: Perfluorinated chemicals and flame retardants are halogenated compounds commonly used in food packaging and in clothing and electronics, respectively. Due to the hazardous effects of many of these chemicals, manufacturers are developing next generation potential less toxic alternatives. The objective of this study was to assess the toxicity of potentially "safer" alternatives, singly and in mixtures, in relation to their first generation counterparts. We used zebrafish embryos as our model organism due to its high structural and functional homology to other vertebrates and its suitability for early developmental studies. We tested three well studied halogens, perfluorooctanoic acid (PFOA), tris (1,3-dichloro-2-propyl) phosphate (TDCPP) and tetrabromobisphenal A (TBBPA), and two less-studied next generation chemicals, 9,10-Dihydro-9-oxa-10-phosphaphenanthrene 10-oxide (DOPO) and perfluorobutyric acid (PFBA). First, we identified their lethal concentration (LC50) under 96 h exposures using zebrafish embryos; chemical LC50 values ranged from 1.3 to 13,795 ppm. Next, we tested the toxicity of tertiary mixtures containing the estimated LC50 values for each chemical which ranged from 126 to 5,094 ppm. We found that chemicals within these mixtures displayed concentration addition suggesting a similar mode of toxic action. Importantly, next generation chemicals were less acutely toxic singly and in mixtures than their first generation counterpart.
Pub.: 10 May '17, Pinned: 29 Jun '17
Abstract: Polybrominated diphenyl ethers (PBDEs) are commonly used flame retardants in foams, building material, electronics, and textiles. These chemicals leach into the environment, where they persist, and are found today in virtually every population worldwide. Several studies in recent years have detected the presence of PBDEs in maternal and infant samples. However, few of these studies were conducted in the U.S., and few examined paired or matched mother blood-cord blood samples. We analyzed serum from 10 mother-infant pairs for the presence of PBDEs in a patient population in the Southeastern U.S. Out of 35 measured PBDE congeners, five (BDE-28, -47, -99, -100, and -153) were present, with detection frequencies of 65-100 %. The total PBDE concentrations in maternal and infant sera were highly correlated (r(2) = 0.710, p = 0.0043). The levels of BDE-47, -99, and -100 and of total PBDEs were higher in the infant cord sera when compared with those in maternal sera (p < 0.017), suggesting that fetuses and neonates might have higher circulating concentrations of these potentially neurotoxic and endocrine disrupting chemicals compared with their mothers. The primary focus henceforward should be whether there are any deleterious effects from exposure to these chemicals on human health.
Pub.: 11 Jun '17, Pinned: 29 Jun '17
Abstract: Normal thyroid function is essential for general growth and metabolism, but can be affected by endocrine disrupting chemicals (EDCs). Polybrominated diphenyl ethers (PBDEs) have been used worldwide to reduce flammability in different materials and are suspected to be EDCs. The production of the commercial Penta- and OctaBDE mixtures is banned, but DecaBDEs and existing products may leak PBDEs into the environment. Our aim was to investigate the effect of the PentaBDE mixture DE-71 on human thyroid cells in vitro.Primary human thyroid cells were obtained as paraadenomatous tissue and cultured in monolayers. The influence of DE-71 on cyclic adenosine monophosphate (cAMP) and thyroglobulin (Tg) production was examined in the culture medium by competitive radioimmunoassay and enzyme-linked immunosorbent assay, respectively. Real-time quantitative PCR analysis of thyroid-specific genes was performed on the exposed cell cultures. PBDE concentrations were determined in cellular and supernatant fractions of the cultures.DE-71 inhibited Tg-release from TSH-stimulated thyrocytes. At 50 mg/L DE-71, mean Tg production was reduced by 71.9% (range: 8.5-98.7%), and cAMP by 95.1% (range: 91.5-98.8%) compared to controls). Expression of mRNA encoding Tg, TPO and TSHr were significantly inhibited (p<0.0001, p = 0.0079, and p = 0.0002, respectively). The majority of DE-71 added was found in the cell fraction. No cytotoxicity was found.DE-71 inhibited differentiated thyroid cell functions in a two phase response manner and a concentration-dependent inhibition of Tg and cAMP production, respectively, as well as expression of mRNA encoding Tg, TPO and TSHr. Our findings suggest an inhibiting effect of PBDEs on thyroid cells.
Pub.: 24 Jun '17, Pinned: 29 Jun '17
Abstract: Children are exposed to flame retardants from the built environment. Brominated diphenyl ethers (BDE) and organophosphate-based flame retardants (OPFRs) are associated with poorer neurocognitive functioning in children. Less is known, however, about the association between these classes of compounds and children's emotional and social behaviors. The objective of this study was to determine if flame retardant exposure was associated with measurable differences in social behaviors among children ages 3-5 years.We examined teacher-rated social behaviors measured using the Social Skills Improvement Rating Scale (SSIS) and personal exposure to flame retardants in children aged 3-5 years who attended preschool (n = 72). Silicone passive samplers worn for 7 days were used to assess personal exposure to 41 compounds using gas chromatography-mass spectrophotometer. These concentrations were then summed into total BDE and total OPFR exposure prior to natural log transformation. Separate generalized additive models were used to evaluate the relationship between seven subscales of the SSIS and lnΣBDE or lnΣOPFR adjusting for other age, sex, adverse social experiences, and family context.All children were exposed to a mixture of flame retardant compounds. We observed a dose dependent relationship between lnΣOPFR and two subscales where children with higher exposures were rated by their preschool teachers as having less responsible behavior (p = 0.07) and more externalizing behavior problems (p = 0.03). Additionally, children with higher lnΣBDE exposure were rated by teachers as less assertive (p = 0.007).We observed a cross-sectional association between children's exposure to flame retardant compounds and teacher-rated social behaviors among preschool-aged children. Children with higher flame retardant exposures exhibited poorer social skills in three domains that play an important role in a child's ability to succeed academically and socially.
Pub.: 10 Mar '17, Pinned: 29 Jun '17
Abstract: Organophosphorous flame retardants (OPFRs) are contaminants of emerging concern. There is growing evidence of environmental contamination and exposures to both humans and wildlife. Here, the objective was to increase understanding of the potential neurodevelopmental effects of two relevant OPFRs, TMPP (tri (methylphenyl) phosphate; a non-halogen-containing OPFR) and TDCIPP (tris (1,3-dichloro-isopropyl) phosphate; a halogen-containing OPFR) in an avian embryo/chick model. We injected white leghorn chicken eggs with a range of TMPP (0, 10, 100, and 1000 ng/g) or TDCIPP (0, 10, 100, 1000, 50,000 ng/g) concentrations at incubation day 0 exposing embryos throughout the ~21-day in ovo period. Hatching success was unaffected by TMPP, but TDCIPP-exposed chicks had higher early-incubation mortality in 100 and 50,000 ng/g groups. On 7-9-day-old chicks, we assessed behavior via tests concerning righting reflex, angled balance beams, gait patterns, wing flap reflex, and open field movements. Chicks exposed to 100 ng/g TDCIPP achieved 40% lower maximum velocity in the open field test than vehicle-exposed controls, while those exposed to 1000 ng/g TDCIPP achieved 20% higher maximum velocity than vehicle-exposed controls. Chicks exposed to 50,000 ng/g TDCIPP showed reduced righting response success. There were no dose- or treatment-related differences in angled beam, gait analysis, or wing flap reflex tests. Cerebrum hemispheres from 10-day-old chicks were examined for neurochemistry (acetylcholinesterase [AChE] activity and both nicotinic [nACh] and muscarinic [mACh] acetylcholine receptor levels) and cerebellums were examined for histopathology. TDCIPP-exposed chicks had reduced number of degenerate Purkinje cells (TDCIPP, 1000 ng/g), possibly indicating disruption of neurodevelopment. No neurochemical effects were found in TMPP- or TDCIPP-exposed chicks. In general this study shows some possible neurodevelopmental effects in chicks exposed to TDCIPP when levels greatly exceeded those measured in wild bird eggs and no clear changes in TMPP-exposed chicks. This study builds upon previous in vitro studies as well as work on adult birds showing that toxic responses in avian models can vary among species and OPFRs.
Pub.: 19 Aug '15, Pinned: 29 Jun '17
Abstract: Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is one of the most detected organophosphorus flame retardants (OPFRs) in the environment, especially in indoor dust. Continuous daily exposure to TDCPP-containing dust may adversely impact human cornea. However, its detrimental effects on human corneal epithelium are largely unknown. In this study, we investigated the cell apoptosis in normal human corneal epithelial cells (HCECs) after TDCPP exposure and elucidated the underlying molecular mechanisms. Our data indicated a dose-dependent decrease of cell viability after TDCPP exposure with LC50 at 202 μg/mL. A concentration-dependent apoptotic sign was observed in HCECs after exposing to ≥2 μg/mL TDCPP. Endoplasmic reticulum stress induction was evidenced by up-regulation of its biomarker genes (ATF-4, CHOP, BiP, and XBP1). Furthermore, alternation of Bcl-2/Bax expression, mitochondrial membrane potential loss, cellular ATP content decrease, and caspase-3 and -9 activity increase were observed after exposing to 2 or 20 μg/mL TDCPP. Taken together, the data implicated the involvement of endoplasmic reticulum stress in TDCPP-induced HCEC apoptosis, probably mediated by mitochondrial apoptotic pathway. Our findings showed TDCPP exposure induced toxicity to human cornea. Due to TDCPP's presence at high levels in indoor dust, further study is warranted to evaluate its health risk on human corneas.
Pub.: 24 Jun '17, Pinned: 29 Jun '17
Abstract: As polybrominated diphenyl ethers are phased out, numerous compounds are emerging as potential replacement flame retardants for use in consumer and electronic products. Little is known, however, about the neurobehavioral toxicity of these replacements. This study evaluated the neurobehavioral effects of acute or developmental exposure to t-butylphenyl diphenyl phosphate (BPDP), 2-ethylhexyl diphenyl phosphate (EHDP), isodecyl diphenyl phosphate (IDDP), isopropylated phenyl phosphate (IPP), tricresyl phosphate (TMPP; also abbreviated TCP), triphenyl phosphate (TPHP; also abbreviated TPP), tetrabromobisphenol A (TBBPA), tris (2-chloroethyl) phosphate (TCEP), tris (1,3-dichloroisopropyl) phosphate (TDCIPP; also abbreviated TDCPP), tri-o-cresyl phosphate (TOCP), and 2,2-,4,4'-tetrabromodiphenyl ether (BDE-47) in zebrafish (Danio rerio) larvae. Larvae (n≈24 per dose per compound) were exposed to test compounds (0.4-120 μM) at sub-teratogenic concentrations either developmentally or acutely, and locomotor activity was assessed at 6 days post fertilization. When given developmentally, all chemicals except BPDP, IDDP and TBBPA produced behavioral effects. When given acutely, all chemicals produced behavioral effects, with TPHP, TBBPA, EHDP, IPP, and BPDP eliciting the most effects at the most concentrations. The results indicate that these replacement flame retardants may have developmental or pharmacological effects on the vertebrate nervous system.
Pub.: 09 Sep '15, Pinned: 29 Jun '17
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