Newborns are colonized by maternal microbiota that is essential for offspring health and development. The composition of these pioneer communities exhibits individual differences, but the importance of this early-life heterogeneity to health outcomes is not understood. Here we validate a human microbiota-associated model in which fetal mice are cesarean delivered and gavaged with defined human vaginal microbial communities. This model replicates the inoculation that occurs during vaginal birth and reveals lasting effects on offspring metabolism, immunity, and the brain in a community-specific manner. This microbial effect is amplified by prior gestation in a maternal obesogenic or vaginal dysbiotic environment where placental and fetal ileum development are altered, and an augmented immune response increases rates of offspring mortality. Collectively, we describe a translationally relevant model to examine the defined role of specific human microbial communities on offspring health outcomes, and demonstrate that the prenatal environment dramatically shapes the postnatal response to inoculation.

FiremasterV R 550 (FM 550) is a commercial mixture of organophosphate and brominated flame retardants currently in use as a replacement for pentaBDE. Its organophosphate components include triphenyl phosphate (TPHP) and a suite of isopropylated triarylphosphate isomers (ITPs); its brominated components include 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) and bis (2-ethylhexyl)-2,3,4,5-tetrabromophthalate (BEH-TEBP). Taken together, these chemicals have been shown to be endocrine disrupting and potentially toxic, and human exposure to them is widespread. In this study, maternal transfer of FM 550 components, and in some cases their metabolites, was investigated in dosed Wistar rats. Gestational and lactational transfer were examined separately, with dams orally exposed to 300 or 1000 mg of FM 550 for 10 consecutive days during gestation (gestational day [GD] 9-18) or lactation (postnatal day [PND] 3-12). Levels of parent compounds were measured in fetus and whole pup tissue homogenates, and in dam and pup serum, and several metabolites were measured in dam and pup urine. EH-TBB body burdens resulting from lactational transfer were approximately 200-to 300-fold higher than those resulting from placental transfer, whereas low levels of BEH-TEBP were transferred during both lactation and gestation. TPHP and ITPs were rapidly metabolized by the dams and were not detected in whole tissue homogenates. However, diphenyl phosphate (DPHP) and mono-isopropylphenyl phenyl phosphate (ip-PPP) were detected in urine from the dosed animals. This study is the first to confirm ip-PPP as a urinary metabolite of ITPs and establish a pharmacokinetic profile of FM 550 in a mammalian model.

The perinatal window represents a critical and extremely vulnerable period of time during which chemical insult can alter the morphological and functional trajectory of the developing brain. Numerous chemical classes have been associated with alterations in neurodevelopment including metals, solvents, pesticides, and, more recently, endocrine-disrupting compounds. Although mechanisms of neurotoxicity have traditionally been identified as pathways leading to neuronal cell death, neuropathology, or severe neural injury, recent research highlights alternative mechanisms that result in more subtle but consequential changes in the brain and behavior. These emerging areas of interest include neuroendocrine and immune disruption, as well as indirect toxicity via actions on other organs such as the gut and placenta. Understanding of the myriad ways in which the developing brain is vulnerable to chemical exposures has grown tremendously over the past decade. Further progress and implementation in risk assessment is critical to reducing risk of neurodevelopmental disorders.

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6-hydroxy-2,2′,4,4′-tetrabromodiphenyl ether (6-OH-BDE-47) is both a polybrominated diphenyl ether (PBDE) flame retardant metabolite and a marine natural product. It has been identified both as a neurotoxicant in cell-based studies and as a developmental toxicant in zebrafish. Hydroxylated PBDE metabolites are also considered thyroid hormone disruptors due to their structural similarity to endogenous thyroid hormones. The purpose of this study was to evaluate the effects of 6-OH-BDE-47 on a developmental pathway regulated by thyroid hormones in zebrafish. Morphological measurements of development (head trunk angle, otic vesicle length, and eye pigmentation) were recorded in embryos at 30 hours post fertilization (hpf) and detailed craniofacial morphology was examined in 4 day old larvae using cartilage staining. Exposure to 6-OH-BDE-47 resulted in severe developmental delays. A 100 nM concentration resulted in a 26% decrease in head trunk angle, a 54% increase in otic vesicle length, and a 42% decrease in eye pigmentation. Similarly, altered developmental morphology was observed following: Thyroid Receptor β morpholino knockdown;, exposure to the thyroid hormone triiodothyronine (T3) and to thyroid disrupting chemicals (TDC; iopanoic acid and propylthiouracil). The threshold for lower jaw deformities and craniofacial cartilage malformations was at doses greater than 50 nM. Of interest, these developmental delays and effects were rescued by microinjection of TRβ mRNA during the 1–2 cell stage. These data indicate that OH-BDEs can adversely affect early life development of zebrafish and suggest they may be impacting thyroid hormone regulation in vivo through downregulation of the thyroid hormone receptor.

Per- and polyfluoroalkyl substances (PFAS) are a class of structurally diverse synthetic organic chemicals that are chemically stable, resistant to degradation, and persistent in terrestrial and aquatic environments. Widespread use of PFAS in industrial processing and manufacturing over the last 70 years has led to global contamination of built and natural environments. The brain is a lipid rich and highly vascularized organ composed of long-lived neurons and glial cells that are especially vulnerable to the impacts of persistent and lipophilic toxicants. Generally, PFAS partition to protein-rich tissues of the body, primarily the liver and blood, but are also detected in the brains of humans, wildlife, and laboratory animals. Here we review factors impacting the absorption, distribution, and accumulation of PFAS in the brain, and currently available evidence for neurotoxic impacts defined by disruption of neurochemical, neurophysiological, and behavioral endpoints. Emphasis is placed on the neurotoxic potential of exposures during critical periods of development and in sensitive populations, and factors that may exacerbate neurotoxicity of PFAS. While limitations and inconsistencies across studies exist, the available body of evidence suggests that the neurobehavioral impacts of long-chain PFAS exposures during development are more pronounced than impacts resulting from exposure during adulthood. There is a paucity of experimental studies evaluating neurobehavioral and molecular mechanisms of short-chain PFAS, and even greater data gaps in the analysis of neurotoxicity for PFAS outside of the perfluoroalkyl acids. Whereas most experimental studies were focused on acute and subchronic impacts resulting from high dose exposures to a single PFAS congener, more realistic exposures for humans and wildlife are mixtures exposures that are relatively chronic and low dose in nature. Our evaluation of the available human epidemiological, experimental, and wildlife data also indicates heightened accumulation of perfluoroalkyl acids in the brain after environmental exposure, in comparison to the experimental studies. These findings highlight the need for additional experimental analysis of neurodevelopmental impacts of environmentally relevant concentrations and complex mixtures of PFAS.

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.

There is a pressing need to develop tools for assessing possible neurotoxicity, particularly for chemicals where the mode of action is poorly understood. Tetrabromobisphenol a (TBBPA), a highly abundant brominated flame retardant, has lately been targeted for neurotoxicity analysis by concerned public health entities in the EU and United States because it is a suspected thyroid disruptor and neurotoxicant. In this study, infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) coupled to a Q Exactive Plus mass spectrometer was used for the analysis of neurotransmitters in the brains of rats exposed to TBBPA in gestation and lactation through their mothers. Three neurotransmitters of interest were studied in three selected regions of the brain; caudate putamen, substantia nigra (SN) and dorsal raphe. Stable Isotope Labelled (SIL) standards were used as internal standards and a means to achieve relative quantification. This study serves as a demonstration of a new application of IR-MALDESI, namely that neurotransmitter distributions can be confidently and rapidly imaged without derivatization.