The Toxicologist - Society of Toxicology

2061 HEPATIC EFFECTS OF VERY LOW TEQ
CONTAMINATED NDL-PCBS 180 AND 52 IN ADULT
SPRAGUE-DAWLEY RATS.
R. Roos 1 , P. Andersson 2 , H. Schmitz 1 , H. M. Miettinen 3 , P. Heikkinen 3 , L. van
der Ven 4 , M. Viluksela 3 and D. Schrenk 1 . 1 University of Kaiserslautern,
Kaiserslautern, Germany, 2 University of Umea, Umea, Sweden, 3 National Public
Health Institute, Kuopio, Finland and 4 National Institute for Public Health and the
Environment (RIVM), Bilthoven, Netherlands.
Non-dioxinlike (NDL-) PCBs represent about 90% of the PCBs found in the environment,
PCBs 180 and 52 being among the most abundant. Hepatotoxicity and
adaptive hepatic effects are considered critical for the risk assessment of NDL-
PCBs. There, the problem of contamination with dioxinlike (DL) compounds is of
major importance since earlier studies found marked hepatic EROD induction
with certain NDL-PCBs in rats. Therefore, rats were treated by gavage over 28 days
with total doses between 0 and 1700 mg/kg b.w. of highly purified PCB 180, containing
2.7 ng TEQ/g, or between 0 and 3000 mg/kg b.w. of highly purified PCB
52, containing 0.5 ng TEQ/g. No increase in serum ALAT activity was found for
both PCBs, while PCB 180 increased liver weight at ≥100 mg/kg b.w. in males and
at ≥1700 mg/kg b.w. in females, PCB 52 in females at 3000 mg/kg b.w.
Furthermore, significant increases in hepatic PROD activity, and CYP2B1, 3A1,
UGT1A1 and 1A6 mRNAs and proteins were found for both PCBs and genders,
the induction being more pronounced for PCB 180, especially in males. EROD induction
was weak with both congeners, which was confirmed by CYP1A1,
CYP1A2 and CYP1B1 mRNA and protein determination. The findings suggest
that PCB 180 and 52 lead to adaptive changes in the liver but do not exhibit overt
hepatotoxicity in rats within 28 days. The pattern of enzyme induction indicates
that the congeners act as CAR/PXR agonists. The very weak effects on CYP1A2
and 1B1 suggest that PCBs 180 and 52 do not exert characteristics of AhR agonists.
The weak effects on EROD activity by PCB 180 could be due to an overlap in catalytic
activity (EROD vs. PROD) since they were found at doses which did not induce
AhR-dependent CYP mRNAs or proteins.
2062 BIOAVAILABILITY NORMALIZED CLEARANCE OF
POLYCHLORINATED BIPHENYL ENANTIOMERS IS
ENANTIOSELECTIVE IN FEMALE C57BL/6 MICE.
I. Kania-Korwel 1 , M. El-Komy 2 , P. Veng-Pedersen 2 and H. Lehmler 1 .
1
Department of Occupational and Environmental Health, University of Iowa, Iowa
City, IA and 2 Division of Pharmaceutics, College of Pharmacy, University of Iowa,
Iowa City, IA.
Several polychlorinated biphenyls (PCB) with three or four ortho chlorine substituents
are chiral. These PCB congeners undergo enantiomeric enrichment in vivo
and enantiospecifically interact with target molecules such as Ryanodine receptors.
The present study investigates the toxicokinetics of PCB enantiomers in female
C57Bl/6 mice after oral administration of a mixture containing racemic PCBs 91,
95, 132, 136, 149, 174, and 176 to test the hypothesis that the enantiomeric enrichment
of PCBs is due to differences in the clearance and half-lives of the respective
enantiomers. On the Chirasil-Dex column, an enrichment of the second eluting
enantiomers was generally observed; however, only the first eluting enantiomers
E1-PCB 95, (-)-PCB 132, and (-)-PCB 149 had half-lives that were distinctively
longer compared to the second eluting enantiomers. The bioavailability normalized
clearance of first eluting enantiomers in blood was faster compared to that of second
eluting enantiomers; whereas, the opposite trend was observed for the accumulation
factors in adipose tissue. This is consistent with the slower clearance of the
first eluting enantiomer. The only exception was PCB 174, which showed no differences
in the toxicokinetic parameters of both enantiomers. The differences in the
toxicokinetic parameters between PCB enantiomers suggest that changes in the
enantiomeric composition of polychlorinated biphenyls may have human health
implications because of their enantiospecific toxicity.
2063 LEVELS OF DIOXINS AND POLYBROMINATED
DIPHENYL ETHERS IN HUMAN MILK IN NORTHERN
CHINA AND THE RELATED DIETARY RISK FACTORS.
F. Kayama 1 , S. Sun 1, 2 , J. Zhao 3 , J. Leng 4 , H. Fukatsu 5 , D. Liu 2 and X. Liu 2 .
1
Center for Community Medicine, Jichi Medical University, Shimotsuke, Tochigi,
Japan, 2 College of Public Health, Hebei Medical University, Shijazhuang, Hebei,
China, 3 The Second Hospital, Hebei Medical University, Shijazhuang, Hebei, China,
4
School of Public Health, Peking University, Beijing, Beijing, China and 5 S.R.L. Inc.,
Hachioji, Tokyo, Japan. Sponsor: M. Denison.
The concentrations of persistent organic pollutants (POPs), such as dioxins,
dioxin-like polychlorinated biphenyls (Co-PCBs) and polybrominated diphenyl
ethers (PBDEs) were detected by high-resolution gas chromatography/high-resolution
mass spectrometry in human milk collected from 20 women in Shijiazhuang,
Tianjin and Yantai areas in northern China, respectively. Our results show that the
highest geometric concentration of total dioxins and total PBDEs were in Tianjin
and Yantai, respectively. Based on the results of an in-person interview of mothers
using a questionnaire, freshwater fish consumption was found to correlate with
total mono-ortho Co-PCBs and sea fish consumption was found to correlate with
total non-ortho Co-PCBs of body burdens in these areas. But no correlation was
found between concentrations of total PBDEs and total dioxins and consumption
of food. Our results indicate that comprehensive monitoring of POPs in the environment
as well as in food is urgently needed in China to prevent environmental
contamination by POPs.
2064 SUPPRESSION OF TELOMERASE ACTIVITY AND
EROSION OF TELOMERES BY PCB CONGENERS AND
MIXTURES: A POSSIBLE NEW MECHANISM OF PCB
CARCINOGENESIS?
S. Pk, J. Jacobus, H. Lehmler, L. Robertson and G. Ludewig. Human Toxicology
program, The University of Iowa, Iowa city, IA.
Polychlorinated Biphenyls (PCBs), a group of 209 different congeners, are ubiquitous
environmental pollutants. They induce cancer in rodents and are classified as
probable human carcinogens. A hallmark of carcinogenesis is chromosome instability
and immortality, which are influenced by telomere length and telomerase activity.
We hypothesized that exposure to PCBs alters telomerase activity and telomere
length. To explore this possibility, we exposed immortal human skin keratinocytes
(HaCat) to PCB congeners 28, 52, 126, 153 and a synthetic Chicago Air Mixture
(CAM) at a concentration of 5uM for eight weeks. Medium and compounds were
changed every 3 days. Cells were trypsinized, counted, and re-seeded at low density
every sixth day. The remaining cells were used to measure cell viability and cell cycle
distribution by flow cytometry and telomerase activity and telomere length by RT-
PCR. None of the treatments were cytotoxic. The population doubling times and
cell cycle distributions were similar in all treatment groups except PCB126, where a
doubling of cells in S-phase compared to controls was observed. PCBs 28, 52 and
CAM produced a significant reduction in telomerase activity from weeks three to
eight. PCB126 and PCB153 significantly reduced telomerase activity from the first
week on, reaching an almost 50% reduction of activity compared to control by
week eight. In the PCB126- and PCB153-treated groups telomeres began to
shorten at week five and lost 50% of their mean length in week eight. In summary,
several PCB congeners and the synthetic Chicago Air Mixture reduced telomerase
activity and telomere length, indicating that constant exposure to these compounds
could lead to premature senescence, genomic instability and cancer. Further studies
are needed to explore the mechanisms and consequences of reduced telomerase activity
and telomere length. (Supported by NIEHS P42 ES013661, ES 05605, and
DOD DAMD17-02-1-0241)
2065 PHOTO-ACTIVATED TITANIUM DIOXIDE
NANOPARTICLES INDUCE TOXICITY THROUGH AN
OXIDATIVE STRESS MECHANISM IN ZEBRAFISH
EMBRYOS.
O. Bar-Ilan, J. Pedersen, R. E. Peterson and W. Heideman. Division of
Pharmaceutical Sciences and NSEC, University of Wisconsin, Madison, WI.
Although previous studies report titanium dioxide nanoparticles (TiO 2
NPs) as
nontoxic, absorption of light energy ≥ the band gap results in separated electrons (e -
) and holes (h + ), which form reactive oxygen species (ROS) upon interaction with
H 2
O or O 2
. Because shorter-wavelength light reaching Earth’s surface can generate
these e - -h + pairs, we used zebrafish embryos to investigate possible toxicological implications
of TiO 2
NP photochemistry on development. Oxidative conditions,
where ROS outnumber their neutralizing antioxidant counterparts, result in ROS
indiscriminately damaging cellular macromolecules, leading to cellular death.
Therefore, we hypothesized that photo-activated (p-) TiO 2
NPs induce oxidative
toxicity in zebrafish embryos. Embryos exposed to graded concentrations of
TiO 2
NPs (75% anatase; 25% rutile) under simulated sunlight from 4-120 h postfertilization
had significantly higher mortality and incidence of malformations
(opaque/nondepleted yolk; craniofacial and tail malformations) than zebrafish controls
exposed to TiO 2
NPs or H 2
O under dim light and H 2
O under simulated sunlight.
To test whether photo-activation leads to ROS formation, we used a fluorescent
superoxide (O 2
.-
) probe, which revealed O 2
.-
presence in embryos exposed to
p-TiO 2
NPs. Furthermore, these embryos had increased abundance of antioxidant
gene transcripts compared to control embryos. To track oxidative stress, the trans-
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