EDC IMPACT: Molecular effects of developmental FM 550 exposure in Wistar rat placenta and fetal forebrain

Abstract

Firemaster 550 (FM 550) is a flame retardant (FR) mixture that has become one of the most commonly used FRs in foam-based furniture and baby products. Human exposure to this commercial mixture, composed of brominated and organophosphate components, is widespread. We have repeatedly shown that developmental exposure can lead to sex-specific behavioral effects in rats. Accruing evidence of endocrine disruption and potential neurotoxicity has raised concerns regarding the neurodevelopmental effects of FM 550 exposure, but the specific mechanisms of action remains unclear. Additionally, we observed significant, and in some cases sex-specific, accumulation of FM 550 in placental tissue following gestational exposure. Because the placenta is an important source of hormones and neurotransmitters for the developing brain, it may be a critical target of toxicity to consider in the context of developmental neurotoxicity. Using a mixture of targeted and exploratory approaches, the goal of the present study was to identify possible mechanisms of action in the developing forebrain and placenta. Wistar rat dams were orally exposed to FM 550 (0, 300 or 1000 µg/day) for 10 days during gestation and placenta and fetal forebrain tissue collected for analysis. In placenta, evidence of endocrine, inflammatory and neurotransmitter signaling pathway disruption was identified. Notably, 5-HT turnover was reduced in placental tissue and fetal forebrains indicating that 5-HT signaling between the placenta and the embryonic brain may be disrupted. These findings demonstrate that environmental contaminants, like FM 550, have the potential to impact the developing brain by disrupting normal placental functions.

Prenatal exposure to organophosphate esters and cognitive development in young children in the Pregnancy, Infection, and Nutrition Study

“…Evidence pertaining to cognitive-related effects of exposure to FM550 are more abundant. For example, available evidence suggests that exposure to FM550 disrupts endocrine system function [64], interferes with placental endocrine, inflammatory, and neurotransmitter signaling pathways [70], and can produce behavioral effects in model organisms [64,71,72]. Because FM550 as a mixture has been associated with cognitive-related effects, as have specific compounds of the mixture [63], the associations we observed with ip-PPP may be confounded by other components of FM550 (e.g., brominated components such as 2-ethylhexyl-2,3,4,5 tetrabromobenzoate and bis (2ethylhexyl) tetrabromophthalate) [63].…”

Developmental Exposure to the Flame Retardant Mixture Firemaster 550 Compromises Adult Bone Integrity in Male but not Female Rats

“…FM 550 contains a mixture of organophosphates: (1) triphenyl phosphate (TPHP; previously abbreviated TPP); and (2) a mixture of isopropylated triphenylphosphate isomers (ITPs); as well as two brominated compounds (3) 2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB); and (4) bis(2-Ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH). Work by us and others have identified this mixture to be developmentally neurotoxic, endocrine disrupting, and obesogenic [5][6][7][8][9][10][11][12][13]. Human exposure is nearly ubiquitous with both gestational and lactational transfer as significant exposure routes in addition to direct exposure via household dust, which is inadvertently ingested or inhaled [14][15][16][17].…”

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

“…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 ).…”

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