Effects of PCB 126 on primary immune organ development in chicken embryos

This experiment evaluated the immunotoxic effects of developmental exposure to a planar polychlorinated biphenyl (3,3',4,4',5-pentachlorobiphenyl; PCB 126) in chicken embryos. Previous investigations on the immunotoxic effects of PCBs and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in developing avian embryos were undertaken with embryos exposed only during the latter stages of incubation. To simulate exposure in embryos in the wild, chicken eggs were injected with PCB 126 (sunflower oil carrier) into the air cell before initiation of incubation. It was hypothesized that exposure to PCB 126 during the complete incubation period would decrease immune organ masses and lymphocyte numbers. Doses of PCB 126 ranged from 0.051 to 0.80 ng/g egg. Control groups consisted of carrier-injected and noninjected eggs. The thymus and bursa of Fabricius were removed and weighed on d 20 of incubation (1 d before hatch). The immune organs were homogenized, and viable lymphoid cells were counted using the trypan blue exclusion method. Probit analysis estimated the LD20 to be 0.21 ng/g and the LD50 to be 1.01 ng/g. Thymus mass dropped sharply between 0.13 and 0.32 ng/g, and lymphoid cell numbers in the thymus fell sharply between 0.051 and 0.13 ng/g. Bursa mass began to decrease at the lowest dose of 0.051 ng/g and reached a minimum at 0.32 ng/g. The number of viable cells decreased slightly at 0.051 ng/g and reached a minimum at the 0.13- and 0.32-ng/g doses. In general, lymphoid cell numbers were more sensitive to PCB 126 than organ masses, and the bursa tended to be more sensitive than the thymus. Doses necessary to reduce the number of viable lymphoid cells in the thymus and bursa were at least one order of magnitude lower with full-term incubation as compared to exposure only during later stages of incubation.     

Effects of PCB 126 on thymocyte surface marker expression and immune organ development in chicken embryos

Previous studies have shown that chicken (Gallus domesticus) embryos are sensitive to the immunotoxic effects of Ah receptor agonists. These chemicals cause atrophy of the thymus gland and bursa of Fabricius, the sites of T- and B-lymphocyte maturation, respectively. The objectives of this study were (1) to evaluate the effects of 3,3,4,4',5-pentachlorobiphenyl (PCB 126) on thymocyte phenotypes (CD4-CD8-, CD4+CD8+, CD4+CD8-, CD4-CD8+, TCRalphabeta+, and TCRgammadelta) in chicken embryos, and (2) to compare phenotype alterations with masses and cellularity of lymphoid organs. To simulate exposure in wild avian embryos, chicken eggs were injected with PCB 126 (sunflower oil carrier) into the air cell before incubation. Doses ranged from 0.051 to 0.8 ng/g egg with carrier-injected and noninjected control groups. The thymus and bursa were removed, weighed, and homogenized on d 20 of egg incubation (1 d before hatch). Thymocyte phenotypes were quantified by flow cytometry using monoclonal antibodies for CD4, CD8, TCRalphabeta (Vbeta1), and TCRgammadelta. Right thymus mass declined with dose, decreasing significantly between 0.32 and 0.8 ng/g to a size 28% lower than controls. Live lymphoid cell numbers in the right thymus dropped markedly (21% lower than controls) between 0.051 and 0.13 ng/g, with a further decrease (35% lower than controls) at higher doses. There was no significant change in the percentage of thymocytes expressing TCRalphabeta. The total number of TCRalphabeta+ thymocytes decreased with dose as a function of the declines in TCRalphabeta+ percentages and total thymocyte numbers. The percentages of all other measured phenotypes were unaltered by PCB 126. The total number of CD4+CD8+ cells, and to a lesser degree CD4-CD8+ cells, decreased in a dose-dependent manner following the pattern of total live thymocytes. The number of viable lymphoid cells in the bursa decreased to 45% lower than controls at 0.13 ng/g and fell to 76% lower than controls at 0.8 ng/g. Lymphoid atrophy occurred at doses that were 8- to 12-fold lower with full-term incubation as compared to exposure only during later stages of incubation, and the lymphoid atrophy was associated with decreased TCRalphabeta+ thymocytes at higher doses. These immunological effects were observed at concentrations of PCB 126 comparable to those found in Great Lakes herring gull eggs, after correcting for interspecies differences in sensitivity to PCB 126.     

Effects of furazolidone, PCB77, PCB126, Aroclor 1248, paraquat and p,p'-DDE on transketolase activity in embryonal chicken brain

The effect of in ovo exposure to PCBs, DDE and paraquat on transketolase activity was measured in 19-day-old chicken embryos. Furazolidone was used as a positive control for decreased activity of the enzyme. The potency of contaminants to interact with transketolase was also tested in an in vitro system, using control brain 7000xg supernatants containing the enzyme. No effects were found on transketolase activity after in ovo or in vitro exposure to PCB126, Aroclor, DDE or paraquat. PCB77 decreased transketolase activity in vitro, but only at concentrations that, extrapolated to in ovo exposure, would be lethal to the embryo. Furazolidone decreased transketolase activity both in ovo and in vitro. For this contaminant, thiamine residues were analysed in the yolk sacs, but no differences were found between exposed and non-exposed eggs. Transketolase is dependent on thiamine pyrophosphate as a cofactor, and therefore, the decreased enzyme activity could be the result of an interaction between furazolidone and thiamine metabolism. Since thiamine residues were not affected by furazolidone and transketolase inhibition in vitro was similar to the inhibition after in ovo exposure, it was concluded that furazolidone interacted with transketolase on the enzymatic level rather than by a depletion of thiamine.     

Effects of perinatal exposure to low doses of PCB 153 and PCB 126 on lymphocyte proliferation and hematology in goat kids

Pregnant does (10 goats/group) were dosed orally with either PCB 153 or PCB 126 dissolved in corn oil or only corn oil (control group) from day 60 of gestation until delivery. Effects on in vitro mitogen-induced lymphocyte proliferation and blood cell counts in their goat kids exposed to low levels of PCB 153 and PCB 126 during gestation and lactation were assessed. The concentrations of PCB 153 and PCB 126 in adipose tissue in the goat kids 9 mo postpartum were 5800 ng/g (fat weight) and 0.49 ng/g (fat weight), respectively. Kids exposed to PCB 153 had a significantly higher number of white blood cells, neutrophils, and lymphocytes at 2 wk of age compared to controls. In the kids exposed to PCB 126 there was a significantly lower concentration of monocytes at 2, 4, and 8 wk of age. The mean lymphocyte response to phytohemagglutinin (PHA) and to concanavalin A (Con A) was significant lower in the PCB 153 compared to the control group at wk 2, 4, and 8 postnatally. The results of the present study support previous reports on immunotoxic effects of PCB exposure in animals. However, this is the first report to demonstrate immunotoxicity in animals by using low doses of PCB 153. The difference in results between PCB 126 and PCB 153 treatment groups may strengthen the hypothesis that PCBs mediate immunotoxic effects through both AhR-dependent and -independent mechanisms.     

Effects of sea water pollution on chicken embryos.

Organic matter and heavy metal contamination in sea water obstruct vital functions of chicken embryos and interrupt their growth. Histological examination of contaminated fetuses showed a menacing growth of abnormal protuberances in the lungs as well as highly impeded formation of capillaries, although the windpipes exhibited normal expansion. Compared with controls, liver tissue also showed retarded growth accompanied by decrease in liver weight. Consequently, vital metabolic functions were impaired, hydropsy and evisceration developed, and fetuses were deformed.     

In vivo and in vitro effects of PCB126 and PCB153 on rat testicular androgenesis

In this study we compared the effects of PCB126 and PCB153 on adult rat testicular androgenesis and the status of antioxidant enzymes in the interstitial cell compartment 96h after local intratesticular application. Obtained results indicated PCB126-induced inhibition of conversion of progesterone (P) and Δ(4)-androstenedione (A(4)) to testosterone (T), and stimulation of conversion of P to T induced by PCB153, while combined application had no effect. Activities of antioxidant enzymes were unchanged, except of decreased activity of SOD in PCB126-treated group. In parallel experiments, adult purified Leydig cells challenged with PCB congeners were incubated for 2h in the presence of corresponding steroid substrates. Results demonstrated that in the presence of subsaturating substrate concentrations PCB126 induced inhibition of conversion of P and A(4) to T at nM to μM doses, while PCB153 caused stimulation at nM concentrations. Further studies should indicate possible mechanism(s) of modulation of androgenesis by tested PCB congeners.     

Effect of PCB 126 and PCB 153 on incidence of apoptosis in cultured theca and granulosa cells collected from small,medium and large preovulatory follicles

The aim of the presented study was to evaluate the effects of PCB 126 and PCB 153 on granulosa and theca cell apoptosis. Granulosa and theca cells were collected from small, medium, and large preovulatory porcine follicles and cultured as monolayers. Cells were initially cultured for 24 h to allow attachment to the plates. Media were changed and 100 pg/ml PCB 126 or 100 ng/ml PCB 153 were added. After 48 h, granulosa and theca cells were fixed for assessment of the number of apoptotic cells utilizing a Hoechst staining technique or frozen for measurement of caspase-3 activity. Media were collected for testosterone concentration analysis from theca cell cultures or estradiol from granulosa cell cultures. Neither PCB 153 nor PCB 126 had an effect on testosterone secretion by theca cells collected from small and medium size follicles, while both PCBs decreased testosterone secretion by large follicles. The decrease in testosterone secretion by large follicles under the influence of both PCBs was paralleled by a suppression of caspase-3 activity and a decreased incidence of apoptotic bodies. Neither of the PCBs had an effect on estradiol secretion by granulosa cells collected from small and medium size follicles, while both PCBs increased estradiol in granulosa cells collected from large follicles. PCB-associated increased estradiol secretion by granulosa cells collected from large follicles was accompanied by suppression of caspase-3 activity and a decreased incidence of apoptotic bodies. In conclusion, we have presented evidence that in preovulatory follicles PCBs inhibit both theca and granulosa cells apoptosis. Therefore, an exposure to PCBs may cause alterations in the pattern of terminal differentiation of follicles and attenuate spontaneous elimination of atretic follicles.     

头孢地秦和阿米卡星治疗肺炎克雷伯氏菌感染对小鼠胸腺细胞凋亡的影响

目的研究肺炎克雷伯氏菌感染及应用头孢地秦、阿米卡星治疗后对NIH小鼠胸腺细胞凋亡的影响。方法给NIH小鼠腹腔注射肺炎克雷伯氏菌悬液,建立肺炎克雷伯氏菌感染模型。TUNEL法染色后用流式细胞仪观察24h内胸腺细胞的凋亡量。腹腔注射不同剂量的头孢地秦和阿米卡星,观察注射后9h胸腺细胞的凋亡量。结果胸腺细胞凋亡在感染后逐渐增高,至24h达高峰(P<0.01)。与感染组相比,头孢地秦5、15mg组的凋亡率分别下降56%、81%,两组比较有显著性差异(P<0.05)。阿米卡星5、15mg组的凋亡率分别下降41%、76%,两组比较也有显著性差异(P<0.05)。结论肺炎克雷伯氏菌感染能引起胸腺细胞发生凋亡,应用头孢地秦和阿米卡星能明显抑制胸腺细胞的凋亡。     

Morphological alterations of Vero cell exposed to coplanar PCB 126 and noncoplanar PCB 153

Polychlorinated biphenyls (PCBs) are widespread, persistent environmental contaminants that display a complex spectrum of toxicological properties. Exposure to PCBs has been associated with morphological anomalies in cell cultures. However, most mechanistic studies of PCBs' toxic activity have been focused on coplanar congeners. It is of importance to determine whether PCB treatment would influence cell configuration and whether these changes would depend on the structural characteristics of PCBs. In this study, we investigated cell morphological alteration in Vero cell cultures after exposure to coplanar PCB 126 and noncoplanar PCB 153. The survival of Vero cells was measured through the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) test. Cytotoxicity results suggested that PCB congeners had a toxic, antiproliferative effect on Vero cells. Morphological studies described structural modifications and provided evidence that apoptosis might be the main cell death pathway in PCB 153‐treated cells. The comparison between PCB 126 and PCB 153 indicated that the cell death mechanisms involved in coplanar or noncoplanar PCB congener exposure were different in Vero cells. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2012.     

Developmental toxicity,EROD, and CYP1A mRNA expression in zebrafish embryos exposed to dioxin‐like PCB126

Dioxin‐like PCB126 is a persistent organic pollutant that causes a range of syndromes including developmental toxicity. Dioxins have a high affinity for aryl hydrocarbon receptor (AhR) and induce cytochrome P4501A (CYP1A). However, the role of CYP1A activity in developmental toxicity is less clear. To better understand dioxin induced developmental toxicity, we exposed zebrafish (Danio rerio) embryos to PCB126 at concentrations of 0, 16, 32, 64, and 128 μg L^?1 from 3‐h post‐fertilization (hpf) to 168 hpf. The embryonic survival rate decreased at 144 and 168 hpf. The fry at 96 hpf displayed gross developmental malformations, including pericardial and yolk sac edema, spinal curvature, abnormal lower jaw growth, and non‐inflated swim bladder. The pericardial and yolk sac edema rate significantly increased and the heart rate declined from 96 hpf compared with the controls. PCB126 did not alter the hatching rate. To elucidate the mechanism of PCB126‐induced developmental toxicity, we conducted ethoxyresorufin‐O‐deethylase (EROD) in vivo assay to determine CYP1A enzyme activity, and real‐time PCR to study the induction of CYP1A mRNA gene expression in embryo/larval zebrafish at 24, 72, 96, and 132 hpf. In vivo EROD activity was induced by PCB126 at 16 μg L^?1 concentration as early as 72 hpf but significant increases were observed only in zebrafish exposed to 64 and 128 μg L^?1 doses (p < 0.005) at 72, 96, and 132 hpf. Induction of CYP1A mRNA expression was significantly upregulated in zebrafish exposed to 32 and 64 μg L^?1 at 24, 72, 96, and 132 hpf. Overall, the severe pericardial and yolk sac edema and reduced heart rate suggest that heart defects are a sensitive endpoint, and the general trend of dose‐dependent increase in EROD activity and induction of CYP1A mRNA gene expression provide evidence that the developmental toxicity of PCB126 to zebrafish embryos is mediated by activation of AhR. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 201–210, 2016.     

Effects of three aziridine alkylating compounds on the gross development of chicken embryos

The effects of apholate, metepa, and tepa on developing chicken embryos were studied after yolk sac injection of saline solutions of these compounds at various dosages. Without regard to day of injection or dose (days 1–4 of incubation), apholate-injected eggs had the highest incidence of cumulative mortality and the lowest mean body weight of day 18 viable embryos, followed by the tepa-injected group, then the metepa-injected group. Cumulative mortality differed significantly between compound-treated groups and controls (p < 0.005), between apholate and metepa groups (p<0.005), between tepa and metepa groups (p<0.005), but not between apholate and tepa groups. Using mortality as an index of toxicity, LD50 values obtained for these compounds in day 4 or day 10 embryos proved apholate to be the most toxic, followed by tepa, then metepa. Significant differences in mean body weights for viable day 18 embryos existed between compound-treated groups and controls (p<0.005), between apholate and metepa groups (p < 0.005), between tepa and metepa groups (p < 0.005), but not between apholate and tepa groups. The incidence of defective embryos, combined on day 18, differed significantly between compound-treated groups and controls (p < 0.005). Within compound-injected groups, significant differences in the combined incidence of defective nonviable and viable embryos existed between apholate and tepa groups (p < 0.05), between metepa and tepa groups (p < 0.05), but not between apholate and metepa groups. For day 18 viable embryos, the incidence of defective embryos differed significantly between apholate and metepa groups (p < 0.025), between metepa and tepa groups (p < 0.005), but not between apholate and tepa groups. The 62.5 μg/egg dose of metepa or tepa had greater teratogenic activity on embryos as evidenced by the incidence of defective embryos produced. All doses of apholate except the 250 μg/egg dose produced about the same incidence of defective embryos. Each aziridine compound induced one or more malformations in chicken embryos that were basically similar and increased the incidence of certain spontaneous defects. Deformities common to compound-treated groups were beak, cranial, ocular, leg, and digit defects. Defects common to both compound-treated and control groups were ectopic viscera, deformed digits, and general edema. This study demonstrates a significant teratogenic effect on chicken embryos by each aziridine compound.     

Effects of Lycii Fructus on primary cultured chicken brain cells

Effects of Lycii Fructus on primary cultured chicken embryonic brain cells were studied by microscopic observation, determination of the activity of pyruvate dehydrogenase complex (PDHC), and syntheses of protein, RNA and DNA. The brain cells were prepared from the brains of 10-day-old chicken embryos and cultured with a deficient medium. The activity of PDHC in the brain cells cultured with a deficient medium was increased to 1.8 times by the addition of 30 μg/ml of the total methanol extract of Lycii Fructus. To seek the active fraction, total methanol extract was further fractionated by the polarity. The survival rate of neuronal cells was significantly increased by the addition of 100 μg/ml of the buthanol or aqueous fraction. At this concentration, the significant increase of the syntheses of protein and RNA, but not of DNA, indicates that the fractions may act on the neuronal cells which are known to be non-dividing cells.     

Perinatal exposure to low doses of PCB 153 and PCB 126 affects maternal and neonatal immunity in goat kids

Pregnant does (10 goats/group) were dosed orally either with polychlorinated biphenyl (PCB) 153 (98 microg/kg body weight/d) or PCB 126 (ng/kg body weight/d) dissolved in corn oil or with corn oil only (control group) from gestation day (GD) 60 until delivery. An additional group (n = 5) of pregnant does received the synthetic estrogen diethylstilbestrol (DES; 0.4 microg/kg body weight/d) by intramuscular injection using the same treatment schedule as for the PCB groups. Blood samples for immune analysis were collected at wk 0, 1, 2, 4, 6, and 8 of age. The effects of perinatal PCB exposure on postnatal humoral immune responses were examined by assessing the levels of total immunoglobulin G (IgG) and immunoglobulins to specific microbes at wk 0, 1, 2, 4, 6, and 8 of age, and immune responses following immunization of kids at 2 wk of age. PCB 153 exposure suppressed maternal and neonatal immunity, as demonstrated by reduced transfer of maternal IgG and specific antibodies to the environmental microbes Arcanobacterium pyogenes, Mannheimia haemolytica, and reovirus (REO-1). Furthermore, PCB 153 reduced the level of maternal antibodies to Mycobacterium avium paratuberculosis and equine influenza virus (EIV-1) in the newborn kids. The antibody response against EIV-1 was significantly higher in PCB 153-exposed kids 2 wk following immunization. PCB 126 exposure reduced the levels of maternal antibodies to REO-1. In contrast, gestational exposure to PCB 126 increased the concentrations of maternal antibodies to tetanus toxoid. No differences from controls in plasma total IgG levels at birth or colostrum IgG concentrations were observed in the PCB 126-treated does. However, a significant reduction in IgG levels from GD 60 until delivery was found in this group. Gestational exposure to DES reduced the concentrations of maternal antibodies against A. pyogenes, M. haemolytica, M. avium Paratuberculosis, and REO-1. These results suggest that perinatal exposure to low doses of PCB 126 and PCB 153 affects the maternal immunity in kids. The difference in responses between PCB 126 and PCB 153 treatment groups may strengthen the hypothesis that PCBs mediate immunotoxic effects through both AhR-dependent and -independent mechanisms. The observation that the effects produced by PCB 153 resembled those produced by DES raises the question of whether this congener may modulate immunity by estrogenic mechanisms.     

全身广谱治疗仪对大鼠免疫器官cAMP和CA含量的影响

为探讨全身广谱治疗仪照射对大鼠免疫器官ｃＡＭＰ和ＣＡ的影响。采用全身广谱治疗仪照射７天后,用ＳＲＢＣＶ免疫Ｗｉｓｔａｒ大鼠。在免疫后４天和７天脾脏,胸腺和下丘脑ｃＡＭＰ含量均降低。而在免疫后４天脾脏去甲肾上腺素、肾上腺素均增高,提示：全身广谱治疗仪照射大鼠,使免疫器官儿茶酚胺释放增加,ｃＡＭＰ代谢降低,可能导致淋巴细胞增殖和免疫功能增强。     

组织蛋白酶B对自发性高血压大鼠胸腺细胞凋亡的影响(英文)

目的:本实验研究自发性高血压大鼠胸腺机能异常的机制。方法:用原位杂交确定蛋白酶B的表达位置,Northern杂交分析组织蛋白酶B的表达水平,用TUNEL和流式细胞仪分别检测胸腺细胞的凋亡情况。结果:在离体和在体水平,胸腺组织蛋白酶B的表达与胸腺细胞凋亡伴行,在胸腺细胞的胞浆中检测到组织蛋白酶B的转录产物在6周和8周的自发性高血压大鼠胸腺中的表达高于WKY大鼠。结论:自发性高血压大鼠的胸腺细胞凋亡增加,与组织蛋白酶B的表达相关。     

Genomic and non-genomic effects of different glucocorticoids on mouse thymocyte apoptosis

Glucocorticoids, widely used therapeutic agents for several pathologies, act upon diverse cells and tissues, including the lympho-haemopoietic system. Glucocorticoid-mediated apoptosis has been described as one of the mechanisms underlying their pharmacological and physiological effects. Glucocorticoids induce apoptosis in thymocytes through genomic and non-genomic signals. We tested thymocyte apoptosis rates as induced by a panel of glucocorticoids. Using four glucocorticoids that are widely adopted in clinical practice we compared their induction of thymocyte apoptosis and activation of non-genomic and genomic signals, including phosphatidylinositol-specific phospholipase C (PI-PLC), caspase-8, -9 and -3, and Glucocorticoid-Induced Leucine Zipper (GILZ). GILZ is a protein that is rapidly induced by glucocorticoids treatment and involved in apoptosis modulation. Results indicate different glucocorticoids have different apoptotic activity which is related to their ability to induce both genomic, evaluated as caspases activation and GILZ expression, and non-genomic effects, evaluated as PI-PLC phosphorylation.     

Involvement of cPLA2 inhibition in dexamethasone-induced thymocyte apoptosis

Various molecular mechanisms have been suggested to be involved in dexamethasone induced thymocyte apoptosis. In this study we show that pharmacological inhibition of cytoplasmic PLA2 in mouse thymocytes for 18 h with arachidonyl trifluoromethyl ketone (AACOCF3) (10 microM) and palmitoyl trifluoromethyl ketone (PACOCF3) (10 microM) induced a drastic increase of thymocyte apoptosis comparable to that observed following Dex (10(-7) M) treatment, while inhibition of secretory PLA2 with p-bromophenacyl bromide (pBPB) (20 microM) did not. AACOCF3-induced thymocyte apoptosis, similarly to Dex-induced thymocyte apoptosis, was eliminated by cell pre-treatment with the PI-PLCbeta inhibitor, U73122, but not by the PC-PLC inhibitor D609. These observations were corroborated by the ability of AACOCF3, like Dex, to induce a rapid and transient increase in DAG generation. In addition, AACOCF3-induced apoptosis involved the activation of the acidic sphingomyelinase (aSMase) but not of the neutral sphingomyelinase (nSMase), as evaluated by measurements of enzyme activity in cell extracts following thymocyte exposure to AACOCF3 and by the ability of monensin to inhibit AACOCF3-induced thymocyte apoptosis. In addition, the AACOCF3 apoptotic effect resulted in an early increase of ceramide levels. AACOCF3-induced thymocyte apoptosis involved the activation of caspase 3, and cell pre-treatment with a caspase 3 inhibitor prevented AACOCF3-induced apoptosis. These observations suggest that cPLA2 inhibition may have a role in Dex-induced thymocyte apoptosis and highlight the importance of cPLA2 activity in thymocyte survival.     

三丁基氯化锡对小鼠胸腺细胞凋亡及其Fas蛋白表达的影响

目的研究三丁基氯化锡(TBTCL)对小鼠胸腺细胞凋亡及Fas蛋白表达的影响,探讨TBTCL的免疫毒性机制。方法ICR种小鼠体重20~25 g,雄、雌各半,共40只,随机分为4组,每组10只,即1个对照组和低、中和高3个组,经口灌胃21 d,流式细胞仪检测胸腺细胞凋亡状况,免疫组化染色,观察Fas蛋白在胸腺的表达。结果低、中和高剂量组,胸腺细胞的早期凋亡率高于对照组P<0.05,且有随剂量增加而升高的趋势,Fas蛋白阳性表达率在染毒组亦强于对照组P<0.05。结论TBTCL可诱导胸腺细胞凋亡,且可导致Fas蛋白表达增强,这可能是其免疫毒性作用机制之一。     

A physiologically based pharmacokinetic model for lactational transfer of PCB 153 with or without PCB 126 in mice

Chemical exposure via breast milk is one of the great concerns in public health. Previously, we demonstrated that most body burden of PCB 153 can be transferred from the mother to the pups in mice during lactational period. Here we present a physiologically based pharmacokinetic (PBPK) model to describe the lactational transfer of PCB 153 with or without PCB 126 in mice. The model incorporated physiological changes on the volume and the blood flow into mammary tissues, and considered mechanistic information on the movement of PCB 153 from adipose tissue to the mammary gland during lactational period. The mechanistic consideration includes fat volume changes, binding of PCB 153 to very low density lipoprotein (VLDL) and increased uptake of VLDL in mammary tissues. Model parameters depicting physiological changes were obtained from research articles dealing with chemical transfer during lactational period in rodents. Chemical-specific parameters were derived from previous PBPK models focusing on the PCB disposition in rodents. The developed model adequately described the lactational transfer of PCB 153 with or without PCB 126 in mice. Our model will provide a useful mechanistic tool to estimate the disposition of PCBs in diverse experimental designs regarding PCB effects during developmental period and to improve quantitative risk assessment of PCBs in the developing organisms.