Developmental Exposure to Low Concentrations of Organophosphate Flame Retardants Causes Life-Long Behavioral Alterations in Zebrafish

Abstract Background Exposure to traffic-related air pollution (TRAP) during development and/or in adulthood has been associated in many human studies with both neurodevelopmental and neurodegenerative diseases, such as autism spectrum disorder (ASD) and Alzheimer’s disease (AD) or Parkinson’s disease (PD). Methods In the present study, C57BL/6 J mice were exposed to environmentally relevant levels (250+/−50 μg/m3) of diesel exhaust (DE) or filtered air (FA) during development (E0 to PND21). The expression of several transcription factors relevant for CNS development was assessed on PND3. To address possible mechanistic underpinnings of previously observed behavioral effects of DE exposure, adult neurogenesis in the hippocampus and laminar organization of neurons in the somatosensory cortex were analyzed on PND60. Results were analyzed separately for male and female mice. Results Developmental DE exposure caused a male-specific upregulation of Pax6, Tbr1, Tbr2, Sp1, and Creb1 on PND3. In contrast, in both males and females, Tbr2+ intermediate progenitor cells in the PND60 hippocampal dentate gyrus were decreased, as an indication of reduced adult neurogenesis. In the somatosensory region of the cerebral cortex, laminar distribution of Trb1, calbindin, and parvalbumin (but not of Ctip2 or Cux1) was altered by developmental DE exposure. Conclusions These results provide additional evidence to previous findings indicating the ability of developmental DE exposure to cause biochemical/molecular and behavioral alterations that may be involved in neurodevelopmental disorders such as ASD.

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Developmental Exposure of Rats to Chlorpyrifos Leads to Behavioral Alterations in Adulthood, Involving Serotonergic Mechanisms and Resembling Animal Models of Depression

Environmental Health Perspectives ◽

10.1289/ehp.7867 ◽

2005 ◽

Vol 113 (5) ◽

pp. 527-531 ◽

Cited By ~ 169

Author(s):

Justin E. Aldridge ◽

Edward D. Levin ◽

Frederic J. Seidler ◽

Theodore A. Slotkin

Keyword(s):

Animal Models ◽

Behavioral Alterations ◽

Developmental Exposure ◽

Animal Models Of Depression

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The Age of Chemicals in the 21st Century

10.1093/med/9780190490911.003.0001 ◽

2017 ◽

Author(s):

Carol F. Kwiatkowski

Keyword(s):

Public Health ◽

Human Exposure ◽

Flame Retardants ◽

Endocrine System ◽

Daily Basis ◽

Medical Professionals ◽

Low Concentrations ◽

Wide Range ◽

Exposure Routes

Chapter 1 profiles the history, exposure routes, and health effects of chemicals in categories such as pesticides, solvents, flame retardants, plastics, and antimicrobials. Human exposure to low concentrations of chemicals, prenatal and childhood exposures, and effects on the endocrine system are highlighted. The goal is to raise awareness about the wide range of chemicals humans encounter on a daily basis. Medical professionals are urged to use this information to educate patients, and governments are called on to adopt new regulatory approaches to protect public health.

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Sex-Specific Disruption of the Prairie Vole Hypothalamus by Developmental Exposure to a Flame Retardant Mixture

Endocrinology ◽

10.1210/endocr/bqab100 ◽

2021 ◽

Author(s):

Sagi Enicole A Gillera ◽

William P Marinello ◽

Kevin T Cao ◽

Brian M Horman ◽

Heather M Stapleton ◽

...

Keyword(s):

Flame Retardants ◽

Prairie Vole ◽

Zona Incerta ◽

Prairie Voles ◽

Behavioral Deficits ◽

Developmental Exposure ◽

Neuronal Populations ◽

Increased Risk ◽

Osmotic Balance ◽

Multiple Species

Abstract Prevalence of neurodevelopmental disorders (NDDs) with social deficits is conspicuously rising, particularly in boys. Flame retardants (FRs) have long been associated with increased risk, and prior work by us and others in multiple species has shown that developmental exposure to the common FR mixture Firemaster 550 (FM 550) sex-specifically alters socioemotional behaviors including anxiety and pair bond formation. In rats, FRs have also been shown to impair aspects of osmoregulation. Because vasopressin (AVP) plays a role in both socioemotional behavior and osmotic balance we hypothesized that AVP and its related nonapeptide oxytocin (OT) would be vulnerable to developmental FM 550 exposure. We used the prairie vole (Microtus ochrogaste) to test this because it is spontaneously prosocial. Using siblings of prairie voles used in a prior study that assessed behavioral deficits resulting from developmental FM 550 exposure across three doses, here we tested the hypothesis that FM 550 sex-specifically alters AVP and OT neuronal populations in critical nuclei, such as the paraventricular nucleus (PVN) that coordinate those behaviors, as well as related dopaminergic (determined by tyrosine hydroxylase (TH) immunolabeling) populations. Exposed females had fewer AVP neurons in the anterior PVN and more A13 TH neurons in the zona incerta compared to controls. By contrast, in FM 550 males, A13 TH neuron numbers in the zona incerta were decreased but only in one dose group. These results expand on previous work showing evidence of endocrine disruption of OT/AVP pathways, including to subpopulations of PVN AVP neurons that coordinate osmoregulatory functions in the periphery.

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Low concentrations of the brominated flame retardants BDE-47 and BDE-99 induce synergistic oxidative stress-mediated neurotoxicity in human neuroblastoma cells

Toxicology in Vitro ◽

10.1016/j.tiv.2009.08.020 ◽

2010 ◽

Vol 24 (1) ◽

pp. 116-122 ◽

Cited By ~ 82

Author(s):

Sara Tagliaferri ◽

Andrea Caglieri ◽

Matteo Goldoni ◽

Silvana Pinelli ◽

Rossella Alinovi ◽

...

Keyword(s):

Oxidative Stress ◽

Flame Retardants ◽

Neuroblastoma Cells ◽

Brominated Flame Retardants ◽

Human Neuroblastoma Cells ◽

Human Neuroblastoma ◽

Low Concentrations

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Endocrine active industrial chemicals: Release and occurrence in the environment

Pure and Applied Chemistry ◽

10.1351/pac200375111895 ◽

2003 ◽

Vol 75 (11-12) ◽

pp. 1895-1904 ◽

Cited By ~ 18

Author(s):

A. Johnson ◽

M. Jürgens

Keyword(s):

Hot Spots ◽

Endocrine Disruptor ◽

Flame Retardants ◽

Aquatic Ecology ◽

Careful Consideration ◽

Industrial Chemicals ◽

Antifouling Paints ◽

Low Concentrations ◽

Active Substances ◽

Marine Antifouling

Of the xenobiotic endocrine active substances (EASs), tributyltin (TBT) has had the clearest link to an impact on aquatic ecology. Its release from marine antifouling paints had a drastic impact on dogwhelk populations in polluted harbors due to a masculization effect. 4-tert-nonylphenol is seen as the most significant of the industrial xenobiotic estrogen mimics, being implicated as the dominant endocrine disruptor in certain industrialized river reaches. Apart from hot spots associated with particular industries, the estrogenic alkylphenols, phthalates, and bisphenol A are present in effluent and receiving water at concentrations below that which would give cause for concern. Other more bioaccumulative compounds such as polybrominated flame retardants, dioxins, furans may possess some endocrine active properties. The possibility of additivity effects may yet mean that low concentrations of xenobiotic EASs will need careful consideration. It is noted that considerable quantities of many of these compounds are often found in sewage sludge and sediments.

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Developmental exposure to the DE-71 mixture of polybrominated diphenyl ether (PBDE) flame retardants induce a complex pattern of endocrine disrupting effects in rats

PeerJ ◽

10.7717/peerj.12738 ◽

2022 ◽

Vol 10 ◽

pp. e12738

Author(s):

Louise Ramhøj ◽

Karen Mandrup ◽

Ulla Hass ◽

Terje Svingen ◽

Marta Axelstad

Keyword(s):

Mammary Gland ◽

Polybrominated Diphenyl Ethers ◽

Flame Retardants ◽

Developmental Stages ◽

Developmental Toxicity ◽

Diphenyl Ether ◽

Male Offspring ◽

Developmental Exposure ◽

Endocrine Disrupting

Polybrominated diphenyl ethers (PBDEs) are legacy compounds with continued widespread human exposure. Despite this, developmental toxicity studies of DE-71, a mixture of PBDEs, are scarce and its potential for endocrine disrupting effects in vivo is not well covered. To address this knowledge gap, we carried out a developmental exposure study with DE-71. Pregnant Wistar rat dams were exposed to 0, 40 or 60 mg/kg bodyweight/day from gestation day 7 to postnatal day 16, and both sexes were examined. Developmental exposure affected a range of reproductive toxicity endpoints. Effects were seen for both male and female anogenital distances (AGD), with exposed offspring of either sex displaying around 10% shorter AGD compared to controls. Both absolute and relative prostate weights were markedly reduced in exposed male offspring, with about 40% relative to controls. DE-71 reduced mammary gland outgrowth, especially in male offspring. These developmental in vivo effects suggest a complex effect pattern involving anti-androgenic, anti-estrogenic and maybe estrogenic mechanisms depending on tissues and developmental stages. Irrespective of the specific underlying mechanisms, these in vivo results corroborate that DE-71 causes endocrine disrupting effects and raises concern for the effects of PBDE-exposure on human reproductive health, including any potential long-term consequences of disrupted mammary gland development.

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