The placenta: a novel target of sex specific neurotoxicity by fire retardants

Project Summary
Prenatal chemical exposures are widely suspected to contribute to risk of neurodevelopmental disorders but
direct evidence linking specific chemicals to adverse neural effects is sparse, and very little is known about the
mechanisms by which they impact the developing brain. The pressing need to understand how prenatal
chemical exposures contribute to disorders of neurodevelopment is the scientific premise for this
proposal. Our preliminary data show that disruption of placental serotonin (5-HT) constitutes a potentially key
and novel mechanism of neurodevelopmental disruption. The proposed studies will test the hypothesis that
chemical exposures disrupt serotonergic communication between the placenta and developing
forebrain resulting in ASD-related behavioral deficits and compromised synaptic organization and
neurodevelopment. 5-HT, arising from the fetal placenta, has profound effects on the developing brain,
particularly forebrain. Our preliminary data in rats shows that prenatal exposure to the chemical flame retardant
(FR) mixture Firemaster® 550 (FM550) disrupts the placental 5-HT biosynthetic pathway and results in higher
anxiety in males and hyperactivity in females later in life. We further show that FM550 components
bioaccumulate in rat placenta and the brominated components transfer across the placenta into the fetus. An
important aspect of this proposed work is a focus on sex differences, both in susceptibility and the exposure
phenotype. We have found that FM550 components bioaccumulate to a greater degree in males, an outcome
similar to what we have also seen for other FRs in humans, suggesting males are at greater risk of exposure-
related consequences. This mirrors the male-biased incidence of many neurobehavioral disorders. FM550
contains two brominated FRs and a mixture of organophosphate ester FRs, the latter of which have large volume
applications as plasticizers, so human exposure is widespread and predates the introduction of FM550. The
potential toxicity of these replacement FRs is poorly characterized. Sex-specific disruption of placental 5-HT
constitutes a potentially key and novel mechanism of neurodevelopmental disruption.
Aim 1: Establish the toxicokinetics of FM550 components in gestating rats, and quantify the degree to
which FM550 bioaccumulates in rats and humans of each sex.
Aim 2: Elucidate the capacity of FM550 to disrupt placental 5-HT biosynthesis and serotonergic input on
the developing forebrain.
Aim 3: Understand the long term impact of developmental FM550 exposure on neural development and
behavior.
The long term goal of our work is to elucidate the impact of prenatal chemical exposures on brain development
so that strategies can be devised to limit exposure to harmful compounds, and mitigate their harmful effects.