Maternal dietary loads of α-tocopherol depress protein kinase C signaling and synaptic plasticity in rat postnatal developing hippocampus and promote permanent deficits in adult offspring.
Vitamin E (α-tocopherol) supplementation has been tested as prophylaxis against gestational disorders associated with oxidative damage. However, recent evidence showing that high maternal α-tocopherol intake can adversely affect offspring development raises concerns on the safety of vitamin E extradosages during pregnancy. Besides acting as an antioxidant, α-tocopherol depresses cell proliferation and modulates cell signaling through inhibiting protein kinase C (PKC), a kinase that is deeply involved in neural maturation and plasticity. Possible effects of α-tocopherol loads in the maturing brain, where PKC dysregulation is associated to developmental dysfunctions, are poorly known. Here, supranutritional doses of α-tocopherol were fed to pregnant and lactating dams to evaluate the effects on PKC signaling and morphofunctional maturation in offspring hippocampus. Results showed that maternal supplementation potentiates hippocampal α-tocopherol incorporation in offspring and leads to marked decrease of PKC phosphorylation throughout postnatal maturation, accompanied by reduced phosphorylation of growth-associated protein-43 and myristoylated alanine-rich C kinase substrate, two PKC substrates involved in neural development and plasticity. Although processes of neuronal maturation, synapse formation and targeting appeared unaffected, offspring of supplemented mothers displayed a marked reduction of long-term synaptic plasticity in juvenile hippocampus. Interestingly, this impairment persisted in adulthood, when a deficit in hippocampus-dependent, long-lasting spatial memory was also revealed. In conclusion, maternal supplementation with elevated doses of α-tocopherol can influence cell signaling and synaptic plasticity in developing hippocampus and promotes permanent adverse effects in adult offspring. The present results emphasize the need to evaluate the safety of supranutritional maternal intake of α-tocopherol in humans.
Betti
Michele
M
Section of Physiology, Department of Human, Environmental and Natural Sciences, University of Urbino Carlo Bo, 61029, Italy. michele.betti@uniurb.it
Ambrogini
Patrizia
P
Minelli
Andrea
A
Floridi
Alessandro
A
Lattanzi
Davide
D
Ciuffoli
Stefano
S
Bucherelli
Corrado
C
Prospero
Emilia
E
Frontini
Andrea
A
Santarelli
Lory
L
Baldi
Elisabetta
E
Benetti
Fernando
F
Galli
Francesco
F
Cuppini
Riccardo
R
D000818:Animals; D019587:Dietary Supplements / Q000633:toxicity; D015536:Down-Regulation; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007774:Lactation; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D008565:Membrane Proteins / Q000378:metabolism; D008569:Memory Disorders / Q000139:chemically induced; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*
D019922:GAP-43 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D011493:Protein Kinase C; D024502:alpha-Tocopherol