Effects of Prenatal Exposure to a Mixture of Organophosphate Flame Retardants on Placental Gene Expression and Serotonergic Innervation in the Fetal Rat Brain

Abstract

There is a growing need to understand the potential neurotoxicity of organophosphate flame retardants (OPFRs) and plasticizers because use and, consequently, human exposure, is rapidly expanding. We have previously shown in rats that developmental exposure to the commercial flame retardant mixture Firemaster 550 (FM 550), which contains OPFRs, results in sex-specific behavioral effects, and identified the placenta as a potential target of toxicity. The placenta is a critical coordinator of fetal growth and neurodevelopment, and a source of neurotransmitters for the developing brain. We have shown in rats and humans that flame retardants accumulate in placental tissue, and induce functional changes, including altered neurotransmitter production. Here, we sought to establish if OPFRs (triphenyl phosphate and a mixture of isopropylated triarylphosphate isomers) alter placental function and fetal forebrain development, with disruption of tryptophan metabolism as a primary pathway of interest. Wistar rat dams were orally exposed to OPFRs (0, 500, 1000, or 2000 μg/day) or a serotonin (5-HT) agonist 5-methoxytryptamine for 14 days during gestation and placenta and fetal forebrain tissues collected for analysis by transcriptomics and metabolomics. Relative abundance of genes responsible for the transport and synthesis of placental 5-HT were disrupted, and multiple neuroactive metabolites in the 5-HT and kynurenine metabolic pathways were upregulated. In addition, 5-HTergic projections were significantly longer in the fetal forebrains of exposed males. These findings suggest that OPFRs have the potential to impact the 5-HTergic system in the fetal forebrain by disrupting placental tryptophan metabolism.

Associations between the exposure to organophosphate flame retardants during early pregnancy and the risk of spontaneous abortion based on metabolomics combined with tandem mass spectrometry

“…(12). In view of the fact that developing fetuses are particularly susceptible to a variety of toxicants, a high concentration of OPFRs and their metabolites in pregnant women has attracted increasing attention (13,14).…”

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

“…2018 ). In addition, serotonergic projections were shown to be significantly longer in the fetal forebrains of exposed males ( Rock et al. 2020 ).…”

“…2016 ; Baldwin et al. 2017 ) and can induce functional changes, including altered neurotransmitter production ( Rock et al. 2020 ).…”

“…Recent studies in rats exposed in utero to FM 550 have demonstrated that forebrain serotonin (5-HT) turnover was reduced, with evidence of endocrine disruption, inflammation, and altered neurotransmitter production found in the placentas (Rock et al 2018). In addition, serotonergic projections were shown to be significantly longer in the fetal forebrains of exposed males (Rock et al 2020). This suggests a DNT mechanism that involves the placenta, which is biologically plausible because the placenta coordinates fetal growth and neurodevelopment and is likely the only source of 5-HT and other neurotransmitters for the developing brain at certain developmental time points (Bonnin et al 2011a;Bonnin and Levitt 2011b;Broad et al 2016).…”

“…It has been shown, for example, in developmentally exposed Wistar rats, that FM 550 can have endocrine disrupting properties (e.g., increased serum thyroxine) and could produce sex-specific effects on anxiety and other complex behaviors (Patisaul et al 2013;Baldwin et al 2017). Further, OPEs accumulate in rat placental tissue, in some cases to a higher degree in male-associated placentas than female (Phillips et al 2016;Baldwin et al 2017) and can induce functional changes, including altered neurotransmitter production (Rock et al 2020). Recent studies in rats exposed in utero to FM 550 have demonstrated that forebrain serotonin (5-HT) turnover was reduced, with evidence of endocrine disruption, inflammation, and altered neurotransmitter production found in the placentas (Rock et al 2018).…”