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IntroductionChronic low-grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll-like receptor 4 (TLR4) mediates both infection-induced and sterile inflammation by recognizing pathogen-associated molecular patterns and endogenous molecules, respectively. Saturated fatty acids can activate TLR4, and TLR4-deficient mice were protected from high fat diet (HFD)-induced obesity and insulin resistance, suggesting that TLR4-mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance.MethodsWe generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance.ResultsTG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild-type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild-type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet.ConclusionsTogether, these results suggest that constitutively active TLR4-induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet-induced insulin resistance may require other signals in addition to TLR4-mediated inflammation.

Non-fullerene acceptor-based polymer solar cells (NFA-PSCs) can exhibit high morphological stability under thermal stress, often resulting in the fabrication of thermally stable NFA-PSCs. Here, our stability study with systematic steps shows that high morphological stability of active layers does not necessarily guarantee high thermal stability for NFA-PSCs. Furthermore, a degradation pathway is elucidated by using two NFA-PSCs comprising well-known polymer donors and non-fullerene acceptors such as PTB7-Th, PBDB-T-2Cl, and ITIC-4F. Morphologies of the PTB7-Th:ITIC-4F and PBDB-T-2Cl:ITIC-4F blends are highly stable at a high temperature of 110 °C. However, the corresponding NFA-PSCs degrade severely at the same temperature. For example, all the NFA-PSCs show an efficiency reduction of greater than 30% within an hour, particularly owing to the significant decrease in the short-circuit current density (JSC) and fill factor (FF). A series of experiments, including time-of-flight secondary ion mass spectrometry measurements, demonstrate that the penetration of metal oxide molecules into the photoactive layer occurs upon heating, resulting in degradation. The diffused molecules can act as charge recombination centers, leading to decreases in JSC and FF. Finally, we provide insights, from a material design perspective, into the prevention of undesirable penetration of metal oxide molecules. [ABSTRACT FROM AUTHOR]

Organic indoor photovoltaics (IPVs) are attractive energy harvesting devices for low‐power consumption electronic devices and the Internet of Things (IoTs) owing to their properties such as being lightweight, semitransparent, having multicoloring capability, and flexibility. It is important to match the absorption range of photoactive materials with the emission spectra of indoor light sources that have a visible range of 400–700 nm for IPVs to provide sustainable, high‐power density. To this end, benzo[1,2‐b:4,5‐b′]dithiophene‐based homopolymer (PBDTT) is synthesized as a polymer donor, which is a classical material that has a wide bandgap with a deep highest occupied molecular orbitals (HOMO) level, and a series of random copolymers by incorporating thieno[3,4‐c]pyrrole‐4,6,‐dione (TPD) as a weak electron acceptor unit in PBDTT. The composition of the TPD unit is varied to fine tune the absorption range of the polymers; the polymer containing 70% TPD (B30T70) perfectly covers the entire range of indoor lamps such as light‐emitting diodes (LEDs) and fluorescent lamp (FL). Consequently, B30T70 shows a dramatic enhancement of the power conversion efficiency (PCE) from 1‐sun (PCE: 6.0%) to the indoor environment (PCE: 18.3%) when fabricating organic IPVs by blending with PC71BM. The simple, easy molecular design guidelines are suggested to develop photoactive materials for efficient organic IPVs. [ABSTRACT FROM AUTHOR]

Aims Angiotensin II (AngII) is a potent vasoconstrictor implicated in both hypertension and insulin resistance. Insulin dilates the vasculature in skeletal muscle to increase microvascular blood flow and enhance glucose disposal. In the present study, we investigated whether acute AngII infusion interferes with insulin's microvascular and metabolic actions in skeletal muscle. Methods and results Adult, male Sprague-Dawley rats received a systemic infusion of either saline, AngII, insulin (hyperinsulinaemic euglycaemic clamp), or insulin (hyperinsulinaemic euglycaemic clamp) plus AngII. A final, separate group of rats received an acute local infusion of AngII into a single hindleg during systemic insulin (hyperinsulinaemic euglycaemic clamp) infusion. In all animals' systemic metabolic effects, central haemodynamics, femoral artery blood flow, microvascular blood flow, and skeletal muscle glucose uptake (isotopic glucose) were monitored. Systemic AngII infusion increased blood pressure, decreased heart rate, and markedly increased circulating glucose and insulin concentrations. Systemic infusion of AngII during hyperinsulinaemic euglycaemic clamp inhibited insulin-mediated suppression of hepatic glucose output and insulin-stimulated microvascular blood flow in skeletal muscle but did not alter insulin's effects on the femoral artery or muscle glucose uptake. Local AngII infusion did not alter blood pressure, heart rate, or circulating glucose and insulin. However, local AngII inhibited insulin-stimulated microvascular blood flow, and this was accompanied by reduced skeletal muscle glucose uptake. Conclusions Acute infusion of AngII significantly alters basal haemodynamic and metabolic homeostasis in rats. Both local and systemic AngII infusion attenuated insulin's microvascular actions in skeletal muscle, but only local AngII infusion led to reduced insulin-stimulated muscle glucose uptake. While increased local, tissue production of AngII may be a factor that couples microvascular insulin resistance and hypertension, additional studies are needed to determine the molecular mechanisms responsible for these vascular defects. [ABSTRACT FROM AUTHOR]

Our previous study presented evidence that the inflammation-related S100A9 gene is significantly upregulated in the brains of Alzheimer's disease (AD) animal models and human AD patients. In addition, experiments have shown that knockdown of S100A9 expression improves cognition function in AD model mice (Tg2576), and these animals exhibit reduced amyloid plaque burden. In this study, we established a new transgenic animal model of AD by crossbreeding the Tg2576 mouse with the S100A9 knockout (KO) mouse. We observed that S100A9KO/Tg2576 (KO/Tg) mice displayed an increased spatial reference memory in the Morris water maze task and Y-maze task as well as decreased amyloid beta peptide (Aβ) neuropathology because of reduced levels of Aβ, C-terminal fragments of amyloid precursor protein (APP-CT) and phosphorylated tau and increased expression of anti-inflammatory IL-10 and also decreased expression of inflammatory IL-6 and tumor neurosis factor (TNF)-α when compared with age-matched S100A9WT/Tg2576 (WT/Tg) mice. Overall, these results suggest that S100A9 is responsible for the neurodegeneration and cognitive deficits in Tg2576 mice. The mechanism of S100A9 is able to coincide with the inflammatory process. These findings indicate that knockout of S100A9 is a potential target for the pharmacological therapy of AD. [ABSTRACT FROM AUTHOR]

Long-chain acyl-CoA synthetases (ACSL) are the enzymes that convert long-chain fatty acids to long-chain fatty acyl-CoAs that are utilized for various cellular processes, including triglyceride synthesis, energy metabolism, sphingolipid formation, and modification of lipids and proteins. Among five common isotypes (ACSL1, 3, 4, 5, and 6), ACSL1 is the predominant isotype in adipose tissue and essential for fatty acid oxidation during the cold adaption in brown adipose tissue. However, it is unknown whether ACSL1 is involved in brown adipocyte differentiation. Since the smooth muscle-like cells (mural cells) are the progenitors of brown adipocytes, we hypothesize that the ACSL1 in smooth muscle cells contributes to brown adipocyte differentiation and energy metabolism. We generated a smooth muscle-specific ACSL1 knockout mouse (ACSL1SM-/-) by breeding SM22α-cre mouse with ACSL1flox/flox mouse. ACSL1 deficiency in smooth muscle cells protected from high-fat diet (HFD)-induced obesity without changes in food intake and physical activity. Furthermore, HFD-fed ACSL1flox/flox mice were more glucose tolerant and insulin sensitive compared to HFD-fed wild-type mice. We also observed that cold adaptation, thermogenesis, was significantly impaired in ACSL1SM-/- mice. We isolated stromal vascular cells (SVCs) from inguinal and brown adipose tissues and then subjected them to adipocyte differentiation. We found that the adipocyte differentiation was impaired, and the expression of UCP1 was significantly reduced in the absence of ACSL1. These results suggest that ACSL1 in smooth muscle cells contributes to energy metabolism and glucose homeostasis by regulation of brown fat differentiation. Disclosure: G. Ren: None. M. Young: None. J. Kim: None. Funding: National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079626); National Heart, Lung, and Blood Institute (HL128695); National Institute on Aging (AG058078) [ABSTRACT FROM AUTHOR]

Groundwater can flow into or out of surface water and thus can greatly affect the quantity and quality of surface water. In this study, we conducted a water quantity and quality analysis for 11 months in 2018 and 2019 to evaluate the temporal contribution of groundwater to surface water at Osongji, a small lake located in Jeonju-si, Jeollabuk-do, Korea. Groundwater fluxes and groundwater and surface water levels were measured using seepage meters and a piezometer, respectively. On-site water quality parameters, cations, and anions for groundwater and surface water were analyzed. Hydrogen and oxygen isotopes for groundwater, surface water, and rainwater were also analyzed. Groundwater influx did not correlate directly to precipitation, suggesting that it may be delayed after rainwater infiltration. Aqueous chemistry indicated that the hydrogeochemical characteristics of surface water were substantially affected by groundwater. The isotopic composition of surface water changed over time, indicating a different contribution of groundwater in different seasons. This study shows that water quantity and quality data can be used in combination to evaluate temporal changes in the groundwater contribution to surface water. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is characterized by reduction of the bioavailability of nitric oxide (NO), and is associated with metabolic syndrome including, obesity, insulin resistance, hypertension, coronary heart disease, and aging. Because NO plays important roles in mitochondrial biogenesis, we hypothesize that exogenous application of NO may prevent high fat diet (HFD)-induced obesity and insulin resistance by promotion of adipose tissue browning. In the current study, we developed a novel NO releasing nanomatrix gel with natural peptide amphiphiles (PANO). 8 week old male C57BL/6 mice were randomly divided into 2 groups, and then either vehicle (PA) or PANO was subcutaneously injected into brown adipose tissue area every 2 weeks for 11 weeks while the mice were fed HFD. The mice injected with PANO gained less body weight compared to the mice injected with vehicle. PANO injected mice demonstrated improved glucose tolerance and insulin tolerance. Fasting glucose, insulin and leptin levels were lower in the PANO injected mice compared to the vehicle injected mice. Furthermore, the expression of pro-inflammatory genes in epididymal fat tissue was lower, and the expression of uncoupled protein (UCP1) in brown adipose tissue and inguinal adipose tissue was higher in the PANO-injected mice compared to the vehicle injected mice. Thus, the novel nitric oxide releasing nanomatrix gel ameliorated HFD-induced obesity and insulin resistance by promotion of adipose tissue browning. The results suggest that injection of PANO can be a novel therapeutic for obesity and insulin resistance. Disclosure: G. Ren: None. A.L. Shaw: None. P. Hwang: None. R.C. Millican: None. H. Jun: None. J. Kim: None. Funding: National Institutes of Health (1R01HL125391-01) [ABSTRACT FROM AUTHOR]

Long chain acyl-CoA synthetases (ACSLs) convert fatty acids (FA) to fatty acyl-CoAs that are utilized for various cellular processes, including triglyceride synthesis, activation of transcription factors, signal transduction, and providing energy sources via oxidation. Among 5 isotypes (ACSL1, 3, 4, 5, and 6), ACSL1 is the predominant isotype in adipocytes, and it is known to play important roles in adipocyte physiology, including FA uptake, triglyceride (TG) synthesis, thermogenesis, and FA oxidation. However, the roles of ACSL1 in brown adipocyte differentiation is incompletely understood. During the in vitro differentiation of brown adipocytes from stromal vascular cells (SVC), mRNA expression of ACSL1 was drastically increased. Pharmacological inhibition of ACSLs by triacsin C suppressed the differentiation of brown adipocytes. Interestingly, triacsin C inhibited the expression of uncoupled protein 1 (UCP1), which plays the major role in thermogenesis in mitochondria. Thus, we hypothesize that ACSL1 regulates thermogenesis and energy utilization by regulation of brown adipocyte differentiation. To examine the role of ACSL1 in brown adipose tissue (BAT), we generated BAT specific ACSL1 knockout mice by breeding UCP1-Cre with ACSL1 flox/flox mice (ACSL1BATKO). ACSL1 deficiency in BAT reduced the weight gain and glucose intolerance in high fat diet (HFD)-fed mice. ACSL1BATKO mice were severely cold intolerant. Furthermore, ACSL1BATKO mice were resistant to beta 3-agonist (CL-316243)-stimulated weight loss. Fat mass in HFD-fed ACSL1BATKO was lower than HFD-fed wild type mice. These data suggest that ACSL1 in BAT contributes to BAT differentiation, which causes the impairment of FA utilization. However, the mechanisms by which deficiency of ACSL1 in BAT reduces HFD-induced weight gain need to be further investigated. Disclosure: G. Ren: None. J. Kim: None. Funding: National Institutes of Health (R01HL128695R03AG058078) [ABSTRACT FROM AUTHOR]

Consumption of green tea is associated with decreased cardiovascular morbidity and mortality. Tissue and circulating levels of the potent vasoconstrictor ET-1 are elevated in patients with diabetes. We hypothesized that EGCG, a bioactive polyphenol in green tea, may reduce expression of ET-1 in vascular endothelial cells. In bovine aortic endothelial cells (BAEC) in primary culture, acute treatment of cells with EGCG increased phosphorylation of Akt (Ser[sup 473]) and FOXO-1 (Akt phosphorylation site Thr[sup 24]) in a time- and dose-dependent manner (maximal increases at 30 min and 50 µM as determined by immunoblotting with phospho-specific antibodies). Chronic EGCG treatment (8 h, l0 µM) also caused phosphorylation of Akt and FOXO-1 (immunoblotting) with an increase in the amount of FOXO-1 localized to the cytoplasm (immunohistochemistry). Treatment of BAEC with EGCG (8 h, l0 µM) reduced ET-1 mRNA by 60% (quantitative real time PCR, p < 0.001). Moreover, ET-l protein secreted into conditioned media was also reduced 70% (ELISA, p < 0.0001) and intracellular ET-1 protein levels were reduced 65% (ELISA, p <0.005). Treatment of human aortic endothelial cells (HAEC) with EGCG (50 µM, 1 h) reduced ET- 1 promoter activity (assessed by chromatin immunoprecipitation with FOXO-1 antibodies; p < 0.05). We examined ET-l promoter activity by transfecting BAEC with a luciferase reporter containing the human ET-1 promoter. Co-transfection of BAEC with the reporter and human FOXO-1 increased ET-1 promoter activity 2.5-fold when compared with cells co-transfected with reporter and empty vector (p < 0.05). When we truncated or mutated a putative FOXO-1 binding sequence in our reporter (TGTTTAC to TGTcTAC), co-transfection of BAEC with these mutants and either wild-type or constitutively active FOXO-1 did not increase luciferase activity. Finally, results from EMSA assays demonstrate that recombinant FOXO-1 binds to the human ET-1 promoter. Thus, our data suggest that EGCG reduces ET-1 expression and secretion in endothelial cells using a mechanism involving phosphorylation of FOXO-1 and dissociation of FOXO-1 from the ET-1 promoter. We conclude that the ET-1 promoter is a novel target for FOXO-1 and that beneficial effects of green tea consumption on cardiovascular health may be mediated, in part, by actions of EGCG to reduce ET-1 expression and secretion. [ABSTRACT FROM AUTHOR]

Metal recovery from electronic waste and industrial wastewater has attracted increasing attention to recycle precious metals and inhibit the emission of hazardous heavy metals. However, the selective recovery of precious metals with a large quantity is still very challenging because wastewater contains a variety of different cations while precious metal ions are relatively scarce. Here, we introduce a simple method to selectively increase the adsorption of gold ions using tannin-coated porous polymer microspheres through photochemical reduction. Mesoporous poly(ethylene glycol dimethacrylate- co-acrylonitrile) microspheres with an average pore diameter of 13.8 nm were synthesized and used as an adsorbent matrix. Tannic acid (TA) was deposited onto the internal pores of the polymer matrix by simple immersion in an aqueous milieu. TA coatings increased the maximum number of adsorbed gold ions by 1.3 times because of the well-known metal ion chelation of TA. Under light illumination, the maximum number of adsorbed gold ions dramatically increased by 6.1 times. We examined two distinct mechanisms presumably involved in the enhanced adsorption: the photooxidation of TA and plasmon-induced hot electrons. Moreover, TA-coated microspheres exhibited remarkable selectivity for gold ions among competing metal ions commonly found in waste resources. This work suggests that the photochemically activated TA can serve as an excellent adsorbent for the selective and efficient recovery of gold ions from wastewater.

Historically, Plasmodium vivax malaria has been one of the most highly endemic parasitic diseases in the Korean Peninsula. Until the 1970s, vivax malaria was rarely directly lethal and was controlled through the Korean Government Program administered by the National Malaria Eradication Service in association with the World Health Organization's Global Malaria Eradication Program. Vivax malaria has re-emerged in 1993 near the Demilitarized Zone between South and North Korea and has since become an endemic infectious disease that now poses a serious public health threat through local transmission in the Republic of Korea. This review presents major lessons learned from past and current malaria research, including epidemiological and biological characteristics of the re-emergent disease, and considers some interesting patterns of diversity. Among other features, this review highlights temporal changes in the genetic make-up of the parasitic population, patient demographic features, and spatial distribution of cases, which all provide insight into the factors contributing to local transmission. The data indicate that vivax malaria in Korea is not expanding expo- nentially. However, continued surveillance is needed to prevent future resurgence.

Plasmodium vivax is more challenging to control and eliminate than P. falciparum due to its more asymptomatic infections with low parasite densities making diagnosis more difficult, in addition to its unique biological characteristics. The potential re-introduction of incidence cases, either through borders or via human migrations, is another major hurdle to sustained control and elimination. The Republic of Korea has experienced re-emergence of vivax malaria in 1993 but is one of the 32 malaria-eliminating countries to-date. Despite achieving successful nationwide control and elimination of vivax malaria, the evolutionary characteristics of vivax malaria isolates in the Republic of Korea have not been fully understood. In this review, we present an overview of the genetic variability of such isolates to increase understanding of the epidemiology, diversity, and dynamics of vivax populations in the Republic of Korea.

Innovative biomaterial strategies are required to improve islet cell retention, viability, and functionality, and thereby obtain clinically successful outcomes from pancreatic islet cell transplantation. To address this need, we have developed a peptide amphiphile-based nanomatrix that incorporates multifunctional bioactive cues and sustained release of nitric oxide. The goal of this study was to evaluate the effect of this peptide amphiphile nanomatrix on the viability and functionality of MIN-6 islet cells. Additionally, this study provides insight into the role of nitric oxide in islet cell biology, given that conventional nitric oxide donors are unable to release nitric oxide in a controlled, sustained manner, leading to ambiguous results. It was hypothesized that controlled nitric oxide release in synergy with multifunctional bioactive cues would promote islet cell viability and functionality. Nitric oxide-releasing peptide amphiphile nanomatrices within the range of 16.25 μmol to 130 μmol were used to analyze MIN-6 cell behavior. Both 32.5 μmol and 65 μmol peptide amphiphiles showed improved MIN-6 functionality in response to glucose over a 7-day time period, and the elevated functionality was correlated with both PDX-1 and insulin gene expression. Our results demonstrate that nitric oxide has a beneficial effect on MIN-6 cells in a concentration-dependent manner.

This study examined the deleterious effects of di(n-butyl) phthalate (DBP) on the male reproductive organs in hypothyroid rats. Hypothyroidism was induced in prepubertal male rats (28 days of age) by an intraperitonial (i.p.) injection of 10 mg/kg/day propylthiouracil (PTU) for 30 days. DBP (100 and 500 mg/kg/day) was administered by oral gavages to the intact or hypothyroid rats for 30 days. The body weight of the PTU-treated rats was significantly lower than the control group. The total triiodothyronine (T3) and thyroxine (T4) serum level was lower, and the thyroid-stimulating hormone (TSH) level was higher in the hypothyroid rats than in the control rats. The DBP treatment rats showed significantly lower testes, epididymides, seminal vesicles, and ventral prostate weights than the untreated rats. The hypothyroid rats had significantly higher thyroid weights and lower adrenal glands weights than the control rats. The histomorphological examination showed diffused Leydig cells hyperplasias and germ cells loss in the DBP (500 mg/kg)-treated rats, whereas these effects were mild in the DBP-treated hypothyroid rats. The serum levels of monobutyl phthalate (MBP) were significantly lower in PTU-induced hypothyroid rats than in the DBP-treated rats. This data suggests that the hypothyroid status might offer some protection from male reproductive organ toxicity caused by a disturbance in the metabolic activation of the parent compound, DBP.

The cellular susceptibility of cancer cells to histone deacetylase (HDAC) inhibitors is increased by the etopic expression of oncogenic Ras. However, the ability of HDAC inhibitors to regulate the apoptotic pathway in human breast cancer cells is still not completely understood. In this study, the anti-proliferative effects of apicidin were compared in H-ras-transformed human breast epithelial (MCF10A-ras) and non-transformed epithelial (MCF10A) cells. MCF10A-ras cells showed a significantly higher growth rate than MCF10A cells. Apicidin significantly increased the levels of acetylated histone H3 and H4 in both cell lines. Western blot analysis and flow cytometry were used to determine if the anti-proliferative effects of apicidin in MCF10A and MCF10A-ras cells could be mediated by modulating the cell cycle. Apicidin attenuated the expression of cyclin E and CDK2 in MCF10A cells, decreased cyclin D1 and cyclin E levels in MCF10A-ras cells, and increased the levels of CDK inhibitors, p21WAF1/Cip1 and p27Kip1, in both cell lines. Notably, the levels of hyperphosphorylation of the Rb protein levels were lower in the MCF10A-ras cells after apicidin treatment. Studies on the regulation of apoptosis showed that apicidin induces the up-regulation of p53 and the downstream activation of ERK in MCF10A-ras cells. The up-regulation of p53 promoted Bax expression leading to activation of caspases-9 and -6, and eventually to apoptosis in MCF10A-ras cells. In addition, apicidin significantly increased the levels of ERK1/2 phosphorylation in MCF10A-ras cells. Therefore, the apicidin-mediated ERK pathway appears to play an important role in modulating the pro-apoptotic pathway in MCF10A-ras cells.

Histone deacetylase (HDAC) inhibitors have been shown to modify the expression of a variety of genes related to cell cycle regulation and apoptosis in several cancer cells. However, the precise mode of action of HDAC inhibitors in prostate cancer cells is not completely understood. This study examined whether an HDAC inhibitor affects cell death in human prostate cancer cells through the epigenetic regulation of androgen receptor (AR) expression. The molecular mechanism of the HDAC inhibitor, sodium butyrate, on the epigenetic alterations of cell cycle regulators was evaluated in androgen-dependent human prostate cancer LNCaP cells. The expression levels of acetylated histone H3 and H4 increased significantly after 48 h treatment with sodium butyrate. Sodium butyrate induced the expression of AR after 48 h treatment. In addition, immunofluorescence assay revealed the nuclear localization of the AR after sodium butyrate treatment. Sodium butyrate also significantly decreased the expression of the cell cycle regulatory proteins (cyclin D1/cyclin dependent kinase (CDK)4, CDK6, and cyclin E/CDK2) in the LNCaP cells after 48 h treatment. Furthermore, p21Waf1/Cip1 and p27Kip1 were upregulated as a result of the sodium butyrate treatment. These results suggest that sodium butyrate effectively inhibited cell proliferation and induced apoptosis of human prostate cancer cells by altering the expression of cell cycle regulators and AR. This study indicated that sodium butyrate may be a potential agent in prostate cancer treatment.

Di(2-ethylhexyl) phthalate (DEHP) is a well-known hepatic and reproductive toxicant whose toxicity may be mediated by peroxisome proliferators-activated receptor (PPAR). This study examined the effects of DEHP on the expression of PPAR-regulated genes involved in testicular cells apoptosis. Sprague-Dawley male rats were treated orally with 250, 500, or 750 mg/kg/d DEHP for 28 d, while control rats were given corn oil. The levels of cell cycle regulators (pRb, cyclins, CDKs, and p21) and apoptosis-related proteins were analyzed by Western blot analysis. The role of PPAR-gamma (PPAR-gamma), class B scavenger receptor type 1 (SR-B1), and ERK1/2 was further studied to examine the signaling pathway for DEHP-induced apoptosis. Results showed that the levels of pRB, cyclin D, CDK2, cyclin E, and CDK4 were significantly lower in rats given 500 and 750 mg/kg/d DEHP, while levels of p21 were significantly higher in rat testes. Dose-dependent increases in PPAR-gamma and RXRalpha proteins were observed in testes after DEHP exposure, while there was a significant decrease in RXRgamma protein levels. In addition to PPAR-gamma, DEHP also significantly increased SR-B1 mRNA and phosphorylated ERK1/2 protein levels. Furthermore, DEHP treatment induced pro-caspase-3 and cleavage of its substrate protein, poly(ADP-ribose) polymerase (PARP), in a dose-dependent manner. Data suggest that DEHP exposure may induce the expression of apoptosis-related genes in testes through induction of PPAR-gamma and activation of the ERK1/2 pathway.