• The Korean Journal of Physiology and Pharmacology
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• v.22 no.6
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• pp.679-688
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• 2018

Autism spectrum disorders (ASDs) are neurodevelopmental disorders that share behavioral features, the results of numerous studies have suggested that the underlying causes of ASDs are multifactorial. Behavioral and/or neurobiological analyses of ASDs have been performed extensively using a valid model of prenatal exposure to valproic acid (VPA). Abnormal synapse formation resulting from altered neurite outgrowth in neural progenitor cells (NPCs) during embryonic brain development has been observed in both the VPA model and ASD subjects. Although several mechanisms have been suggested, the actual mechanism underlying enhanced neurite outgrowth remains unclear. In this study, we found that VPA enhanced the expression of brain-derived neurotrophic factor (BDNF), particularly mature BDNF (mBDNF), through dual mechanisms. VPA increased the mRNA and protein expression of BDNF by suppressing the nuclear expression of methyl-CpG-binding protein 2 (MeCP2), which is a transcriptional repressor of BDNF. In addition, VPA promoted the expression and activity of the tissue plasminogen activator (tPA), which induces BDNF maturation through proteolytic cleavage. Trichostatin A and sodium butyrate also enhanced tPA activity, but tPA activity was not induced by valpromide, which is a VPA analog that does not induce histone acetylation, indicating that histone acetylation activity was required for tPA regulation. VPA-mediated regulation of BDNF, MeCP2, and tPA was not observed in astrocytes or neurons. Therefore, these results suggested that VPA-induced mBDNF upregulation was associated with the dysregulation of MeCP2 and tPA in developing cortical NPCs.

• Journal of Korean Medical Science
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• v.33 no.50
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• pp.318.1-318.10
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• 2018

Background: In this prospective cohort study, we investigated the association between fatty acid ethyl esters (FAEEs) in meconium as biomarkers of prenatal ethanol exposure and growth deficits, as birth outcomes, that constitute several of the key cardinal features of fetal alcohol syndrome. Methods: A total of 157 meconium samples were collected from enrolled infants within 24 hours of birth, and nine FAEEs were quantified using liquid chromatography/tandem mass spectrometry. The relationships between cumulative concentrations of nine species of FAEEs in meconium and birth parameters of growth (age-sex-specific centiles of head circumference [HC], weight, and length) and respective and combined birth outcomes of growth deficits (HC ${\leq}10th$ centile, weight ${\leq}10th$ centile, and length ${\leq}10th$ centile) were determined. Results: Multivariate logistic regression analysis demonstrated that higher cumulative concentrations of meconium FAEEs correlated with elevated risks for HC and length, both, 10th percentile or less (adjusted odds ratio [aOR], 2.94; 95% confidence interval [CI], 1.12-7.74; P = 0.029) and HC and weight and length, all of them, 10th percentile or less (aOR, 3.27; 95% CI, 1.12-9.59; P = 0.031). Conclusion: The elevated cumulative FAEEs in meconium were associated with combined growth deficits at birth, specifically HC and length, both, 10th percentile or less, which might be correlated with detrimental alcohol effects on fetal brain and bone development, suggesting a plausible alcohol-specific pattern of intrauterine growth restriction.

• Clinical and Experimental Pediatrics
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• v.65 no.2
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• pp.85-89
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• 2022

Background: There is evidence of a relationship between prenatal excess androgen exposure and central nervous developmental problems and attention-deficit/hyperactivity disorder (ADHD) in the offspring of mothers with polycystic ovary syndrome (PCOS). Purpose: Here we aimed to use a meta-analysis to investigate whether the offspring of mothers with PCOS are at an increased chance of developing ADHD. Methods: Three main English databases were searched for articles published through December 2020. The Newcastle-Ottawa Scale was used to assess study quality. Study heterogeneity was determined using I² statistics and publication bias was assessed using Begg and Egger tests. The results are presented as odds ratio (OR) and relative ratio (RR) estimates with 95% confidence intervals (CIs) using a random-effects model. Results: Six articles (3 cohort and 3 case-control studies; 401,413 total ADHD cases) met the study criteria. Maternal PCOS was associated with an increased risk of ADHD in the offspring based on OR and RR (OR, 1.42; 95% CI, 1.27-1.57) and (RR, 1.43; 95% CI, 1.35-1.51), respectively. There was no heterogeneity among the included articles based on OR (I²=0.0%, P=0.588) and RR (I²=0.0%, P=0.878). Conclusion: Our study showed that maternal PCOS is a risk factor for ADHD. Therefore, screening their offspring for ADHD should be considered part of the comprehensive clinical care of women with PCOS.

• Korean Journal of Biological Psychiatry
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• v.24 no.3
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• pp.142-148
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• 2017

Objectives The ratio of second to fourth digit length (2D : 4D) could be a potential epigenetic marker of sexual dimorphism reflecting prenatal testosterone exposure. Testosterone is known to affect the development of the brain through an epigenetic mechanism. The purpose of this study was to investigate the effects of exposure to fetal testosterone on the metabolic syndrome based on 2D : 4D of schizophrenia patients and the relationship with the age of onset of schizophrenia. Methods A total of 214 schizophrenia patients participated in this study. The participant's physical and blood tests were performed according to the American National Cholesterol Education Program's Third Amendment of the Metabolic Syndrome Diagnostic Criteria, and the 2D : 4D was measured by the method designed by McFadden. Data were statistically analyzed by t-test, Pearson's correlation analysis and multiple regression model analysis. Results 2D : 4D was significantly higher in female than male in both hands, and there was a statistically significant negative correlation between 2D : 4D and the age of onset of schizophrenia in male. However, 2D : 4D did not show statistically significant correlation with metabolic factors. Conclusions Fetal testosterone suggests the possibility of affecting the age of onset of schizophrenia through the epigenetic mechanism, but there is no clear relationship with metabolic factors.

• Development and Reproduction
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• v.4 no.1
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• pp.95-100
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• 2000

A large number of man-made chemicals that have been released into the environment have the potential to disrupt the endocrine system of animals and humans. There is a critical developmental period during which sexual brain differentiation proceeds irreversibly under the influence of gonadal hormone. Recently we identified KAP3 gene expressed during the critical period of rat brain sexual differentiation. KAP3 functions as a microtubule-based motor that transports membranous organelles anterogradely in cells, including neurons. In the present study, we aimed to investigate the effect of endocrine disrupter, Dichlorodiphenyl trichloroethane (DDT), on the KAP3 gene expression during critical period of rat brain development. Maternal exposure to DDT increased the level of KAP3 mRNA in male and female fetus brains when examined on the gestational day 17 (GDl7). In postnatal day 6, DDT suppressed the expression of KAP3 gene in male and female rat brain. Also, the body weight and fertilization rate were decreased in the DDT exposured rats. These results showed that endocrine disrupter, DDT, can affect the transcriptional level of brain sexual differentiation related gene, KAP3, in the prenatal and the neonatal rat brain and that maternal exposure to endocrine disruptors may lead to a toxic response in embryonic differentiation of brain. And so KAP3 gene may be used a gene maker to analyse the molecular mechanism for toxic response in animal nerve tissues exposed to endocrine disruptors.

• Development and Reproduction
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• v.16 no.2
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• pp.95-100
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• 2012

Bisphenol A (BPA), a chemical with weak estrogenic activity is reported to affect preimplantation embryos, fetuses and alter their postnatal development. This study amied to determine the relation between the levels of BPA in the amniotic fluid and pregnancy outcomes. ELISA was used to measure amniotic fluid BPA in 120 pregnant women who underwent genetic amniocentesis at 15~20 weeks gestation. The most common indication for amniocentesis was advanced maternal age (35 yrs or older). BPA was detected in all amniotic fluid. The range of amniotic fluid BPA concentrations was from 0.89 ng/mL to 37.13 ng/mL with a mean level of 7.24 ng/mL. We compared the means of amniotic fluid BPA concentrations according to maternal age (${\geq}35$ vs. <35 yrs), fetal sex (male vs. female), gestational age at birth (${\geq}37$ vs. <37 weeks), and infant birth weight (${\geq}2.5$ vs. <2.5 kg). No significant differences were found in these outcomes. This is the first report of amniotic fluid BPA levels in Korean pregnant women. Our findings suggest that BPA may not affect the pregnancy outcomes such as fetal sex, preterm delivery and low birth weight. Whether prenatal exposure to BPA can have teratogenic effect on developing embryo needs to be studied.

• Korean Journal of Medicinal Crop Science
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• v.24 no.5
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• pp.341-350
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• 2016

Background: Prenatal exposure to infectious and/or inflammatory insults can increase the risk of developing neuropsychiatric disorder such as bipolar disorder, autism, and schizophrenia later in life. We investigated whether Valeriana fauriei (VF) treatment alleviates prepulse inhibition (PPI) deficits and social interaction impairment induced by maternal immune activation (MIA). Methods and Results: Pregnant mice were exposed to polyriboinosinic-polyribocytidilic acid (5 mg/kg, viral infection mimic) on gestational day 9. The adolescent offspring received daily oral treatment with VF (100 mg/kg) and injections of clozapine (5 mg/kg) for 30 days starting on the postnatal day 35. The effects of VF extract treatment on behavioral activity impairment and protein expression were investigated using the PPI analysis, forced swim test (FST), open field test (OFT), social interaction test (SIT), and immunohistochemistry. The MIA-induced offspring showed deficits in the PPI, FST, OFT, and SIT compared to their non MIA-induced counterparts. Treatment with the VF extract significantly recovered the sensorimotor gating deficits and partially recovered the aggressive behavior observed in the SIT. The VF extract also reversed the downregulation of protein expression induced by MIA in the medial prefrontal cortex. Conclusions: Our results provide initial evidence of the fact that the VF extract could reverse MIA-induced behavioral impairment and prevent neurodevelopmental disorders such as schizophrenia.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.13 no.5
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• pp.2170-2177
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• 2012

The ratio of index finger length to ring finger length(2D:4D) is an index of prenatal testosterone and/or estrogen exposure. The aim of this study is to investigate digit ratio and the type of gender-role orientation, to identify the correlation between 2D:4D and gender-role orientation in health and medical students. Participants were 120 male and 146 female university students majoring in health or medicine. After filling in KSRI(Korean Sex Role Inventory), 2nd and 4th finger lengths were measured on both hands using vernier callipers with photocopy. This study showed 2D:4D in the males was 0.95, and that in the females was 0.96 (p<0.01). 38.3% male students revealed androgyny, on the other hand, 35.6% female students revealed undifferentiated type from KSRI. And also, there was a significant difference in masculinity score between male and female but not in feminity score. There was no significant difference in 2D:4D according gender role orientation. The KSRI masculinity score was negatively related to 2D:4D of left hand in male (p<0.05). The results of this study suggest that a more masculine gender role orientation in males is associated with low 2D:4D revealing higher testosterone and/or lower estrogen level in utero. However, more research in 2D:4D ratio to Korean is needed for support of this result.

• Journal of Preventive Medicine and Public Health
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• v.40 no.2
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• pp.155-161
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• 2007

Objectives : Bisphenol A diglycidyl ether (BADGE) is the major component in commercial liquid epoxy resins, which are manufactured by co-reacting bisphenol A with epichlorohydrin. This study was performed to show the developmental effects of prenatal and postnatal exposures to BADGE in male rat offspring. Methods : Mated female rats were divided into four groups, each containing 12 rats. The dosing solutions were prepared by thoroughly mixing BADGE in corn oil at the 0, 375, 1500 and 3000 mg/kg/day concentrations. Mated females were dosed once daily by oral gavage on gestation day (GD) 6 - 20 and postnatal day (PND) 0 - 21. Pregnant female dams were observed general symptoms and body weight. Also, male pups were observed the general symptoms, body weight, developmental parameters (e.g. anogenital distance, pina detachment, incisor eruption, nipple retention, eye opening, testis descent), organ pathologic changes and hormone levels of plasma. Results : Pregnant rats treated with BADGE died at a rate of about 70% in the 1500 mg/kg/day group and all rats treated with 3000 mg/kg/day died. Body weight, for male pups treated with doses of 375 mg/kg/day, was significantly lower than in the control group at PND 42, 56, and 63 (p<0.05). Evaluation of body characteristics including; separation of auricle, eruption of incisor, separation of eyelid, nipple retention, descent of testis, and separation of the prepuce in the BADGE treated group showed no difference in comparisons with the control group. AGD and adjusted AGD (mm/kg) for general developmental items in BADGE 375 mg/kg/day treated pups tended to be longer than in controls, however, these differences were not statistically significant. Relative weights of adrenal gland, lung (p<0.05), brain, epididymis, prostate, and testis (p<0.01) were heavier than in control in measures at PND 9 weeks. There were no significant changes in comparisons of histological findings of these organs. Loss of spermatids was observed in the seminiferous tubule at PND 9 weeks, but no weight changes were observed. The plasma estrogen levels were similar in the control and treatment groups at PND 3, 6 and 9 weeks. The plasma testosterone levels in the control group tended to increase with age. However, in the BADGE 375 mg/kg/day treated male pups it did not tend to increase. Conclusions : These findings suggest that BADGE is a chemical that has developmental effects consistent with it being an endocrine disruptor.

• Journal of Life Science
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• v.28 no.12
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• pp.1536-1544
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• 2018

Depression is a common, serious, and recurring mental disorder. The pathogenesis of depression involves many factors such as environmental factor, genetic factor and alteration of structure and function in neurobiological systems. Increasing evidence supports that epigenetic alteration may be associated with depression. The epigenetics is explained as the mechanisms by which environmental factor causes changes in chromatin structure and alters gene expression without changing DNA base sequence. DNA methylation and histone modification involving histone acetylation and methylation are the main epigenetic mechanisms. Animal studies have shown that stressful environment such as early life stress can leave persistent epigenetic marks in the genome, which alter gene expression and influence neural and behavioral function through adulthood. A potentially important gene in depression is brain-derived neurotrophic factor (BDNF). BDNF plays a central role in depression and antidepressant action. In studies of the rodent, exposure to stress at prenatal, postnatal, and adult stages alters BDNF expression through histone modification and DNA methylation of the BDNF gene which results in anxiety and depressive-like behavior. This review discusses recent advances in the study of the epigenetic mechanisms that contribute to depression, particularly histone modification and DNA methylation of the BDNF gene, that may help in the development of new targets for depression treatment.