Beyond Cholinesterase Inhibition: Developmental Neurotoxicity of Organophosphate Ester Flame Retardants and Plasticizers - PubMed (original) (raw)

. 2021 Oct;129(10):105001.

doi: 10.1289/EHP9285. Epub 2021 Oct 6.

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Beyond Cholinesterase Inhibition: Developmental Neurotoxicity of Organophosphate Ester Flame Retardants and Plasticizers

Heather B Patisaul et al. Environ Health Perspect. 2021 Oct.

Abstract

Background: To date, the toxicity of organophosphate esters has primarily been studied regarding their use as pesticides and their effects on the neurotransmitter acetylcholinesterase (AChE). Currently, flame retardants and plasticizers are the two largest market segments for organophosphate esters and they are found in a wide variety of products, including electronics, building materials, vehicles, furniture, car seats, plastics, and textiles. As a result, organophosphate esters and their metabolites are routinely found in human urine, blood, placental tissue, and breast milk across the globe. It has been asserted that their neurological effects are minimal given that they do not act on AChE in precisely the same way as organophosphate ester pesticides.

Objectives: This commentary describes research on the non-AChE neurodevelopmental toxicity of organophosphate esters used as flame retardants and plasticizers (OPEs). Studies in humans, mammalian, nonmammalian, and in vitro models are presented, and relevant neurodevelopmental pathways, including adverse outcome pathways, are described. By highlighting this scientific evidence, we hope to elevate the level of concern for widespread human exposure to these OPEs and to provide recommendations for how to better protect public health.

Discussion: Collectively, the findings presented demonstrate that OPEs can alter neurodevelopmental processes by interfering with noncholinergic pathways at environmentally relevant doses. Application of a pathways framework indicates several specific mechanisms of action, including perturbation of glutamate and gamma-aminobutyric acid and disruption of the endocrine system. The effects may have implications for the development of cognitive and social skills in children. Our conclusion is that concern is warranted for the developmental neurotoxicity of OPE exposure. We thus describe important considerations for reducing harm and to provide recommendations for government and industry decision makers. https://doi.org/10.1289/EHP9285.

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Figures

Figure 1A to 1C is a set of three tabular representations. Figure 1A titled Glutamate has three columns, namely, Cellular and Organ Effects, Organism Effects, and Human Effects. Cellular and Organ Effects displays the following information: Monolayer in vitro cell culture: Reduced response to glutamate; three-Dimensional in vitro cell culture: Alternation in expression of glutamate N-methyl-d aspartate receptor, N A A and L aspartic decreased, and Reduced levels of glutamate; Rodent in vivo: Disruption of glutamate, Disruption of N A A, creatine and lactic acid, Increased levels of glutamate, and Neuronal death. Organism Effects displays the following information: Rodent in vivo: Impaired learning and memory. Human Effects displays the following information: Adverse impacts on cognitive development, including early language ability, and fine motor skills, Adverse behavioral development including withdrawal, attention problems, depression, hyperactivity, and aggression, Decrease in I Q and working memory, and Social behavioral problems including less responsible behavior, and more externalizing behaviors. Figure 1B titled G A B A (Gamma-Aminobutyric acid) has three columns, namely, Cellular and Organ Effects, Organism Effects, and Human Effects. Cellular and Organ Effects displays the following information: Monolayer in vitro cell culture: Inhibition of G A B A R. Three-Dimensional in vitro cell culture: Decrease in genes involved in G A B A production and signaling and Decrease in G A B A. Zebrafish: Altered levels of G A B A. Rodent in vivo: G A B A antagonist and Disruption of G A B A. Organism Effects displays the following information: Zebrafish: Hyperactivity. Rodent in vivo: Impaired learning and memory and Increased ambulatory behavior. Human Effects displays the following information: Adverse impacts on cognitive development, including early language ability, and fine motor skills, Adverse behavioral development including withdrawal, attention problems, depression, hyperactivity, and aggression, Decrease in I Q and working memory, and Social behavioral problems including less responsible behavior, and more externalizing behaviors. Figures 1C titled Other Neurotransmitters has three columns, namely, Cellular and Organ Effects, Organism Effects, and Human Effects. Cellular and Organ Effects displays the following information: Monolayer in vitro cell culture: Increase in differentiation of dopaminergic neurons. Three-Dimensional in vitro cell culture: Decrease in dopamine. Zebrafish: Dopamine levels decreased, Dopamine and dopamine signaling related genes decreased, and Decreased serotonin and histamine levels. Rodent in vivo: Dopamine signaling altered, Disruption in serotonin pathways, and Serotonin levels increased. Organism Effects displays the following information: Zebrafish: Vulnerability to anxiety-like behavior potentially due to decrease in dopamine. Rodent in vivo: Increased ambulatory behavior. Human Effects displays the following information: Adverse impacts on cognitive development, including early language ability, and fine motor skills, Adverse behavioral development including withdrawal, attention problems, depression, hyperactivity, and aggression, Decrease in I Q and working memory, and Social behavioral problems including less responsible behavior, and more externalizing behaviors.

Figure 1.

Developmental neurotoxicity: neurotransmitters—(A) glutamate, (B) GABA, and (C) other neurotransmitters. Effects seen in humans may be associated with many different systems and thus are repeated for each outcome category. Note: 3D, three dimensional; GABA, gamma-aminobutyric acid; IQ, intelligence quotient; NAA, n-acetyl aspartate; NMDA, N-methyl-

d

aspartate; R, receptor.

Figure 2A and 2B is a set of two tabular representations. Figure 2A is Inflammation, Glia activation and oxidative stress has three columns, namely, Cellular and Organ Effects, Organism Effects, and Human Effects. Cellular and Organ Effects displays the following information: Monolayer in vitro cell culture: Increased glia/neuro ratio and Inflammatory response. Three-Dimensional in vitro cell culture: Gliosis or activated astrocytes and Increased cytokine release. Zebrafish: Oxidative stress, Increased G F A P levels, and Decreased histamine levels. Rodent in vivo: Oxidative stress, Microglia mediated inflammation, and Increase in proinflammatory cytokines. Organism Effects displays the following information: Zebrafish: Altered locomotor behavior. Human Effects displays the following information: Adverse impacts on cognitive development, including early language ability, and fine motor skills, Adverse behavioral development including withdrawal, attention problems, depression, hyperactivity, and aggression, Decrease in I Q and working memory, and Social behavioral problems including less responsible behavior, and more externalizing behaviors. Figure 2B titled neuronal morphology and function has three columns, namely, Cellular and Organ Effects, Organism Effects, and Human Effects. Cellular and Organ Effects displays the following information: Monolayer in vitro cell culture: Decrease in neurite outgrowth, Decreased neuronal network activity, and Cytotoxic to neural cells. Three-Dimensional in vitro cell culture: Decrease in expression of neurite skeleton genes, and Decreased expression of genes involved in synaptogenesis. Zebrafish: Decrease in genes involved in cytoskeleton organization and Synaptogenesis marker altered. Organism Effects displays the following information: Zebrafish: Altered locomotor behavior. Human Effects displays the following information: Adverse impacts on cognitive development, including early language ability, and fine motor skills, Adverse behavioral development including withdrawal, attention problems, depression, hyperactivity, and aggression, Decrease in I Q and working memory, and Social behavioral problems including less responsible behavior, and more externalizing behaviors.

Figure 2.

Developmental neurotoxicity: nervous system—(A) inflammation, glia activation, and oxidative stress and (B) neuronal morphology and function. Effects seen in humans may be associated with many different systems and thus are repeated for each outcome category. Note: 3D, three dimensional; GFAP, glial fibrillary acidic protein; IQ, intelligence quotient.

Figure 3 is a tabular representation titled Endocrine Disruption has three columns, namely, Cellular and Organ Effects, Organism Effects, and Human Effects. Cellular and Organ Effects displays the following information: Monolayer in vitro cell culture: Antagonist and/or agonist for human hormone receptors, Increased estradiol and testosterone levels, Up-regulation of genes involved in thyroid synthesis, and Peroxisome Proliferator-Activated Receptor lowercase gamma 1 agonist. Zebrafish: Thyroxine and triiodothyronine decreased in plasma, Alteration of steroidogenesis, and estrogen metabolism, Alteration in genes involved in thyroid metabolism, and Increased triiodothyronine, decreased thyroxine in adult females and F1 eggs. Rodent in vivo: Altered gene expression linked to endocrine disruption, Increased serum thyroxine levels, and Endocrine disruption. Organism Effects displays the following information: Zebrafish: Vulnerability to anxiety-like behavior in females and Altered locomotor behavior. Rodent in vivo: Sex differences in activity and anxiety behavior. Human Effects displays the following information: Altered levels of thyroid stimulating hormone, Thyroid hormone disruption, Disruption of sex steroids and sex steroid binding globulins, and Increased risk of attention deficit hyperactivity disorder mediated by maternal thyroid.

Figure 3.

Endocrine Disruption. Note: 3D, three dimensional; ADHD, attention deficit hyperactivity disorder; F1, first filial generation; IQ, intelligence quotient; PPARγ, peroxisome proliferator-activated receptor-gamma; T3, triiodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone.

References

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