Background: The solute carrier family 22 member 23 (Slc22a23), a gene encoding a membrane-orphan transporter, is irreversibly upregulated in the brains of rats following fetal undernutrition. Materials and Method: To identify potential substrates of the SLC22A23 transporter, we analyzed the plasma of both Slc22a23-proficient and deficient rats. Results: We found that the level of lysophosphatidylcholine a C20:4 (LPC(20:4)) in plasma was more than twofold lower in the Slc22a23−/− rats than in the Slc22a23+/+ rats. We then conducted a series of animal behavioral tests on Slc22a23-proficient (Slc22a23+/+) and deficient (Slc22a23−/−) rats to investigate the effects of LPC(20:4) administration. We observed considerable effects in both Slc22a23+/+ and Slc22a23−/− rats, with more pronounced effects in the Slc22a23+/+ rats. These effects included reductions in total distance travelled in an open field test, reductions in access to the novel objects in a novel object recognition test, reductions in sociability to a familiar rat in a social interaction test, and shorter latencies to the target in the Morris water maze test. Discussion: These findings suggest that LPC(20:4) administration enhances memory acquisition in both Slc22a23+/+ and Slc22a23−/− rats, though it appears to be more effective in the Slc22a23+/+ rats. While the SLC22A23 transporter is likely involved in facilitating the transport of LPC(20:4), other transporters may also play a role in its transport in vivo.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased. MASLD notably increases after menopause in women owing to the drastic reduction in estrogen, which regulates lipid metabolism. While prenatal undernutrition leads to hepatic steatosis after birth, whether prenatal undernutrition affects the onset of postmenopausal MASLD remains unknown. Therefore, we examined the impact of early prenatal undernutrition on the predisposition to postmenopausal MASLD in a rat model of menopause. Pregnant female rats were assigned to the control (CNTL) group, while the undernourished (UN) group was fed 40% of the diet of the control group. Furthermore, both groups were assigned to the ovariectomized (CNTL-OVX/UN-OVX) and sham-operated (CNTL-Sham/UN-Sham) groups at 12 weeks of age. Two-way analysis of variance revealed significant main effects of ovariectomy and prenatal undernutrition on body weight and hepatic triglyceride content. Triglycerides accumulated in the liver at 12 and 24 weeks after ovariectomy, while hepatic steatosis was histologically observed at 24 weeks after ovariectomy in UN-OVX rats. Hepatic gene expression analyses showed an interaction effect between prenatal undernutrition × ovariectomy in ESR1 expression; however, PPARα, RXRα, RARα, Raldh1, and Raldh3 expression was not affected by prenatal undernutrition and ovariectomy. These results suggest that early prenatal undernutrition predisposes postmenopausal women to MASLD by uncovering aberrant estrogen signaling, which may be influenced by estrogen reduction.

Epidemiological studies suggest that poor nutrition during pregnancy predisposes offspring to the development of lifestyle-related noncommunicable diseases and psychiatric disorders later in life. However, the molecular mechanisms underlying this predisposition are not well understood. In our previous study, using rats as model animals, we showed that behavioral impairments are induced by prenatal undernutrition. In this study, we identified solute carrier 22 family member 23 (Slc22a23) as a gene that is irreversibly upregulated in the rat brain by undernutrition during fetal development. Because the substrate of the SLC22A23 transporter has not yet been identified and the biological role of the Slc22a23 gene in vivo is not fully understood, we generated pan-Slc22a23 knockout rats and examined their phenotype in detail. The Slc22a23 knockout rats showed a lean phenotype, an increase in spontaneous locomotion, and improved endurance, indicating that they are not overweight and are even healthier in an ad libitum feeding environment. However, the knockout rats had reduced hippocampal volume, and the behavioral analysis suggested that they may have impaired cognitive function regarding novel objects.

近年，エピジェネティクスの概念が導入され，Developmental Origins of Health and Disease（DOHaD）学説に基づくmetabolic syndrome（MS）などの非感染性疾患リスク上昇が危惧されるようになってきた。本邦では2000年代以降，低出生体重児（Low birth weight infant：LBWI）が急増している。そこで，2000年前後に生まれた男子大学生を対象とし，MS と関連の深い筋機能がLBWI の影響を受けているのかを確認する目的で調査を行った。対象よりLBWI 群（5名）と正常出生体重児（normal birth weight infant：NBWI）群（5名）を抽出し，筋力，運動耐容能，身長，体組成，血圧，腹囲，学齢期と思春期における運動時間の各項目について両群間で比較検討した。その結果，運動耐容能はLBWI 群が有意に低値を示した（p＜0．01）が，他の項目に有意差は認められなかった。LBWI 群における運動耐容能低下の背景として，骨格筋のインスリン抵抗性増大によるエネルギー産出効率低下が引き起こされている可能性が示唆された。MS 予防の観点から，LBWI は成人期を迎える前から筋機能向上に向けた支援を図る必要性があることが示唆された。

Dietary folic acid augmentation during gestation reduces neurodevelopmental disorder risk in offspring; however, it is still unclear if excessive maternal folic acid intake can impair brain function in offspring. We examined if excessive folic acid intake throughout gestation altered the behavior of male offspring under poor nutrition during early gestation (E5.5-E11.5). Dams were divided into four groups: control (CON, 2 mg folic acid/kg of food), excessive folic acid fortification (FF, 10 mg folic acid/kg of food), undernutrition (UN, 40% food reduction from E5.5-E11.5), and excessive folic acid fortification plus undernutrition (UN-FF). Excess maternal folic acid fortification induced hyperactivity in the open-field and lower anxiety-like behavior in the elevated plus maze at 9 weeks of age. These behavioral changes were accompanied by reduced dopamine in the prefrontal cortex (PFC), norepinephrine in the amygdala, and 5-hydroxytryptamine (5-HT) in the dorsal midbrain (DM), PFC, and amygdala where 5-HT neurons project from the DM. Furthermore, canonical discriminant analysis, including dopamine and DOPAC concentrations in the PFC, norepinephrine concentrations in the PFC, amygdala, and pons, and 5-HT and 5-HIAA concentrations in the amygdala and DM, correctly classified 73.5% of the offspring in CON, FF, UN, and UN-FF groups. The first discriminant function mainly classified groups based on nutritional status, whereas the second function mainly classified groups based on folic acid intake. Our study suggests that combined transformations of brain monoamine profiles by maternal undernutrition and excess folic acid intake is involved in the behavioral alteration of offsprings.

本研究の目的は，出生時期に低体重であった者（Low birth weight infant：LBWI）と正常体重であった者（normal birth weight infant：NBWI）が成人期を迎えた際の骨量ならびに骨の発育に与える因子に違いが認められるかを確認し，将来の骨関節疾患発症リスクについて検討することである。対象は，本邦でLBWI 急増時期に生まれ，現在成人期にある女子大生を母集団とし，LBWI 群（6名）とNBWI 群（6名）を抽出した。骨量面積率や骨塩量，下腿身長比や体重などの計測とともに，学齢期と思春期の運動時間を聴取し，両群間で比較した。その結果，両群間で骨量面積率などに有意差は認められなかったが，下腿身長比はLBWI 群が有意に低値を示した（p＜0．05）。従って，出生時体重の違いは成人期の骨密度には影響を及ぼさないが，LBWI は下腿身長比の短縮という形で骨の発育不全を引き起こす可能性が示唆された。今後，この骨発育不全が引き起こされるメカニズムの解明とともに，LBWI が老年期の骨に与える影響についても追跡調査する必要性があることが示唆された。

Epidemiological studies suggest that poor nutrition during pregnancy influences offspring predisposition to experience developmental and psychiatric disorders. Animal studies have shown that maternal undernutrition leads to behavioral impairment, which is linked to alterations in monoaminergic systems and inflammation in the brain. In this study, we focused on the ethanolamine plasmalogen of the brain as a possible contributor to behavioral disturbances observed in offspring exposed to maternal undernutrition. Maternal food or protein restriction between gestational day (GD) 5.5 and GD 10.5 resulted in hyperactivity of rat male adult offspring. Genes related to the phospholipid biosynthesis were found to be activated in the PFC, but not in the NAcc or striatum, in the offspring exposed to prenatal undernutrition. Corresponding to these gene activations, increased ethanolamine plasmalogen (18:0p-22:6) was observed in the PFC using mass spectrometry imaging. A high number of crossings and the long time spent in the center area were observed in the offspring exposed to prenatal undernutrition and were mimicked in adult rats via the intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome. Additionally, plasmalogen (18:0p-22:6) increased only in the PFC, and not in the NAcc or striatum. These results suggest that brain plasmalogen is one of the key molecules to control behavior, and its injection using liposome is a potential therapeutic approach for cognitive impairment. SIGNIFICANCE STATEMENT Maternal undernutrition correlates to developmental and psychiatric disorders. Here, we found that maternal undernutrition in early pregnancy led to hyperactivity in rat male offspring and induced gene activation of phospholipid-synthesizing enzyme and elevation of ethanolamine plasmalogen (18:0p-22:6) level in the PFC. Intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome maintained crossing activity and the activity was circumscribed to the center area for a long time period, as in prenatally undernourished offspring with aberrant behavior. Furthermore, the amount of ethanolamine plasmalogen (18:0p-22:6) increased in the PFC of the rat after injection. Our result suggests that brain plasmalogen is one of the key molecules to control behavior and that its injection using liposome is a potential therapeutic approach for cognitive impairment.

Environmental enrichment (EE) after birth has been reported as an intervention improving the anxiety-like behavior and cognitive deficit due to maternal restraint, foot-shock, or social stress during pregnancy. However, it remains unclear whether EE after birth could benefit the early prenatal undernourished offspring. In this study, we examined the effect of daily handling as a simple EE intervention on the aberrant behavior of prenatally undernourished rats. The male rat offspring exhibited anxiety-like behavior at 9 weeks of age due to maternal food restriction in early pregnancy. Our study shows that the daily handling after weaning has an anxiolytic effect in the prenatally undernourished offspring without affecting the behavior of prenatally well-nourished offspring. Conversely, the concentrations of dopamine, serotonin, norepinephrine, and their metabolites were not altered in the prefrontal cortex by prenatal undernutrition or daily handling after weaning. We investigated whether the anxiolytic effect of daily handling was mediated by the protein kinase C (PKC) pathway using the PKC inhibitor, chelerythrine. The anxiolytic effect of the handling was not canceled by chelerythrine injection in prenatally undernourished offspring, whereas chelerythrine induced an anxiety-like behavior in control rats. Our results suggest that maternal undernutrition in early pregnancy induces an anxiety-like behavior accompanied with a PKC pathway-hyporesponsiveness; however, daily handling ameliorates the anxiety-like behavior through a PKC-independent pathway.

BACKGROUND Epidemiological research indicates that iron deficiency (ID) in infancy correlates with long-term cognitive impairment and behavioral disturbances, despite therapy. However, the mechanisms underlying these effects are unknown. OBJECTIVE We investigated how ID affected postweaning behavior and monoamine concentration in rat brains to determine whether ID during the juvenile period affected gene expression and synapse formation in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). METHODS Fischer 344/Jcl postweaning male rats aged 21-39 d were fed low-iron diets (0.35 mg/kg iron; ID group) or standard AIN-93 G diets [3.5 mg/kg iron; control (CN) group]. After day 39, all rats were fed the iron-adequate diet. The locomotor activity was evaluated by the open field and elevated plus maze tests at 8 and 12 wk of age. Monoamine concentrations in the brain were analyzed using HPLC at 9 and 13 wk of age. Comprehensive gene expression analysis was performed in the PFC and NAcc at 13 wk of age. Finally, we investigated synaptic density in the PFC and NAcc by synaptophysin immunostaining. RESULTS Behavioral tests revealed a significant reduction of the age-related decline in the total distance traveled in ID rats compared with CN rats (P < 0.05), indicating that ID affected hyperactivity, which persisted into adulthood (13 wk of age). At this age, reelin (Reln) mRNA expression (adjusted P < 0.01) decreased and synaptic density (P < 0.01) increased in the NAcc in the ID group. Regarding the mesolimbic pathway, homovanillic acid concentration increased in the NAcc, whereas the dopamine concentration decreased in the ventral midbrain. CONCLUSIONS Our results suggest that ID during the postweaning period in male rats, despite complete iron repletion following ID, led to long-term hyperactivity via monoamine disturbance in the brain and an alteration in the synaptic plasticity accompanied by downregulation of Reln expression in the NAcc.

Epidemiological research has suggested that birth weights are correlated with adult leg lengths. However, the relationship between prenatal undernutrition (UN) and postnatal leg growth remains controversial. We investigated the effects of UN during early pregnancy on postnatal hindlimb growth and determined whether early embryonic malnutrition affects the functions of postnatal chondrocytes in rats. Undernourished Wistar dams were fed 40% of the daily intake of rats in the control groups from gestational days 5.5-11.5, and femurs, tibias, and trunks or spinal columns were morphologically measured at birth and at 16 weeks of age in control and undernourished offspring of both sexes. We evaluated cell proliferation and differentiation of cultured chondrocytes derived from neonatal tibias of female offspring and determined chondrocyte-related gene expression levels in neonatal epiphysis and embryonic limb buds. Tibial lengths of undernourished female, but not male, offspring were longer at birth and shorter at 16 weeks of age (p < .05) compared with those of control rats. In chondrocyte culture studies, stimulating effects of IGF-1 on cell proliferation (p < .01) were significantly decreased and levels of type II collagen were lower in female undernourished offspring (p < .05). These phenomena were accompanied by decreased expression levels of Col2a1 and Igf1r and increased expression levels of Fgfr3 (p < .05), which might be attributable to the decreased expression of specificity protein 1 (p < .05), a key transactivator of Col2a1 and Igf1r. In conclusion, UN stress during early pregnancy reduces postnatal tibial growth in female offspring by altering the function of chondrocytes, likely reflecting altered expression of gene transactivators. (C) 2017 Elsevier Inc. All rights reserved.