Ena Lee

Effects of Gestational Exposure to Decabromodiphenyl Ether on Reproductive Parameters, Thyroid Hormone Levels, and Neuronal Development in Sprague-Dawley Rats Offspring

Polybrominated diphenyl ethers (PBDE) are a class of brominated flame retardants that are recognized as global environmental contaminants with potential adverse effects on human health. This study examined the effects of prenatal exposure to PBDE on reproductive organs, neuronal development, and levels of thyroid hormones. Pregnant rats were exposed to the vehicle or deca-bromodiphenyl ether (BDE) (BDE-209; 5, 40, or 320 mg/kg body weight/d) during gestation days (GD) 6–18. There was a significant decrease in body weight gain in F1 male offspring exposed to high-dose (320 mg/kg) BDE-209. Significant increases in thyroid weight and a decrease in adrenal weight were observed in high-dose BDE-209. Thyroxine (T4) concentrations were significantly lower in F1 female offspring exposed to BDE-209 at postnatal day (PND) 42. This reduction was more pronounced in the group exposed to higher doses. A low dose (5 mg/kg) of BDE-209 significantly reduced serum estradiol concentration in female offspring but did not affect testosterone levels in males. There was no significant effect on hippocampal neurogenesis in BDE-209 treatment groups. In conclusion, there was no apparent association between thyroid hormone concentrations and low birth weight in F1 rats after gestational exposure to BDE-209.

Exposure Assessment of Polybrominated Diphenyl Ethers (PBDE) in Umbilical Cord Blood of Korean Infants

This study examined the levels of polybrominated diphenyl ethers (PBDE) in the umbilical cord blood of infants, and investigated the relationship between PBDE concentration and thyroid hormone levels. The concentration of PBDE were measured in the cord blood samples of 108 infants collected in Cheil Womans Hospital, Seoul, Korea, in 2007. Of 108 pregnant woman reported, the average age was 31.9 ± 3.54 yr (range 20–42 yr). The mean body weight of the infants was 3.15 ± 0.57 kg (1.89–4.43 kg), and no birth defects were documented. The concentrations of the total PBDEs (7 congeners) found in the umbilical cord blood averaged 8.377 ± 6.381 ng/g lipid, ranging from not determined (ND) to 29.407 ng/g lipid. Of the seven congeners detected, BDE-47 (4.571 ± 2.903 ng/g lipid) accounted for the majority (38% of total PBDE) of total PBDE, followed in descending order by BDE-153 (3.080 ± 2.231 ng/g lipid) and BDE-183 (2.933 ± 2.386). There was no apparent correlation between the serum PBDE levels and thyroid hormone concentrations. Similarly, there was no apparent relationship between the infant thyroxine (T4) levels and four prevalent PBDE congener concentrations. Data suggest that the concentration of PBDE in umbilical cord blood of Korean infants is similar to or lower than concentrations reported from North America. In addition, PBDE readily crossed the blood placenta barrier. Therefore, further study on the relationship between the maternal and fetal blood concentrations of PBDE is recommended for a more comprehensive exposure assessment of PBDE in Koreans.

Time-Response Effects of Testicular Gene Expression Profiles in Sprague-Dawley Male Rats Treated with Di(n-Butyl) Phthalate

Phthalate esters were reported to damage fetal and postnatal testes of experimental animals, but the molecular mechanisms underlying these effects remain unknown. The time-response effects of di(n-butyl) phthalate (DBP) on the expression patterns of the testicular genes in male Sprague-Dawley rats were examined for different periods of exposure (1, 7, 14, or 28 d). The steroidogenic- or spermatogenic-related gene expression patterns were measured using reverse-transcription polymerase chain reaction (RT-PCR). After 28 d of exposure, the serum concentrations of DBP and monobutyl phthalate (MBP) increased in a dose-dependent manner, and were significantly higher in the DBP-treated rats than in the control rats. Liver weight was increased markedly at 28 d after DBP exposure at 750 mg/kg/d. Testicular weight was reduced significantly after 14 and 28 d of exposure. DBP (750 mg/kg/d) produced a significant increase in scavenger receptor class B1 (SR-B1) and steroidogenic acute regulatory (StAR) mRNA after 14 and 28 d of exposure. The level of cytochrome P-450 (P450) side-chain cleavage (P450scc) mRNA decreased in the group treated with DBP at 750 mg/kg/d at 7 d. After 14 and 28 d of exposure, there was an apparent increase in P450scc mRNA. High doses of DBP significantly increased the Cyp17 mRNA level after 28 d of exposure. At 7 d, a significant decrease in Cyp19 mRNA was observed only in the group exposed to 750 mg/kg/d DBP. In addition, DBP significantly decreased the levels of a spermatid-specific gene (Spag4) and lactate dehydrogenase A (LDHA) mRNA after 7 d of exposure. The levels of androgen receptor (AR), estrogen receptor-alpha (ER-alpha), and retinoid X receptor-gamma (RXR-r) expression decreased significantly in a time- or dose-dependent manner. DBP significantly increased the peroxisome proliferator-activated receptor-gamma (PPAR-r) and phosphorylated extracellular-signal-regulated kinase (p-ERK1/2) levels in the testis. These results suggest that the acute and chronic effects of DBP on the steroidogenic pathways in the testes show mechanistically distinct patterns. Data thus provide some insights into the molecular mechanisms underlying DBP-induced testicular dysgenesis.

Functional role of phospholipase D (PLD) in di(2-ethylhexyl) phthalate-induced hepatotoxicity in Sprague-Dawley rats.

Phospholipase D (PLD) is an enzyme that catalyzes the hydrolysis of phosphatidyl choline (PC) to generate phosphatidic acid (PA) and choline. PLD is believed to play an important role in cell proliferation, survival signaling, cell transformation, and tumor progression. However, it remains to be determined whether enhanced expression of PLD in liver is sufficient to induce hepatotoxicity. The aim of this study was to investigate the possible role of PLD in di(2-ethylhexyl) phthalate (DEHP)-induced hepatotoxicity in Sprague-Dawley rats. The phthalate, DEHP (500 mg/kg/d), was administered orally, daily to prepubertal rats (4 wk of age, weighing approximately 70-90 g) for 1, 7, or 28 d. In this study, protein expression levels of PLD1/2, peroxisome proliferator-activated receptor (PPAR), and cytochrome P-450 (CYP) were determined by Western blot analysis using specific antibodies. Liver weight was significantly increased in the DEHP treatment groups. Immunohistochemical analysis demonstrated that DEHP produced strong staining of proliferating cell nuclear antigen (PCNA) at 28 d of exposure, suggestive of hepatocyte proliferation. A significant rise in PLD1/2 expression was observed in liver of DEHP-exposed rats after 7 d. Further, PPARα, constitutive androstane receptor (CAR), pregnane X receptor (PXR), and CYP2B1 protein expression levels were markedly elevated in DEHP-treated groups. Our results suggest that DEHP significantly enhanced the expression of PLD, which may be correlated with PPARα-induced hepatotoxicity through a complex interaction with nuclear receptors including CAR and PXR.

Alterations of di( n -butyl)phthalate-induced oxidative stress in the testis of hypothyroid rats

The aim of the present study was to investigate the effects of di(n-butyl)phthalate (DBP) on oxidative damage in the testes of hypothyroid rats. Hypothyroidism was induced by administering 0.1% 6-N-propyl-2-thiouracil (PTU) in drinking water for 30 days. DBP was dissolved in corn oil and administered daily for 30 days by oral gavage. Significant decreases in testes weight were observed both in normal (DBP) and hypothyroid (PTU + DBP) groups. Serum testosterone concentrations were significantly reduced in the DBP groups, but no significant change occurred in hypothyroid rats. Di(n-butyl)phthalate significantly increased malondialdehyde (MDA) and 8-hydroxy-2-deoxyguanosine (8-OHdG) level in the testes, whereas the DBP-induced oxidative lipid (MDA) and DNA (8-OHdG) damage were less in hypothyroid rats. PTU-induced hypothyroid rats decreased testicular catalase activity, whereas superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities did not show any significant changes. However, the DBP and PTU + DBP groups significantly increased catalase and SOD activities in testis. The testicular expression of thyroid hormone receptor α-1 (TRα-1) was significantly increased in the DBP and PTU + DBP groups. In contrast, androgen receptor (AR) protein levels were not detected in the DBP and PTU + DBP groups. Di(n-butyl)phthalate significantly increased the peroxisome proliferator-activated receptor-r (PPAR-r) and retinoid X receptor-α (RXR-α) levels. Peroxisome proliferators activated-receptors-α and RXR-r protein levels were markedly decreased in the DBP groups, but these protein levels increased in the PTU + DBP group, as compared to DBP alone. These results suggest that PTU-induced hypothyroidism may protect against oxidative damage in the testis, probably due to the regulation of the PPAR and RXR expression, which is associated with decreased metabolic activation of DBP.