Abstract
Objectives
Zinc deficiency can affect early brain development. We previously found that developmental marginal zinc deficiency affected neurogenesis leading to a lower number of neurons and altered neural specification in the adult rat brain. Zinc deficiency can occur as low dietary zinc intake and secondary to diseases, infections, and exposure to environmental toxicants such as phthalates. This work investigated if gestational exposure to toxicant Di-2-ethylhexyl phthalate (DEHP) could decrease zinc availability to the fetus and altered neurogenesis.
Methods
Rats were fed an adequate (25 µg zinc/g diet) (C) or a marginal zinc deficient (MZD) (10 µg zinc/g diet), without or with DEHP (300 mg/kg BW) (C + DEHP, MZD + DEHP) from gestational day zero until embryonic day 19 (E19). Zinc concentration was analyzed by atomic absorption spectrometry (AAS). Neurogenesis was evaluated in the offspring at E19 measuring parameters of neural progenitor cells (NPC) proliferation and differentiation by Western blot and/or immunofluorescence.
Results
Fetal brain zinc concentration was significantly decreased in MZD, C + DEHP and MZD + DEHP than in C. Protein Markers of neurogenesis (NeuN, PAX6, SOX2, TBR2) were lower in MZD and C + DEHP than C, and lowest in MZD + DEHP. The excitatory neuron marker vesicular glutamate transporter 1 (VGLUT1) was lower in C + DEHP, MZD and MZD + DEHP than in C, while the marker of inhibitory neurons glutamic acid decarboxylase (GAD65) level were similar among groups. The ERK1/2 pathway, crucial to neurogenesis, was affected by MZD and DEHP. ERK1/2 activation was lower, and at a similar extent in C + DEHP and MZD groups than in C, while it was markedly lower in the MZD + DEHP group compared to all other groups. Lower ERK1/2 activation could be due to activation of the ERK1/2 phosphatase 2A (PP2A). We found that PP2A activation was higher, in MZD and DEHP than in C, being highest in the MZD + DEHP group.
Conclusions
Gestational exposure to DEHP in rats causes a secondary zinc deficiency in the fetal brain and altered neurogenesis. This can be due to the inhibition of the ERK1/2 signaling pathway. DEHP exposure can adversely affect the offspring's brain development and result in irreversible consequences to adult brain structure and function.
Funding Sources
Supported by grants from NIFA CA-D-XXX-7244-H, Packer-Wentz foundation, NIEHS T 32 training grant (T32 ES 0,07059).
MeCP2 Is Critical for Maintaining Mature Neuronal Networks and Global Brain Anatomy during Late Stages of Postnatal Brain Development and in the Mature Adult Brain
