Psoriasis and Systemic Inflammatory Disorders.

Psoriasis is a representative inflammatory skin disease occupied by large surface involvement. As inflammatory cells and cytokines can systemically circulate in various organs, it has been speculated that psoriatic skin inflammation influences the systemic dysfunction of various organs. Recent updates of clinical studies and experimental studies showed the important interaction of psoriasis to systemic inflammatory diseases. Furthermore, the importance of systemic therapy in severe psoriasis is also highlighted to prevent the development of systemic inflammatory diseases. In this review, we introduced representative systemic inflammatory diseases associated with psoriasis and the detailed molecular mechanisms.

Transient appearance of Ca2+ -permeable AMPA receptors is crucial for the production of repetitive LTP-induced synaptic enhancement (RISE) in cultured hippocampal slices.

We have previously shown that repetitive induction of long-term potentiation (LTP) by glutamate (100 µM, 3 min, three times at 24-hr intervals) provoked long-lasting synaptic enhancement accompanied by synaptogenesis in rat hippocampal slice cultures, a phenomenon termed RISE (repetitive LTP-induced synaptic enhancement). Here, we examined the role of Ca2+ -permeable (CP) AMPA receptors (AMPARs) in the establishment of RISE. We first found a component sensitive to the Joro-spider toxin (JSTX), a blocker of CP-AMPARs, in a field EPSP recorded from CA3-CA1 synapses at 2-3 days after stimulation, but this component was not found for 9-10 days. We also observed that rectification of AMPAR-mediated current appeared only 2-3 days after stimulation, using a whole-cell patch clamp recording from CA1 pyramidal neurons. These findings indicate that CP-AMPAR is transiently expressed in the developing phase of RISE. The blockade of CP-AMPARs by JSTX for 24 hr at this developing phase inhibited RISE establishment, accompanied by the loss of small synapses at the ultrastructural level. These results suggest that transiently induced CP-AMPARs play a critical role in synaptogenesis in the developing phase of long-lasting hippocampal synaptic plasticity, RISE.

Reduction in NPY-positive neurons and dysregulation of excitability in young senescence-accelerated mouse prone 8 (SAMP8) hippocampus precede the onset of cognitive impairment.

The senescence-accelerated mouse prone 8 (SAMP8) strain is considered a neurodegeneration model showing age-related cognitive deficits with little physical impairment. Young SAMP8 mice, however, exhibit signs of disturbances in development such as marked hyperactivity and reduced anxiety well before the onset of cognitive impairment. As the key enzyme in local regulation of thyroid hormone (TH) signaling, type 2 deiodinase, was significantly reduced in the SAMP8 hippocampus relative to that of the normally aging SAM-resistant 1 (SAMR1), we used these two strains to compare the development of the hippocampal GABAergic system, which is known to be strongly affected by hypothyroidism. Among GABAergic components, neuronal K+ /Cl- co-transporter 2 was down-regulated in SAMP8 transiently at 2 weeks. Although distribution of total GABAergic neurons was similar in both strains, 22-30% reduction was observed in the neuropeptide Y (NPY)-positive subpopulation of GABAergic neurons in SAMP8. Electrophysiological studies on hippocampal slices obtained at 4 weeks revealed that epileptiform activity, induced by high-frequency stimulation, lasted four times longer in SAMP8 compared with SAMR1, indicating a dysregulation of excitability that may be linked to the behavioral abnormalities of young SAMP8 and to neurodegeneration later on in life. Local attenuation of TH signaling may thus impact the normal development of the GABAergic system.

Action of thyroxine on the survival and neurite maintenance of cerebellar granule neurons in culture.

Developmental hypothyroidism causes severe impairments in the cerebellum. To understand the role of thyroid hormones (THs) in cerebellar development, we examined the effect of three different THs, thyroxine (T4), 3,5,3'-triidothyronine (T3), and 3,3',5'-triiodothyronine (reverse T3; rT3), on the survival and morphology of cerebellar granule neurons (CGNs) in culture and found novel actions specific to T4. Rat CGNs obtained at postnatal day 6 were first cultured for 2 days in serum-containing medium with 25 mM K(+) (K25), then switched to serum-free medium with physiological 5 mM K(+) (K5) or with K25 and cultured for an additional 2 or 4 days. CGNs underwent apoptosis in K5 but survived in K25. Addition of T4 at concentrations of 100-200 nM but not T3 or rT3 rescued CGNs from cell death in K5 in a dose-dependent manner. Furthermore, 200 nM T4 was also effective in maintaining the neurites of CGNs in K5. In K5, T4 suppressed tau phosphorylation at two developmentally regulated sites as well as phosphorylation of c-jun N-terminal kinase (JNK) necessary for its activation and localization to axons. These results suggest that, during cerebellar development, T4 exerts its activity in cell survival and neurite maintenance in a manner distinct from the other two thyroid hormones through regulating the activity and localization of JNK.

Alterations in local thyroid hormone signaling in the hippocampus of the SAMP8 mouse at younger ages: association with delayed myelination and behavioral abnormalities.

The senescence-accelerated mouse (SAM) strains were established through selective inbreeding of the AKR/J strain based on phenotypic variations of aging and consist of senescence-prone (SAMP) and senescence-resistant (SAMR) strains. Among them, SAMP8 is considered as a model of neurodegeneration displaying age-associated learning and memory impairment and altered emotional status. Because adult hypothyroidism is one of the common causes of cognitive impairment and various psychiatric disorders, we examined the possible involvement of thyroid hormone (TH) signaling in the pathological aging of SAMP8 using the senescence-resistant SAMR1 as control. Although plasma TH levels were similar in both strains, a significant decrease in type 2 deiodinase (D2) gene expression was observed in the SAMP8 hippocampus from 1 to 8 months of age, which led to a 35-50% reductions at the protein level and 20% reduction of its enzyme activity at 1, 3, and 5 months. D2 is responsible for local conversion of thyroxine into transcriptionally active 3,5,3'-triiodothyronine (T3), so the results suggest a reduction in T3 level in the SAMP8 hippocampus. Attenuation of local TH signaling was confirmed by downregulation of TH-dependent genes and by immunohistochemical demonstration of delayed and reduced accumulation of myelin basic protein, the expression of which is highly dependent on TH. Furthermore, we found that hyperactivity and reduced anxiety were not age-associated but were characteristic of young SAMP8 before they start showing impairments in learning and memory. Early alterations in local TH signaling may thus underlie behavioral abnormalities as well as the pathological aging of SAMP8.

Sendai virus vector-mediated brain-derived neurotrophic factor expression ameliorates memory deficits and synaptic degeneration in a transgenic mouse model of Alzheimer's disease.

Growing evidence suggests that decreased brain-derived neurotrophic factor (BDNF) levels are associated with Alzheimer's disease (AD) pathogenesis. Therefore, BDNF gene therapy is considered to be a promising therapeutic strategy for treating AD. Sendai virus (SeV) is a type I parainfluenza virus that does not interact with host chromosomes because of its strict cytoplasmic life cycle. Although SeV is nonpathogenic in primates, including humans, its infectivity for neurons is strong. Here we demonstrate that SeV vectors effectively infected neurons, even though they were injected into subcortical white matter. Moreover, SeV vectors significantly induced BDNF expression, ameliorating synaptic degeneration and memory deficits in a transgenic mouse model of AD (Tg2576). This is the first study to demonstrate that viral vector administration in white matter is sufficient to restore cognitive function in vivo. These results also support the feasibility of using SeV vectors for gene therapy targeting the brain.

Structure-related cytotoxic activity of derivatives from kulokekahilide-2, a cyclodepsipeptide in Hawaiian marine mollusk.

Kulokekahilide-2, a 26-membered cyclodepsipeptide, was isolated from Hawaiian marine mollusk and possessed potent cytotoxicity in mammalian tumor cells. In the present study, we synthesized kulokekahilide-2 and its derivatives and examined the structure-activity relationships of these peptides in human cancer cells (A549, K562, and MCF7 cells). This study demonstrated that the cyclization of depsipeptide and the chirality of the 21 position in Ala in kulokekahilide-2 were important for its cytotoxic property and that addition of halogen at the para position of phenyl group in the 24-D-MePhe in kulokekahilide-2 as well as some derivatives remarkably increased their cytotoxicity in human cancer cells. These results suggest that the modifications of 24-D-MePhe in kulokekahilide-2, preserving its cyclization and the chirality at the 21-position, are promising strategy for exploring new derivative of kulokekahilide-2 as anti-tumor drug.

STING expression is an independent prognostic factor in patients with mycosis fungoides.

Mycosis fungoides is recognized as an indolent cutaneous malignant T-cell lymphoma. In contrast, there are few therapeutic options for advanced forms of mycosis fungoides. Since immunotherapy is desirable as an alternative therapeutic option, identifying candidate molecules is an important goal for clinicians. Although tumor-derived negative immunomodulatory molecules, such as PD-1/PD-L1, have been identified in various malignancies, the useful positive immunological drivers of mycosis fungoides are largely unknown. We found that the stimulator of interferon (IFN) genes (STING) was highly upregulated in early-stage mycosis fungoides. Immunohistochemical examination revealed different STING staining patterns in patients with mycosis fungoides. Although there were no significant differences in clinical factors' characteristics, STING expression was associated with the survival of patients with mycosis fungoides. The survival rate was significantly poor in patients with low STING-expressing mycosis fungoides. Univariate and multivariate analyses revealed that low STING expression was associated with an increased hazard ratio. Our results indicate that STING expression independently influences the prognosis of mycosis fungoides.

Analysis of gene expression changes associated with long-lasting synaptic enhancement in hippocampal slice cultures after repetitive exposures to glutamate.

We have previously shown that repetitive exposures to glutamate (100 muM, 3 min, three times at 24-hr intervals) induced a long-lasting synaptic enhancement accompanied by synaptogenesis in rat hippocampal slice cultures, a phenomenon termed RISE (for repetitive LTP-induced synaptic enhancement). To investigate the molecular mechanisms underlying RISE, we first analyzed the time course of gene expression changes between 4 hr and 12 days after repetitive stimulation using an original oligonucleotide microarray: "synaptoarray." The results demonstrated that changes in the expression of synapse-related genes were induced in two time phases, an early phase of 24-96 hr and a late phase of 6-12 days after the third stimulation. Comprehensive screening at 48 hr after the third stimulation using commercially available high-density microarrays provided candidate genes responsible for RISE. From real-time PCR analysis of these and related genes, two categories of genes were identified, 1) genes previously reported to be induced by physiological as well as epileptic activity (bdnf, grm5, rgs2, syt4, ania4/carp/dclk) and 2) genes involved in cofilin-based regulation of actin filament dynamics (ywhaz, ssh1l, pak4, limk1, cfl). In the first category, synaptotagmin 4 showed a third stimulation-specific up-regulation also at the protein level. Five genes in the second category were coordinately up-regulated by the second stimulation, resulting in a decrease in cofilin phosphorylation and an enhancement of actin filament dynamics. In contrast, after the third stimulation, they were differentially regulated to increase cofilin phosphorylation and enhance actin polymerization, which may be a key step leading to the establishment of RISE.

Alterations in gene expression of glutamate receptors and exocytosis-related factors by a hydroxylated-polychlorinated biphenyl in the developing rat brain.

Polychlorinated biphenyls (PCBs), major environmental hormonally active agents, are metabolized into hydroxylated PCBs in the liver to facilitate excretion. Some of hydroxylated PCBs also have potencies disturbing endogenous hormonal activities at least in vitro. Hormonal activities of hydroxylated PCBs raise a possibility of their interfering with normal brain development which is strictly regulated by endogenous hormones. We investigated whether and how prenatal exposure to a congener of hydroxylated PCBs (4-OH-2',3,3',4',5'-penta CB; 4-OH-PCB106) having activities to disrupt thyroid hormone-dependent signals in vitro could perturb normal gene expression in the developing brain in vivo. Pregnant rats were exposed to 4-OH-PCB106 subcutaneously at the dose of 1.0mg/(kgday) from day 7 of gestation to postnatal day 1. Then three brain regions (cerebral cortex, hippocampus and striatum) were obtained from offspring on postnatal day 1 and subjected to further gene expression analyses. Comprehensive analyses of mRNA expression by oligo DNA microarrays and subsequent validations by quantitative RT-PCR revealed that prenatal exposure to 4-OH-PCB106 affected mRNA expression of glutamate receptors as well as that of thyroid hormone-responsive genes in region-specific manners. Concomitantly 4-OH-PCB106 exposure increased mRNA expression of genes related to exocytosis in the three brain regions. These results raise the possibility that prenatal exposure to some hydroxylated PCBs with thyroid hormone-disrupting potencies leads to abnormal brain development via perturbations on the expression of genes involved in glutamatergic neurotransmission.

IGF-1R deficiency in human keratinocytes disrupts epidermal homeostasis and stem cell maintenance.

BACKGROUND: Epidermal stem cells (ESCs) are keratinocytes that reside in the basal layer of the epidermis and mediate epidermal homeostasis. Insulin-like growth factor 1 (IGF-1) signaling through its receptor (IGF-1R) has been identified as an important regulator in rodent skin development and differentiation. However, the role of IGF-1/IGF-1R signaling in human keratinocytes is not yet well understood. OBJECTIVE: This study aimed to clarify the role of IGF-1/IGF-1R signaling in human epidermal homeostasis. METHODS: IGF-1R specific knockout (KO) HaCaT keratinocytes were generated by CRISPR-Caspase-9-mediated non-homologous end joining frame-shift mutations. Further, the behavior of these keratinocytes in epidermal homeostasis was investigated using reconstructed epidermis and human skin equivalents. RESULTS: IGF-1R KO HaCaT keratinocytes were successfully established and produced thin epidermis in three-dimensional culture models. Keratin10-positive cells were frequently found in the basal layer of the reconstructed epidermis. CONCLUSIONS: IGF-1/IGF-1R signaling was demonstrated to play a key role in maintaining human epidermal homeostasis. This method provides a new framework to investigate gene function in human epidermal homeostasis.

Identification of genes mediating thyroid hormone action in the developing mouse cerebellum.

Despite the indispensable role thyroid hormone (TH) plays in brain development, only a small number of genes have been identified to be directly regulated by TH and its precise mechanism of action remains largely unknown, partly because most of the previous studies have been carried out at postnatal day 15 or later. In the present study, we screened for TH-responsive genes in the developing mouse cerebellum at postnatal day 4 when morphological alterations because of TH status are not apparent. Among the new candidate genes selected by comparing gene expression profiles of experimentally hypothyroid, hypothyroid with postnatal thyroxine replacement, and control animals using oligoDNA microarrays, six genes were confirmed by real-time PCR to be positively (orc1l, galr3, sort1, nlgn3, cdk5r2, and zfp367) regulated by TH. Among these, sort1, cdk5r2, and zfp367 were up-regulated already at 1 h after a single injection of thyroxine to the hypothyroid or control animal, suggesting them to be possible primary targets of the hormone. Cell proliferation and apoptosis examined by BrdU incorporation and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay revealed that hypothyroidism by itself did not enhance apoptosis at this stage, but rather increased cell survival, possibly through regulation of these newly identified genes.

Topical treatments with acylceramide dispersions restored stratum corneum lipid lamellar structures in a reconstructed human epidermis model.

Long-periodicity phase (LPP) lamellar structures in intercellular lipid matrixes of the stratum corneum (SC) are considered important for maintenance of skin permeability barriers. Acylceramides are essential components of LPP structures, and their absence influences skin barriers under physiological and pathological conditions, such as atopic dermatitis and dry skin. Although topical applications of acylceramide have been shown to facilitate maintenance of the skin barrier, it is unknown whether topically applied acylceramides are incorporated into intercellular lipids to form LPP structures. Thus, we assessed the effects of topical treatments with monomodal acylceramides on the formation of LPP structures in a surfactant-insulted reconstructed human epidermis model using small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) analyses. In SAXS experiments, LPP structures give rise to a diffraction peak which indicates the presence of a structure with a 13 nm real space repeat distance. LPP patterns of intercellular lipid matrixes in the SC were disrupted' by surfactant treatments and were recovered by topical acylceramide treatments. TEM images also showed specific repeating patterns of LPP structures, indicating that topical acylceramide treatments facilitate recovery of LPP structures in the SC. The present data show that the application of acylceramides might temporarily modify the lipid structure to resemble that of normal skin although the underlying cause of dry or diseased skin is not fully clarified.

Detection of cRNA hybridized on a DNA chip using a tetrakis-acridinyl peptide cassette, consisting of TAP and partially self-complementary oligonucleotide, d[A18(TA)51].

A tetrakis-acridinyl peptide (TAP) cassette, consisting of a double-stranded region of alternating AT sequence bound to TAP and a single stranded overhanging sequence of continuous dA, was prepared by mixing TAP with d[A18(TA)51]. A TAP cassette could be applied to the fluorometric detection of hybridized DNA on the DNA chip, which was prepared by stamping a 45-meric DNA probe onto a gold-coated plastic chip using a high-precision spotter developed at RIKEN. Spots on the DNA chip were imaged by a CCD camera after hybridization with 65-meric target single-stranded DNAs carrying a continuous dA20 sequence (dA tail) on the DNA chip after treatment with a TAP cassette. Their fluorescence intensity on the DNA chip showed a good linear correlation with the concentration of the target DNAs in the range from 10 pM to 1 nM. Fluorescence of their spots derived from the TAP cassette remaining on the surface of the DNA chip through the dA tail of the hybridized target DNA. Furthermore, the TAP cassette could be successfully applied to the quantitative detection of complementary RNAs (cRNAs) prepared from rat brain with reverse transcription and in vitro transcription.

Dysregulation of MAP Kinase Signaling Pathways Including p38MAPK, SAPK/JNK, and ERK1/2 in Cultured Rat Cerebellar Astrocytes Exposed to Diphenylarsinic Acid.

Diphenylarsinic acid (DPAA) was a major compound found in the arsenic poisoning incident that occurred in Kamisu, Ibaraki, Japan in 2003. People exposed to DPAA via contaminated well water suffered from several neurological disorders, including cerebellar symptoms. We previously reported that DPAA induces cellular activation in cultured rat cerebellar astrocytes, dose-dependent promotion of cell growth (low DPAA), cell death (high DPAA), and increased phosphorylation of mitogen-activated protein (MAP) kinases (p38MAPK, SAPK/JNK, and ERK1/2). Moreover, DPAA induces up-regulation of oxidative stress-counteracting proteins, activation of CREB phosphorylation, increased protein expression of c-Jun and c-Fos, and aberrant secretion of brain-active cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Here, we explored the role of MAP kinases in DPAA-induced activation of astrocytes using specific MAP kinase signaling inhibitors [SB203580 (p38MAPK), SP600125 (SAPK/JNK), SCH772984 (ERK1/2), and U0126 (MEK1/2, a kinase for ERK1/2)]. DPAA-induced activation of MAP kinases had little contribution to DPAA-induced cell growth and death. On the other hand, a power relationship among MAP kinases was also observed, in which p38MAPK suppressed DPAA-induced SAPK/JNK and ERK1/2 activation, whereas ERK1/2 and MEK1/2 facilitated p38MAPK and SAPK/JNK activation. In addition, SAPK/JNK had minimal effects on the activation of other MAP kinases. DPAA-induced activation of transcription factors and secretion of brain-active cytokines were submissively but intricately dominated by MAP kinases. Collectively, our results indicate that DPAA-induced activation of MAP kinases is neither a cell growth-promoting response nor a cytoprotective one but leads to transcriptional disruption and aberrant secretion of brain-active cytokines in cerebellar astrocytes.

Impairment of synaptic development in the hippocampus of diabetic Goto-Kakizaki rats.

Insulin receptor signaling has been shown to regulate essential aspects of CNS function such as synaptic plasticity and neuronal survival. To elucidate its roles during CNS development in vivo, we examined the synaptic and cognitive development of the spontaneously diabetic Goto-Kakizaki (GK) rats in the present study. GK rats are non-obese models of type 2 diabetes established by selective inbreeding of Wistar rats based on impaired glucose tolerance. Though they start exhibiting only moderate hyperglycemia without changes in plasma insulin levels from 3 weeks postnatally, behavioral alterations in the open-field as well as significant impairments in memory retention compared with Wistar rats were observed at 10 weeks and were worsened at 20 weeks. Alterations in insulin receptor signaling and signs of insulin resistance were detected in the GK rat hippocampus at 3 weeks, as early as in other insulin-responsive peripheral tissues. Significant reduction of an excitatory postsynaptic scaffold protein, PSD95, was found at 5w and later in the hippocampus of GK rats due to the absence of a two-fold developmental increase of this protein observed in Wistar control rats between 3 and 20w. In the GK rat hippocampus, NR2A which is a NMDA receptor subunit selectively anchored to PSD95 was also reduced. In contrast, both NR2B and its anchoring protein, SAP102, showed similar developmental profiles in Wistar and GK rats with expression peaks at 2 and 3w. The results suggest that early alterations in insulin receptor signaling in the GK rat hippocampus may affect cognitive performance by suppressing synaptic maturation.

Diphenylarsinic Acid Induced Activation of Cultured Rat Cerebellar Astrocytes: Phosphorylation of Mitogen-Activated Protein Kinases, Upregulation of Transcription Factors, and Release of Brain-Active Cytokines.

Diphenylarsinic acid (DPAA) was detected as the primary compound responsible for the arsenic poisoning that occurred in Kamisu, Ibaraki, Japan, where people using water from a well that was contaminated with a high level of arsenic developed neurological (mostly cerebellar) symptoms and dysregulation of regional cerebral blood flow. To understand the underlying molecular mechanism of DPAA-induced cerebellar symptoms, we focused on astrocytes, which have a brain-protective function. Incubation with 10 µM DPAA for 96 h promoted cell proliferation, increased the expression of antioxidative stress proteins (heme oxygenase-1 and heat shock protein 70), and induced the release of cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Furthermore, DPAA overpoweringly increased the phosphorylation of three major mitogen-activated protein kinases (MAPKs) (ERK1/2, p38MAPK, and SAPK/JNK), which indicated MAPK activation, and subsequently induced expression and/or phosphorylation of transcription factors (Nrf2, CREB, c-Jun, and c-Fos) in cultured rat cerebellar astrocytes. Structure-activity relationship analyses of DPAA and other related pentavalent organic arsenicals revealed that DPAA at 10 µM activated astrocytes most effective among organic arsenicals tested at the same dose. These results suggest that in a cerebellum exposed to DPAA, abnormal activation of the MAPK-transcription factor pathway and irregular secretion of these neuroactive, glioactive, and/or vasoactive cytokines in astrocytes can be the direct/indirect cause of functional abnormalities in surrounding neurons, glial cells, and vascular cells: This in turn might lead to the onset of cerebellar symptoms and disruption of cerebral blood flow.

Cell-type-specific and differentiation-status-dependent variations in cytotoxicity of tributyltin in cultured rat cerebral neurons and astrocytes.

Tributyltin (TBT) is an organotin used as an anti-fouling agent for fishing nets and ships and it is a widespread environmental contaminant at present. There is an increasing concern about imperceptible but serious adverse effect(s) of exposure to chemicals existing in the environment on various organs and their physiological functions, e.g. brain and mental function. Here, so as to contribute to improvement of and/or advances in in vitro cell-based assay systems for evaluating brain-targeted adverse effect of chemicals, we tried to evaluate cell-type-specific and differentiation-status-dependent variations in the cytotoxicity of TBT towards neurons and astrocytes using the four culture systems differing in the relative abundance of these two types of cells; primary neuron culture (> 95% neurons), primary neuron-astrocyte (2 : 1) mix culture, primary astrocyte culture (> 95% astrocytes), and passaged astrocyte culture (100% proliferative astrocytes). Cell viability was measured at 48 hr after exposure to TBT in serum-free medium. IC50's of TBT were 198 nM in primary neuron culture, 288 nM in primary neuron-astrocyte mix culture, 2001 nM in primary astrocyte culture, and 1989 nM in passaged astrocyte culture. Furthermore, in primary neuron-astrocyte mix culture, vulnerability of neurons cultured along with astrocytes to TBT toxicity was lower than that of neurons cultured purely in primary neuron culture. On the other hand, astrocytes in primary neuron-astrocyte mix culture were considered to be more vulnerable to TBT than those in primary or passaged astrocyte culture. The present study demonstrated variable cytotoxicity of TBT in neural cells depending on the culture condition.

Altered social interactions in male juvenile cynomolgus monkeys prenatally exposed to bisphenol A.

Bisphenol A (BPA) is a widespread environmental contaminant, and humans are routinely exposed to BPA. We investigated whether prenatal exposure to BPA influences behavioral development in juvenile cynomolgus monkeys (Macaca fascicularis). Pregnant cynomolgus monkeys were implanted with subcutaneous pumps and exposed to 10µg/kg/day BPA or vehicle (control) from gestational day 20 to 132. Both BPA-exposed and control juvenile monkeys (aged 1-2years) were assessed using the peer-encounter test that was conducted to evaluate behaviors in social interaction with a same-sex, same-treatment peer. In the encounter test, prenatal BPA exposure significantly reduced environmental exploration and presenting, a gesture related to sexual reproduction, and increased visual exploration, but only in males; furthermore, it significantly reduced the typical sexual dimorphism of the aforementioned behaviors normally observed between male and female juvenile cynomolgus monkeys. This study demonstrates that prenatal BPA exposure affects behavioral development during adolescence and results in the demasculinization of key sexually dimorphic behaviors in male juvenile monkeys.