Synergistic effect of 2,2',4,4',5,5'-hexachlorobiphenyl and 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic porphyrin levels in the rat.

We studied the effect of polychlorinated biphenyls (PCBs) on hepatic porphyrin accumulation in female Sprague-Dawley rats by feeding them diets containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), or combinations of the single PCB congeners with TCDD for 13 weeks. A dose-dependent increase in hepatic porphyrin accumulation occurred after TCDD, PCB 126, or PCB 156 administration, reaching maximal levels of about twice control values. The lowest dose levels for which a significant increase in hepatic porphyrin accumulation was found were 0.7 microgram TCDD/kg diet, 50 micrograms PCB 126/kg diet, or 6 mg PCB 156/kg diet. These doses are equivalent to 47 ng TCDD/kg/day, 3.2 micrograms PCB 126/kg/day, and 365 micrograms PCB 156/kg/day. Relative potencies for hepatic porphyrin accumulation, using TCDD as a reference, ranged from 0.015 to 0.06 for PCB 126 and from 0.0001 to 0.0003 for PCB 156. CYP1A2 activities significantly correlated with hepatic porphyrin levels, with coefficients of 0.629, 0.483, or 0.808 for TCDD, PCB 126, or PCB 156, respectively. Administration of PCB 153 alone did not result in hepatic porphyrin accumulation. Co-administration of PCB 153 and TCDD revealed a strong synergistic effect on porphyrin accumulation (about 800 times control levels). This synergistic effect was significant in rats fed diets containing any combination of PCB 153 with TCDD. Uroporphyrin III and heptacarboxylic porphyrin were accumulated in porphyrinogenic livers. These results suggest that TCDD induction of CYP1A2 may be involved, leading to oxidation of uroporphyrinogen III to uroporphyrin III, in combination with an increase in delta-aminolevulinic acid synthetase induced by PCB 153. Under porphyrinogenic conditions, an inhibitor of CYP1A2 activity may also be formed. The interactive effects on porphyrin accumulation after co-administration of dioxinlike and non-dioxinlike compounds may have significant implications for the risk assessment of these chemicals.     

Quantifying maternal and dietary sources of 2,2',4,4',5,5'-hexachlorobiphenyl deposited in eggs of the ring dove (Streptopelia risoria)

The influence of maternal versus dietary sources of polychlorinated biphenyls (PCBs) deposited to eggs of ring doves (Streptopelia risoria) was investigated. Mature birds that lay a clutch of two eggs every 12 to 15 d were fed a diet of pellets spiked with 2,2',4,4',5,5'-hexacholorobiphenyl (unlabelled isotope designated as [12C]PCB153) for 25 d. The birds were subsequently switched to a diet containing isotopically labeled [U-13C12]PCB153 at similar concentrations for an additional 63 d. The toxicokinetics of [12C]PCB153 and [13C]PCB153 were followed in egg and carcass samples with time. Isotopic ratios of PCB153 in yolk lipids were identical to those in carcass lipids after introduction of diet 2, and they did not resemble those of the food at the time of egg formation. The data indicate that the PCB composition of eggs directly reflects the composition of maternal tissues, not the diet, at the time of yolk formation. Egg yolk:carcass lipid concentration ratios for the two isotopes were significantly less than one, averaging 0.33+/-0.02 (mean +/- standard error). Lipid normalized egg:maternal tissue contaminant concentration ratios for persistent organochlorine chemicals in the literature were reviewed for other avian species. The results provide a preliminary data set that suggests egg:maternal tissue contaminant concentration ratios vary among species, particularly among species that invest different quantities of lipids to a clutch of eggs. The results support the hypothesis that dilution of contaminants in egg lipids relative to maternal lipids is related to the reproductive strategy employed by the species.     

大鼠新生期暴露2,2',4,4',5,5'-六氯联苯对精子发生的影响

目的 探讨新生期SD大鼠暴露持续性有机污染物2,2',4,4',5,5'-六氯联苯(PCB153)对大鼠精子发生的远期效应.方法 大鼠出生当天(postnatal day O,PNDO),将所有雄性大鼠混合后,重新分为12只,窝.在出生1 d(PND1),按窝别随机分成对照组和处理组,每组24只雄性大鼠.自PND1开始连续7 d经口给予PCB153 0.025、0.250、2.500 mg/kg和等量溶剂对照玉米油.在PND8,每组随机选择16只大鼠称重和测肛殖距离后,经乙醚麻醉并处死,分离和称重睾丸后作组织学检查.剩余大鼠在PND21断奶并饲养至PND90,称重和测肛殖距离后经质量分数为10%的水合氯醛麻醉后解剖,分离并称重睾丸和附睾,其中睾丸用作组织学检查和精子头计数,附睾尾作精子计数.结果 从PND3至PND8,2.500 mg/kg剂量组体重与对照组相比明显下降,差异有统计学意义(P<0.05);在光学显微镜和电子显微镜下观察显示,PND8睾丸组织曲精小管结构疏松,精原细胞体积增大、变性并与管内结构相脱离.随着染毒剂量的增加,PND90睾丸每日精子生成量和附睾尾精子计数与染毒剂量呈剂量-反应关系(r值分别为-0.97和-0.99,P<0.05).0.250和2.500mg/kg剂量组的每日精子生成量分别为30x106/g睾丸和18×106/g睾丸,与对照组(36×106/g睾丸)相比,差异有统计学意义(P<0.05);0.250和2.500 mg/kg剂量组附睾尾精子计数分别为42×107/g附睾尾和18x107/g附睾尾,明显低于对照组(51×107/g附睾尾),差异均有统计学意义(P<0.05).结论 SD大鼠新生期暴露PCB153,可引起成年期睾丸生精功能障碍,导致每日精子生成量和附睾尾精子计数下降.新生期化学物暴露可能引起雄性大鼠生殖功能的远期损害.     

Serum levels of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) in relation to markers of reproductive function in young males from the general Swedish population

A time-related deterioration in male reproductive function caused by exposure to endocrine disrupters, including persistent organochlorines (POCs), has been hypothesized. In animal studies, POCs were found to have adverse effects on male reproductive function. However, little is known about the impact of POC exposure on reproductive parameters in men. In a study of 305 young Swedish men 18-21 years old from the general population, we correlated lipid-adjusted serum levels of 2,2',4,4',5,5' -hexachlorobiphenyl (CB-153)--an index substance for POC exposure--to markers of male reproductive function: testis size assessed by ultrasound, sperm concentration, total sperm count, sperm motility assessed manually and with a computer-aided sperm analyzer (CASA), and serum levels of follicle-stimulating hormone, inhibin B, testosterone, sexual hormone-binding globulin (SHBG), luteinizing hormone, and estradiol. We found weak but statistically significant, negative correlations between CB-153 levels and both the testosterone:SHBG ratio (r = -0.25, p < 0.001)--a measure of the biologically active free testosterone fraction--and CASA sperm motility (r = -0.13, p = 0.02). No statistically significant association with other seminal, hormonal, or clinical markers of male reproductive function was found. In previous studies of more highly POC-exposed groups of adult men, the correlation between POC exposure, including CB-153, and free testosterone levels was not statistically significant. The present study gives some tentative support for weak negative effects of CB-153 exposure on sperm motility and free testosterone levels in young men, but further semen studies on more highly exposed groups may give more firm conclusions on the hazard for male reproductive function from dietary POC exposure.     

Dose-dependent enantiomeric enrichment of 2,2',3,3',6,6'-hexachlorobiphenyl in female mice

Nineteen of the 209 possible polychlorinated biphenyl (PCB) congeners are chiral and stable to racemization at ambient temperature. Chiral PCB congeners are important components of technical and environmental PCB mixtures, and some are highly toxic. Both environmental and laboratory studies have shown that these chiral PCB congeners undergo enantiomeric enrichment in many species; however, the processes and factors influencing the extent of this enantiomeric enrichment are poorly understood. We hypothesized that the exposure levels are an important factor affecting the extent of enantiomeric enrichment. To test this hypothesis, we investigated the levels and enantiomeric fractions of (+/-)-PCB 136 in selected tissues, feces, and urine of female C57Bl/6 mice 3 d after oral administration of 2.5, 10, or 50 mg/kg body weight of (+/-)-PCB 136. The PCB 136 tissue levels typically increased with increasing dose. The extent of the enrichment of (+)-PCB 136 in tissues and feces, however, decreased with increasing dose, an observation that suggests a saturation of the disposition process responsible for the enantiomeric enrichment. Overall, the present study demonstrates that in addition to species, exposure source, exposure frequency, and other factors, levels of PCB exposure are an important determinant of the enantiomeric enrichment of PCBs in mice and, most likely, other species.     

Toxicokinetics of 2,2',4,4'- and 3,3',4,4'-tetrachlorobiphenyl congeners in the house cricket.

Recently, investigators have reported bioaccumulation of polychlorinated biphenyls (PCBs) in insects collected at hazardous waste sites. Little is known about differences in bioaccumulation of particular PCB congeners in insects. The authors report on the toxicokinetics of a non-coplanar ortho substituted congener, 2,2',4,4'-tetrachlorobiphenyl (PCB-47) and a coplanar non-ortho substituted PCB, 3,3',4,4'-tetrachlorobiphenyl (PCB-77) in topically treated house crickets. Penetration and excretion were more rapid for PCB-47 than for PCB-77. PCB-47 demonstrated a high affinity for abdomen, gut, and gonads, whereas, PCB-77 had a greater affinity for the head and thorax. Sex differences were observed in excretion and distribution. Females had an increased excretion of PCBs and increased accumulation in gut and gonads compared to males. Differences in lipophilicity can explain differences in distribution between sexes and of compounds within sexes. However, to explain the observed difference in penetration, it is necessary to invoke explanations based on stearic factors associated with coplanarity of the molecules. Differences in excretion are likely related to sex differences in mixed-function oxidase activities. These toxicokinetic data suggest that the more toxic coplanar congener, PCB-77, is likely to be more persistent in crickets compared to PCB-47, despite its lower lipophilicity.     

Hepatic enzyme induction and acute endocrine effects of 2,2',3,3',4,6'-hexachlorobiphenyl and 2,2',3,4',5',6-hexachlorobiphenyl in prepubertal female rats

Polychlorinated biphenyls (PCBs) with the liable 2,3,6-substitution are important components of certain commercial mixtures and frequently detected in biota, but little is known about their enzyme induction abilities and possible endocrine-disrupting effects. CB 132 (2,2′,3,3′,4,6′-hexachlorophenyl) and CB 149 (2,2′3,4′,5′,6-hexachlorophenyl) were investigated in weanling female rats dosed intraperitoneally on days 21 and 22 and killed on day 24 of age. Uterotropic response, serum thyroid hormone, and hepatic enzyme induction were examined in prepubertal female rats treated with these two environmentally relevant 2,3,6-substituted chlorobiphenyl (CB) congeners from 8 mg/kg to 96 mg/kg. The readily metabolized CB 132 did not cause any significant increase in all endpoints measured in the present study. On the other hand, CB 149 was a weak PROD and BROD inducer and a modest depleter of serum thyroxine in prepubertal female rats. The finding of thyroid hormone disruption by CB 149 may lead to biologically significant neurobehavioral and neurochemical changes in developing animals via milk lactation. Received: 2 January 2001/Accepted: 3 April 2001     

Association of maternal serum concentrations of 2,2', 4,4'5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) levels with birth weight, gestational age and preterm births in Inuit and European populations

Background

Epidemiological studies on the association between maternal exposure to persistent organic pollutants (POPs) and fetal growth alteration report inconsistent findings which weights in favor of additional studies.

Methods

Blood samples were collected from interviewed pregnant women in Greenland (572), Kharkiv (611) and Warsaw (258) and were analyzed for CB-153 and p,p'-DDE by gas chromatography-mass spectrometry. Data on birth weight, gestational age and preterm birth were obtained for 1322 singleton live births. We examined the association between natural log-transformed serum POPs concentration and birth weight and gestational age using multiple linear regression and the association with prematurity using logistic regression controlling for potential confounding factors.

Results

The median serum concentrations of CB-153 and p,p'-DDE were for Inuit mothers 105.6 and 298.9, for Kharkiv mothers 27.0 and 645.4 and for Warsaw mothers 10.7 and 365.2 ng/g lipids, respectively. Increase in CB-153 concentration by one unit on the log scale in Inuit mothers serum was associated with significant decrease in infant birth weight of -59 g and gestational age by -0.2 week. Decreases observed in the cohorts in Kharkiv (-10 g and -0.1 week) and in Warsaw (-49 g and -0.2 week) were not statistically significant. Increase in p,p'-DDE concentration by one unit on the log scale was associated with a statistically significant decrease in infant birth weight of -39.4 g and -104.3 g and shortening of gestational age of -0.2 week and -0.6 week in the Inuit and Warsaw cohorts, respectively. In the Kharkiv cohort decrease in birth weight (-30.5 g) was not significant, however a shortening of gestational age of -0.2 week per increase in p,p'-DDE concentration by one unit on the log scale was of the borderline significance. There was no significant association between CB-153 and p,p'-DDE concentrations and risk of preterm birth however, in all cohorts the odds ratio was above 1.

Conclusions

In utero exposure to POPs may reduce birth weight and gestational age of newborns however, new insights as to why results vary across studies were not apparent.     

Inter-population variations in concentrations, determinants of and correlations between 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE): a cross-sectional study of 3161 men and women from Inuit and European populations

Background

The study is part of a collaborative project (Inuendo), aiming to assess the impact of dietary persistent organochlorine pollutants (POPs) on human fertility. The aims with the present study are to analyze inter-population variations in serum concentrations of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE), to assess inter-population variations in biomarker correlations, and to evaluate the relative impact of different determinants for the inter-individual variations in POP-biomarkers.

Method

In study populations of 3161 adults, comprising Greenlandic Inuits, Swedish fishermen and their wives, and inhabitants from Warsaw, Poland and Kharkiv, Ukraine, serum concentrations of CB-153 and p,p'-DDE, were analysed by gas chromatography-mass spectrometry.

Results

The median serum concentrations of CB-153 were for male and female Inuits 200 and 110, for Swedish fishermen 190 and their wives 84, for Kharkiv men and women 44 and 27, and for Warsaw men and women 17 and 11 ng/g lipids, respectively. The median serum concentrations of p,p'-DDE were for Kharkiv men and women 930 and 650, for male and female Inuits 560 and 300, for Warsaw men and women 530 and 380, and for Swedish fishermen 240 and their wives 140 ng/g lipids, respectively. The correlation coefficients between CB-153 and p,p'-DDE varied between 0.19 and 0.92, with the highest correlation among Inuits and the lowest among men from Warsaw. Men had averagely higher serum concentrations of CB-153 and p,p'-DDE, and there were positive associations between age and the POP-biomarkers, whereas the associations with BMI and smoking were inconsistent. Dietary seafood was of importance only in the Inuit and Swedish populations.

Conclusion

CB-153 concentrations were much higher in Inuits and Swedish fishermen's populations than in the populations from Eastern Europe, whereas the pattern was different for p,p'-DDE showing highest concentrations in the Kharkiv population. The correlations between the POP-biomarkers varied considerably between the populations, underlining that exposure sources differ and that the choice of representative biomarkers of overall POP exposure has to be based on an analysis of the specific exposure situation for each population. Age and gender were consistent determinants of serum POPs; seafood was of importance only in the Inuit and Swedish populations.     

Toxicity and tissue distribution of 2,2',4,4'- and 3,3',4, 4'-tetrachlorobiphenyls in houseflies

Insects selectively retain different polychlorinated biphenyls (PCBs) which are then contributed to the food chain. To quantitate specific differences, adult female houseflies (Musca domestica L.) were topically dosed with 0.5 microgram of two structurally distinct PCB congeners (14C-2,2',4,4'-tetraCB or 14C-3,3',4,4'-tetraCB). Total radioactivity in the acetone rinse of intact flies, several tissues, and excrement was determined at 11 time points over a 48-h period. Ninety-seven percent of the applied 2,2',4,4'-tetraCB disappeared from the surface following an initial rapid absorption of 79% within 3 h. The absorbed 2,2',4,4'-tetraCB was immediately found within the thoracic cuticle, then spreading laterally to the abdominal cuticle and head, through the wax layers, or penetrating to the alimentary canal and ovaries. Penetration of 3,3',4, 4'-tetraCB was markedly slower; even though 87% of the applied dose was absorbed within 48 h, only 19% of the dose penetrated into the fly body within the first 3 h. This PCB very slowly distributed into the tissues. Toxicities of the sublethal doses were determined by monitoring changes in activity of houseflies following dosing with 0. 5 microg of radioactive PCBs. Flies treated with 2,2',5-triCB and 3, 3',4,4'-tetraCB remained very active, whereas 2,2',4, 4'-tetraCB-treated flies were less active, consistent with the previously reported toxicity of this congener.     

次声对豚鼠凝血功能的影响

目的 研究16 Hz、120 dB,16 Hz、125 dB次声暴露后豚鼠凝血功能的变化规律,探讨次声造成生物体循环系统损害的机制.方法 将豚鼠分为对照组及16 Hz、120 dB,16 Hz、125 dB 2个暴露组,每个暴露组均按暴露时间再分成1、7、14、21 d 4个时间亚组,每个亚组8只豚鼠.各个暴露亚组每日暴露1.5 h,分别连续暴露相应的天数后抽取血样测定凝血功能相关指标及血清中一氧化氮(NO)含量.结果 16 Hz、125 dB组凝血酶原时间(PT)、国际标准化比率(INR)分别为(31.16±3.05)s和2.53±1.21,较对照组[(21.36±0.10)s、1.65±0.07]明显延长,差异有统计学意义(P＜0.05);血清中NO含量[(88.304±52.601)μmol/L]较对照组[(30.943±26.864)μmol/L]明显升高,差异有统计学意义(P＜0.05).16 Hz、125 dB组暴露14 d时PT和INR较对照组明显延长,并持续至第21天.16 Hz、125 dB组暴露7 d时血清中NO含量较对照组明显升高,且第14天继续升高,差异均有统计学意义(P＜0.05),21天时有下降趋势.结论 16 Hz、125 dB次声暴露后豚鼠凝血功能减退,INR及PT可做为评价次声对凝血功能影响的指标.

Abstract：

Objective To study the change of the blood coagulation function of guinea pigs exposed to 16 Hz/120 dB, 16 Hz/125 dB infrasound and to explore the mechanism of circulation system damage.Methods Seventy-two guinea pigs were divided into 3 groups: the control group, the group exposed to 16 Hz/120 dB infrasound for 1.5 h a day and the group exposed to 16 Hz/125 dB infrasound for 1.5 h a day. Each exposure group was divided into 4 sub-groups (8 guinea pigs a sub-group) which were exposed to infrasound for 1, 7, 14 and 21 d, respectively. The coagulation function and serum nitric oxide (NO) were measured for control group and all sub-groups after exposure to infrasound. Results The prothrombin time (PT),international normalized ratio (INR) and serum NO of group exposed to 16 Hz/125 dB infrasound were (31.16±3.05) s, 2.53±1.21 and (88.304±52.601)μmol/L, respectively, which were significantly higher than those [(21.36±0.10) s, 1.65±0.07 and (30.943±26.864) μ mol[L] of control group (P＜0.05). PT and INR of sub-groups exposed to 16 Hz/125 dB infrasound for 14 and 21 d were significantly higher than those of control group. NO of sub-groups exposed to 16 Hz/125 dB infrasound for 1 week and 2 weeks were significantly higher than that of control group (P＜0.05), but NO of sub-group exposed to 16 Hz/125 dB infrasound for 3 weeks decreased slightly. Conclusion The blood coagulation function of guinea pigs exposed to 16 Hz/125 dB infrasound decreased, PT and INR may be used as the indexes to assess of blood coagulation function change induced by the infrasound exposure.     

Effects of 2,2',5,5'-tetrachlorobiphenyl (PCB52) on migration of chicken primordial germ cells

Polychlorinated biphenyls cause developmental and physiological anomalies in the reproductive system. This study investigated the effects of 2,22,5,52-tetrachlorobiphenyl (PCB52), which can produce oestrogenic effects on the homeostasis of chicken primordial germ cells from the initial stage until completion of their settlement in the gonadal primordium. The blastoderm of chicken embryos was injected with 1 (1/4)L PCB52 (10 micromol/L) and oestradiol (100 micromol/L) before incubation, and the number of primordial germ cells was determined during their migration and development. The number of primordial germ cells in germinal crescents in PCB52-treated groups was slightly decreased (P = 0.068), but it was reduced significantly at stages 13-15 and 28-30 (P < 0.01, respectively) compared with controls. No obvious effects on primordial germ cell migration were observed with oestradiol treatments. The present results suggest that the influence of PCB52 on chicken primordial germ cell migration and proliferation may be via its toxic effect, not its oestrogen-mimicking effect, and provide information on the sensitivity of primordial germ cells to the direct action of PCB52.     

The effect of litter size on placental blood flow and placental calcium transfer in the multifoetate guinea-pig

1. Placental blood flow rate and calcium transfer rate were measured at 61 d of pregnancy in guinea-pigs carrying between one and eight foetuses. 2. Placental blood flow rate was significantly correlated with foetal weight. Ca transfer rate was related to placental size. Irrespective of litter size the mean amount of Ca transferred across a placenta was between 0.22 and 0.34 mg/h per g placental tissue. 3. It was concluded that there was a limit to the rate of transfer which was produced by a combination of limitations in placental blood flow rate, maternal plasma Ca concentration and placental tissue transfer capacity.