Choline and Fish Oil Can Improve Memory of Mice through Increasing Brain DHA Level.

Docosahexaenoic acid (DHA) is highly enriched in the brain, and is essential for normal brain development and function. However, evidence suggests that currently used supplements, such as fish oil, do not significantly increase brain DHA levels. Therefore, this study aimed to investigate whether combined fish oil and choline supplementation could affect the type and enrich the content of DHA in the brain. The results revealed that the combined intake of fish oil and choline upregulated the expression of key transporters and receptors, including MFSD2A, FATP1, and FABP5, which increased the uptake of DHA in the brain. Additionally, this supplementation improved the synthesis and release of acetylcholine in the brain, which, in turn, enhanced the learning and memory abilities of mice. These findings suggest that the combined intake of fish oil and choline improves the bioavailability of DHA in the brain.

A phase Ia dose-escalation trial of Ametumumab (a fully human monoclonal antibody against epidermal growth factor receptor) in patients with advanced solid malignancies.

Background: Epidermal growth factor receptor (EGFR) is a well-known target for cancer treatment. However, the authorized anti-EGFR monoclonal antibodies generally cause several toxic effects, especially severe cutaneous toxicities as well as infusion reactions, and the clinical indications are limited. Here we developed Ametumumab, a fully human recombinant anti-EGFR monoclonal antibody. Objectives: To assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of Ametumumab. Design: A first-in-human phase Ia dose escalation study of Ametumumab in patients with advanced solid malignancies. Methods: An open-label, first-in-human dose escalation study was done in 22 patients with advanced malignancies who received six ascending dosages ranging from 75 to 750 mg/m2. Following a single dosage and a 28-day dose-limiting toxicity (DLT) monitoring period, patients were given repeated doses weekly. Blood samples were taken to determine the PK parameters of Ametumumab and anti-drug antibody concentrations. Every 8 weeks, radiographic tumor evaluations were conducted. Results: In this trial, no DLT was observed, and the maximum tolerated dose was not reached at doses up to 750 mg/m2. There were no severe adverse events but mild and moderate adverse effects, such as headache, proteinuria, and rash. Single-dose PK results demonstrated a straightforward linear relationship with dosage escalation. The medication concentrations accumulated and attained steady-state after four rounds of injections. It was calculated that 10 patients with disease control would be observed in the 22 evaluable patients. The disease control rate was 45.5%. Conclusion: The Ametumumab was well tolerated and safe in patients with advanced solid malignancies, exhibiting minimal immunogenicity, a long half-life, high levels of drug exposure in the blood, and preliminary effectiveness. Registration: The trial was registered with CTR20170343 on 10 April 2017, The China Center for Drug Evaluation.

Clinical implications of clonal chromosomal abnormalities in Philadelphia negative cells in CML patients after treated with tyrosine kinase inhibitors.

Emergence of clonal chromosomal abnormalities in Philadelphia chromosome-negative (CCA/Ph-) cells in chronic myeloid leukemia (CML) patients during the treatment with tyrosine kinase inhibitors (TKIs) is an interesting phenomenon. Although previous studies revealed some potential impact of CCA/Ph- on CML patients' outcome, clinical significance of CCA/Ph- in CML patients remains to be further elucidated. We retrospectively reviewed the patients with CML evaluated at Genoptix Medical Laboratory in Carlsbad, California from 2005 to 2015. Twenty-four CML patients with CCA/Ph- cells were identified. These include 18 patients with single chromosomal abnormality, 4 patients with double chromosomal abnormalities, and two patients with complex cytogenetic abnormalities. In addition to trisomy 8 and monosomy 7, we identified that 20q- was also a common abnormality in CCA/Ph- cells. Most of the patients with CCA/Ph- cells demonstrated no significant dysplasia or increased blasts with two exceptions: one patient with persistent 7q- exhibiting mild dysmegakaryopoiesis, suggestive of an early evolving myelodysplastic syndrome, and another patient with complex cytogenetic abnormalities who developed acute myeloid leukemia after gained MLL amplification. One patient with complex cytogenetic abnormalities showed optimal response to TKI treatment, no overt dysplasia, and no disease progression during almost 4-years of follow-up. More interestingly, FISH tests could identify more cases with double chromosomal abnormalities and these cases showed suboptimal responses to TKI treatments. Our observation indicates that 20q- was also a common abnormality in CCA/Ph- cells, further FISH tests revealed additional CCA/Ph-, and the majority of CML patients with two or more chromosomal abnormalities in Ph- cells showed inferior response to TKI treatments. The results of our study suggest that CML cases with CCA/Ph- may represent a group of patients with heterogeneous genetic alterations.

Development of an immunochromatographic test based on monoclonal antibodies against surface antigen 3 (TgSAG3) for rapid detection of Toxoplasma gondii.

The immunochromatographic test (ICT) is a convenient and low-cost method that can rapidly obtain results (10 min) under normal conditions. In this study, we established an ICT assay with two monoclonal antibodies: TgSAG3-3A7 and TgSAG3-4D5 based on the conserved protein of TgSAG3 that can be expressed in all the infective stages of T. gondii. 20 nm gold particles were prepared and conjugated with TgSAG3-3A7 MAb at the concentration of 12.5 µg/mL. TgSAG3-4D5 MAb were used as the capture antibody because of its higher affinity tested by ELISA. The detection limit of the ICT assay was 100 ng with visual detection under optimal conditions of analysis. Positive porcine serum of Cryptosporidium suis, Mycoplasma suis, Streptococcus suis, Salmonella choleraesuis, Cysticercus cellulosae, Isospora suis, and Trichinella spiralis were used to evaluate the specificity of this ICT and no cross-reactivity was observed. 310 porcine serum samples obtained from pig farms in Zhejiang Province, China were detected by this ICT and ELISA kit, 23 positive samples were found by the developed strip with the rate of 7.42% comparing with 22 positive samples detected by the commercially ELISA kit which the positive rate was 7.1%, the relative sensitivity and specificity of this ICT are 100% and 99.65%. Therefore, the ICT established in this study is proved effective, simple, specific and sensitive of T. gondii detection.

Targeted overexpression of cyclic AMP-dependent protein kinase subunit in Toxoplasma gondii promotes replication and virulence in host cells.

Toxoplasma gondii (T. gondii) is one of the most common parasite that can infect almost any warm-blooded animals including humans. The cyclic nucleotide-dependent protein kinase (PKA) regulates a spectrum of intracellular signal pathways in many organisms. Protein kinase catalytic subunit (PKAC) is the core of the whole protein, and plays an important role in the life cycle of T.gondii. Here, T.gondii PKAC (TgPKAC) overexpression strain (TgPKAC-OE) was constructed. The growth of the TgPKAC-OE, RH△Ku80, and TgPKAC inhibition strains (TgPKAC-H89) were analysed by SYBR-green real-time PCR, and the ultrastructure was observed by transmission electron microscopy. The survival rate in mice was also recorded to analyse the virulence of the parasites. We also investigated the subcellular localization of TgPKAC in Vero cells by laser scanning microscope. We found that TgPKAC-OE strain exhibited obviously increased growth rate in Vero cells in vitro, and infected mice survived for a shorter time compared to wild type strain. Ultrastructural analysis found more autophagosomes-like structures in TgPKAC-H89 parasite compared to RH△Ku80 strain, and the relative expression level of Toxoplasma gondii autophagy-related protein (ATG8) in TgPKAC-H89 parasite was higher than wild type parasite. Laser confocal results showed that TgPKAC was mainly expressed in the cytoplasm of Vero cells. In conclusion, we hypothesized that inhibition of TgPKAC could cause autophagy of Toxoplasma gondii and then influence the replication of the parasite. TgPKAC plays an important role in parasite virulence in vivo, and the subcellular localization was successfully detected in Vero cells. Our data will provide a basis for further study of TgPKAC function and help screen drug targets of T. gondii.

Late-onset bexarotene-induced CD4 lymphopenia in a cutaneous T-cell lymphoma patient.

Various infections, autoimmune diseases, medications, and total-body irradiation are known factors associated with CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes. We report a rare case of a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy. Bexarotene is a third-generation retinoid that inhibits epithelial cell proliferation and is approved for treatment of advanced CTCL (stages IIB-IVB) in adult patients who have failed at least 1 prior systemic therapy. This case illustrates the importance of surveillance for CD4 leukopenia in patients on long-term bexarotene therapy with routine complete blood cell counts (CBC) and T-cell counts as well as consideration of rotating patients off bexarotene therapy even in those who derive continuous benefit.

Richter transformation with c-MYC overexpression: report of three cases.

Pathogenesis of Richter transformation (RT) or Richter syndrome (RS) of chronic lymphocytic leukemia (CLL) is still largely unknown. Increasing evidences show that c-MYC may play a role in the development of RS. Here we report three cases of RS with overexpression of c-MYC. The first case was a 78-year-old male who initially presented with CLL and then developed diffuse lymphadenopathy and ascites shortly after. Ascites cytology showed a population of large lymphoid cells positive for MYC (8q24) rearrangement by fluorescence in situ hybridization (FISH) and overexpression of c-MYC by immunohistochemistry (IHC). The second case was a 66-year-old male presented with rapidly enlarging lymph nodes and pleural effusion after a long history of CLL. Biopsy showed large B-cells positive for c-MYC overexpression and high Ki-67 proliferation index (80-90%). The third case was a 62-year-old female with CLL who presented for lobectomy for lung adenocarcinoma. Interestingly, along with the carcinoma, large B-cell lymphoma was incidentally found which had the same immunophenotype as the CLL. FISH analysis revealed gain of c-MYC at 8q and IHC showed increased c-MYC expression. This study supports that c-MYC plays a critical role in RS.

Effect of erythropoietin on the expression of dynamin-related protein-1 in rat renal interstitial fibrosis.

This study aimed to observe the expression of dynamin-related protein-1 (Drp-1) in the renal interstitium in a rat model of renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). In addition, the renoprotective effect of erythropoietin in this model was investigated. A total of 81 rats were randomly assigned to sham surgery, UUO model and treatment groups. Following surgery, the rats in the treatment group were subcutaneously administered erythropoietin at a dose of 3,000 IU/kg once a week until the time of sacrifice. Rats in the sham surgery and UUO model groups were administered an identical volume of normal saline. In each group, nine rats were chosen randomly for sacrifice on days 7, 14 and 21 after surgery for histological examination of renal tissue. Renal tissue specimens were examined by hematoxylin and eosin and Masson's trichrome staining. Immunohistochemical analysis was performed to determine the expression of Drp-1 in the renal interstitium. Renal function damage, as evaluated by the measurement of serum creatinine (Cr) and blood urea nitrogen (BUN) levels, was less severe in the treatment group compared with that in the model group at day 21 (P<0.01). Compared with the UUO model group, the renal interstitial injury score and fibrotic area of the treatment group were decreased markedly at the three time points (P<0.05). The expression level of Drp-1 in the treatment group was decreased markedly at the three time points compared with that in the model group (P<0.05). In conclusion, the expression of Drp-1 is increased in rat renal interstitial fibrosis, and erythropoietin may alleviate the degree of renal interstitial fibrosis by downregulating the expression of Drp-1.

The RUNX2 Transcription Factor Negatively Regulates SIRT6 Expression to Alter Glucose Metabolism in Breast Cancer Cells.

Activation of genes promoting aerobic glycolysis and suppression of mitochondrial oxidative phosphorylation is one of the hallmarks of cancer. The RUNX2 transcription factor mediates breast cancer (BC) metastasis to bone and is regulated by glucose availability. But, the mechanisms by which it regulates glucose metabolism and promotes an oncogenic phenotype are not known. RUNX2 expression in luminal BC cells correlated with lower estrogen receptor-α (ERα) levels, anchorage-independent growth, expression of glycolytic genes, increased glucose uptake, and sensitivity to glucose starvation, but not to inhibitors of oxidative phosphorylation. Conversely, RUNX2 knockdown in triple-negative BC cells inhibited mammosphere formation and glucose dependence. RUNX2 knockdown resulted in lower LDHA, HK2, and GLUT1 glycolytic gene expression, but upregulation of pyruvate dehydrogenase-A1 (PDHA1) mRNA and enzymatic activity, which was consistent with lower glycolytic potential. The NAD-dependent histone deacetylase, SIRT6, a known tumor suppressor, was a critical regulator of these RUNX2-mediated metabolic changes. RUNX2 expression resulted in elevated pAkt, HK2, and PDHK1 glycolytic protein levels that were reduced by ectopic expression of SIRT6. RUNX2 also repressed mitochondrial oxygen consumption rates (OCR), a measure of oxidative phosphorylation (respiration). Overexpression of SIRT6 increased respiration in RUNX2-positive cells, but knockdown of SIRT6 in cells expressing low RUNX2 decreased respiration. RUNX2 repressed SIRT6 expression at both the transcriptional and post-translational levels and endogenous SIRT6 expression was lower in malignant BC tissues or cell lines that expressed high levels of RUNX2. These results support a hypothesis whereby RUNX2-mediated repression of the SIRT6 tumor suppressor regulates metabolic pathways that promote BC progression.

Pediatric presentation of splenic marginal zone lymphoma on FDG PET/CT scan.

Splenic marginal zone lymphoma (SMZL) comprises about 1% of B-cell lymphomas and typically occurs after the age of 50 years. Pediatric SMZL is very rare, and no FDG PET/CT imaging of the disease has been reported. In the current study, a 4-year-old boy with biopsy-proven SMZL had FDG PET/CT for staging, which showed increased metabolic activity in the spleen and left cervical lymph nodes. A second FDG PET/CT for evaluation of treatment response showed complete resolution of abnormal FDG uptake in the nodes and spleen with decrease in size of the nodes.

Imbalanced matriptase pericellular proteolysis contributes to the pathogenesis of malignant B-cell lymphomas.

Membrane-associated serine protease matriptase is widely expressed by epithelial/carcinoma cells in which its proteolytic activity is tightly controlled by the Kunitz-type protease inhibitor, hepatocyte growth factor activator inhibitor (HAI-1). We demonstrate that, although matriptase is not expressed in lymphoid hyperplasia, roughly half of the non-Hodgkin B-cell lymphomas analyzed express significant amounts of matriptase. Furthermore, a significant proportion of these tumors express matriptase in the absence of HAI-1. Aggressive Burkitt lymphoma was more likely than indolent follicular lymphoma to express matriptase alone (86% versus 36%). In the absence of significant HAI-1 expression, the lymphoma cells activate and shed active matriptase when the cells are stimulated with mildly acidic buffer or the hypoxia-mimicking agent, CoCl2. The shed active matriptase can initiate pericellular proteolytic cascades by activating urokinase-type plasminogen activator on the cell surface of monocytes, and it can activate prohepatocyte growth factor. In addition, matriptase knockdown suppressed proliferation and colony-forming ability of neoplastic B cells in culture and growth as tumor xenografts in mice. Furthermore, exogenous expression of HAI-1 significantly suppressed proliferation of neoplastic B cells. These studies suggest that dysregulated pericellular proteolysis as a result of unregulated matriptase expression with limited HAI-1 may contribute to the pathological characteristics of several human B-cell lymphomas through modulation of the tumor microenvironment and enhanced tumor growth.

Amplified RPS6KB1 and CDC2 genes are potential biomarkers for aggressive HIV+/EBV+ diffuse large B-cell lymphomas.

RPS6KB1 encodes p70S6K/p85S6K, which plays a role in the PI3K/Akt/mTOR signal transduction pathway. CDC2 gene encodes cdc2, which is critical for G2/M cell cycle progression. We had previously shown that amplified RPS6KB1 and CDC2 are commonly detected in the EBV+ diffuse large B-cell lymphoma (DLBCL) in HIV patients. In current study, we further evaluated the amplified RPS6KB1 and CDC2 genes in 12 HIV-related aggressive B-cell lymphomas and 10 non-HIV-related DLBCL using real time quantitative PCR. The cases were divided into 4 groups: 1) HIV-/EBV-; 2) HIV-/EBV+; 3) HIV+/EBV-; and 4) HIV+/EBV+. Receiver operating characteristic (ROC) curve and the area under the curve (AUC) was used to assess the ability of each gene to distinguish non-HIV+/EBV+ cases from HIV+/EBV+ cases. The AUC was estimated to be 0.76 for RPS6KB1 and 0.74 for CDC2 by using the Mann-Whitney statistic. Amplified RPS6KB1 and CDC2 genes were more frequently detected in common variants of DLBCL associated with HIV infection. Taken together, amplified RPS6KB1 and CDC2 are potential biomarkers for the aggressive DLBCL, particularly in HIV+/EBV+ patients. This study also suggests that the HIV+/EBV+ aggressive DLBCL could be potentially treated by targeting RPS6KB1 and CDC2 genes.

Tertiary center referral patterns for patients with myelodysplastic syndrome are indicative of age and race disparities: a single-institution experience.

Little is known about disparities in myelodysplastic syndromes (MDS). We performed a retrospective chart review of patients with MDS (n = 252) evaluated at the University of Maryland Greenebaum Cancer Center between 2000 and 2010. The median age at diagnosis was 65 years, which was lower than the median age of 76 years for patients with MDS in the Surveillance, Epidemiology and End Results database. Black males were younger than white males (62 vs. 68 years; p = 0.03) and had longer time to referral (9 vs. 1.5 months; p = 0.03), but black and white females did not differ in age or in time to referral. A difference in World Health Organization subtype classification was noted in black and white patients at diagnosis, but not at referral. There was no difference between all other pretreatment characteristics, treatment and survival by race. Our data suggest barriers to tertiary care referral for older patients and for black males.

c-Myc and E2F1 drive PBK/TOPK expression in high-grade malignant lymphomas.

c-Myc has been implicated in a variety of hematologic malignancies including Burkitt's lymphoma. Targeting c-Myc driven growth pathways could be therapeutically useful but might require the identification of critical downstream proteins. Here we show that the serine-threonine kinase PBK/TOPK is frequently overexpressed in high-grade lymphomas and its expression is positively correlated to that of c-Myc and E2F1. Further we demonstrate that c-Myc regulates PBK expression through E2F1. Additionally, inhibition of c-Myc, E2F1 or PBK comparably decreased cell growth and survival. In conclusion, a c-Myc-E2F1-PBK signaling pathway operates in high-grade lymphomas and may provide a useful target for novel antineoplastic therapeutics.

Melatonin alleviates cadmium-induced cellular stress and germ cell apoptosis in testes.

Increasing evidence demonstrates that melatonin has an anti-apoptotic effect in somatic cells. However, whether melatonin can protect against germ cell apoptosis remains obscure. Cadmium (Cd) is a testicular toxicant and induces germ cell apoptosis. In this study, we investigated the effects of melatonin on Cd-evoked germ cell apoptosis in testes. Male ICR mice were intraperitoneally (i.p.) injected with melatonin (5 mg/kg) every 8 hr, beginning at 8 hr before CdCl(2) (2.0 mg/kg, i.p.). As expected, acute Cd exposure resulted in germ cell apoptosis in testes, as determined by terminal dUTP nick-end labeling (TUNEL) staining. Melatonin significantly alleviated Cd-induced testicular germ cell apoptosis. An additional experiment showed that spliced form of XBP-1, the target of the IRE-1 pathway, was significantly increased in testes of mice injected with CdCl(2). GRP78, an endoplasmic reticulum (ER) chaperone, and CHOP, a downstream target of the PERK pathway, were upregulated in testes of Cd-treated mice. In addition, acute Cd exposure significantly increased testicular eIF2α and JNK phosphorylation, indicating that the unfolded protein response (UPR) pathway was activated by CdCl(2). Interestingly, melatonin almost completely inhibited Cd-induced ER stress and the UPR in testes. In addition, melatonin obviously attenuated Cd-induced heme oxygenase (HO)-1 expression and protein nitration in testes. Taken together, these results suggest that melatonin alleviates Cd-induced cellular stress and germ cell apoptosis in testes. Melatonin may be useful as pharmacological agents to protect against Cd-induced testicular toxicity.

Spirulina can increase total-body vitamin A stores of Chinese school-age children as determined by a paired isotope dilution technique.

Spirulina is an alga rich in high-quality protein and carotenoids. It is unclear whether spirulina can improve the total-body vitamin A stores of school-age children in China with a high prevalence of vitamin A malnutrition. We aimed to evaluate the efficacy of spirulina in improving the total-body vitamin A stores of school-age children in rural areas of China when they consumed spirulina in their daily meals. A total of 228 children (6-11 years) were recruited and randomly divided into three groups supplemented with 4 g (containing 4·18 µg ß-carotene), 2 g (containing 2·54 µg ß-carotene) or 0 g spirulina 5 d/week for 10 weeks, respectively. Before and after the intervention period, each child was given 0·5 mg [(2)H4]retinyl acetate and [(2)H8]retinyl acetate, respectively. To assess vitamin A stores, blood samples (3 ml) were collected on the third and the twenty-first day after each labelled retinyl acetate dose for a retinol enrichment analysis using a GC mass spectrometer. The concentrations of retinol and ß-carotene in serum samples were also determined by using HPLC. After the 10-week intervention, serum ß-carotene concentrations of children with 2 or 4 g spirulina supplement increased by 0·160 and 0·389 µmmol/l, respectively. Total-body vitamin A stores increased significantly, with a median increase of 0·160 mmol in children taking 2 g spirulina and of 0·279 mmol in children taking 4 g spirulina. Spirulina is a good dietary source of ß-carotene, which may effectively increase the total-body vitamin A stores of Chinese school-age children.

Crosstalk between endoplasmic reticulum stress and mitochondrial pathway mediates cadmium-induced germ cell apoptosis in testes.

Cadmium (Cd) is associated with male infertility and poor semen quality in humans. Increasing evidence demonstrates that Cd induces testicular germ cell apoptosis in rodent animals. However, the molecular mechanisms of Cd-induced testicular germ cell apoptosis remain poorly understood. In the present study, we investigated the role of endoplasmic reticulum (ER) stress on Cd-evoked germ cell apoptosis in testes. We show that spliced form of XBP-1, the target of the IRE1 pathway, was significantly increased in testes of mice injected with CdCl(2). GRP78, an ER chaperone, and CHOP, a downstream target of the PERK pathway, were upregulated in testes of Cd-treated mice. In addition, acute Cd exposure significantly caused eIF2α and JNK phosphorylation in testes, indicating that the unfolded protein response pathway in testes was activated by Cd. Interestingly, phenylbutyric acid (PBA), an ER chemical chaperone, attenuated Cd-induced ER stress and protected against germ cell apoptosis in testes. In addition, PBA significantly attenuated Cd-evoked release of cytochrome c from mitochondria to cytoplasm in testes. Taken together, these results suggest that crosstalk between ER stress signaling and mitochondrial pathway mediates Cd-induced testicular germ cell apoptosis.

[Biomechanical evaluation of monosegmental and bisegmental anterior fixation for thoracolumbar burst fracture].

This paper is aimed to evaluate the biomechanism of monosegmental and bisegmental anterior fixation for thoracolumbar burst fracture. Twenty-four fresh porcine spines (T13-L3) were used in this study. Three of the fresh porcine spines were randomly selected as intact group, and the others were made into L1 burst fracture models. Fifteen of the twenty one fracture models fitting to the experimental requirements were divided randomly into five groups. Each of the specimens in the five groups and in the intact group underwent the tests of load-strain, load-displacement, stiffness and extreme limit bisegmental fixation group (P<0.05) loading. Data for the monosegmental fixation were insignificantly different on the load- strain and load-displacement tests from those for the bisegmental fixation (P>0.05), but were significantly different from those of the bisegmental fixation on the stiffness test, torsion test and limit loading test. Anterior monosegmental fixation is more stable and has stronger strain of axial compression than the bisemental fixation group. Resect pedicle group is insignificantly different from the monosegmental fixation group,so it is important to keep the pedicle integrity of injured vertebral body in surgery. The biomechanical stability of monosegmental fixation is feasible for thoracolumbar burst fracture.

Effects of maternal cadmium exposure during late pregnant period on testicular steroidogenesis in male offspring.

Cadmium (Cd) is a testicular toxicant and endocrine disruptor. In the present study, we investigated the effects of maternal Cd exposure during the late pregnant period on testicular development and steroidogenesis in male offspring. Pregnant mice were injected intraperitoneally with CdCl(2) (0.5mg/kg) daily from gestational day (gd) 13 to gd 17. As expected, fetal weight and crown length were significantly decreased in pups whose mothers were exposed to Cd. Importantly, absolute and relative weights of testes were significantly decreased in male fetuses. In addition, maternal Cd exposure during pregnancy markedly reduced serum T level and downregulated the expression of steroidogenic acute regulatory (StAR) protein, P450scc, P45017α and 17ß-HSD in testes of male fetuses. Interestingly, the level of serum and testicular T at adulthood remained decreased in male offspring of Cd-exposed mice. Correspondingly, the expression of testicular P450scc was downregulated in male adult offspring whose mothers were exposed to Cd during pregnancy. Fertility analysis found that the number of live fetuses per litter in F2 generation was significantly decreased in Cd-treated group. Additional experiment showed that placental Cd level was increased about 750 folds in dams injected with Cd. However, only traces of blood Cd was measured in fetuses whose mothers were exposed to Cd during the late pregnant period. Taken together, these results suggest that placenta could deter most of Cd from passing from dams to fetuses. The impairments on testicular steroidogenesis in male offspring could not be attributed to a direct action of Cd on fetal testes.