Exposure to organophosphate flame retardants and phthalates alters neuronal activity and network development

Abstract

Exposure to organophosphate flame retardants (OPFRs) and phthalates is associated with neurodevelopmental deficits, impaired neuronal proliferation and differentiation, altered neurotransmitter levels, and impaired learning and memory. Here, we assessed the effects of acute and chronic exposure to the OPFR triphenyl phosphate (TPhP) and several phthalates on neuronal activity and network development in male and female rat primary cortical cultures grown on micro-electrode arrays. Acute exposure to TPhP, diethyl phthalate (DEP), dibutyl phthalate (DBP), and benzyl butyl phthalate (BBzP) inhibited neuronal activity, while chronic exposure to TPhP and DEP induced a hyperexcitation. Chronic exposure to DBP, BBzP, bis(2-ethylhexyl) phthalate (DEHP), and its metabolite mono-2-ethylhexyl phthalate (MEHP) inhibited neuronal network development. Exposure to BBzP and DEHP affected neuronal function at human-relevant concentrations as low as 1 µM. Acute and chronic exposure to the metabolites of DEP, DBP, and BBzP had only limited effects. Although the underlying mechanisms remain to be elucidated, analysis of endocrine mechanisms, including retinoic acid, retinoic X, liver X, and prostaglandin E₂ receptor, suggested that the effects of OPFR and phthalates were not endocrine-mediated. Further research is needed to elucidate the mechanisms underlying the different responses to acute and chronic exposure. Taken together, these results add to the evidence that TPhP and various phthalates illicit neurotoxic effects, some at low concentrations. These novel results should be considered in the risk assessment of these chemicals.