Diet-induced hyperhomocysteinemia causes sex-dependent deficiencies in offspring musculature and brain function
Type
Journal article
Language
English
Date issued
2024
Faculty
Wydział Rolnictwa, Ogrodnictwa i Biotechnologii
Journal
Frontiers in Cell and Developmental Biology
ISSN
2296-634X
Volume
12
Pages from-to
art. 1322844
Abstract (EN)
Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine (Hcy)
levels, is a known risk factor for cardiovascular, renal, and neurological diseases,
as well as pregnancy complications. Our study aimed to investigate whether
HHcy induced by a high-methionine (high-Met) diet exacerbates cognitive and
behavioral deficits in offspring and leads to other breeding problems. Dietary
HHcy was induced four weeks before mating and continued throughout
gestation and post-delivery. A battery of behavioral tests was conducted on
offspring between postnatal days (PNDs) 5 and 30 to assess motor function/
activity and cognition. The results were correlated with brain morphometric
measurements and quantitative analysis of mammalian target of rapamycin
(mTOR)/autophagy markers. The high-Met diet significantly increased parental
and offspring urinary tHcy levels and influenced offspring behavior in a sexdependent manner. Female offspring exhibited impaired cognition, potentially
related to morphometric changes observed exclusively in HHcy females. Male
HHcy pups demonstrated muscle weakness, evidenced by slower surface
righting, reduced hind limb suspension (HLS) hanging time, weaker grip
strength, and decreased activity in the beaker test. Western blot analyses
indicated the downregulation of autophagy and the upregulation of mTOR
activity in HHcy cortexes. HHcy also led to breeding impairments, including
reduced breeding rate, in-utero fetal death, lower pups’ body weight, and
increased mortality, likely attributed to placental dysfunction associated with
HHcy. In conclusion, a high-Met diet impairs memory and cognition in female
juveniles and weakens muscle strength in male pups. These effects may stem
from abnormal placental function affecting early neurogenesis, the dysregulation
of autophagy-related pathways in the cortex, or epigenetic mechanisms of gene
regulation triggered by HHcy during embryonic development
levels, is a known risk factor for cardiovascular, renal, and neurological diseases,
as well as pregnancy complications. Our study aimed to investigate whether
HHcy induced by a high-methionine (high-Met) diet exacerbates cognitive and
behavioral deficits in offspring and leads to other breeding problems. Dietary
HHcy was induced four weeks before mating and continued throughout
gestation and post-delivery. A battery of behavioral tests was conducted on
offspring between postnatal days (PNDs) 5 and 30 to assess motor function/
activity and cognition. The results were correlated with brain morphometric
measurements and quantitative analysis of mammalian target of rapamycin
(mTOR)/autophagy markers. The high-Met diet significantly increased parental
and offspring urinary tHcy levels and influenced offspring behavior in a sexdependent manner. Female offspring exhibited impaired cognition, potentially
related to morphometric changes observed exclusively in HHcy females. Male
HHcy pups demonstrated muscle weakness, evidenced by slower surface
righting, reduced hind limb suspension (HLS) hanging time, weaker grip
strength, and decreased activity in the beaker test. Western blot analyses
indicated the downregulation of autophagy and the upregulation of mTOR
activity in HHcy cortexes. HHcy also led to breeding impairments, including
reduced breeding rate, in-utero fetal death, lower pups’ body weight, and
increased mortality, likely attributed to placental dysfunction associated with
HHcy. In conclusion, a high-Met diet impairs memory and cognition in female
juveniles and weakens muscle strength in male pups. These effects may stem
from abnormal placental function affecting early neurogenesis, the dysregulation
of autophagy-related pathways in the cortex, or epigenetic mechanisms of gene
regulation triggered by HHcy during embryonic development
License
CC-BY - Attribution
CC-BY - Attribution Open access date
March 15, 2024