* Endocrine Disruptors and Dioxin Research Project, National Institute for Environmental Studies, Tsukuba 305-8506, Japan; Department of Human Sciences, Aichi Mizuho University, Toyota 470-0394, Japan;
Graduate School of Life Science, University of Hyogo, Harima Science Garden City, Hyogo 678-1297, Japan; and
Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba 305-8506, Japan
1 To whom correspondence and reprint requests should be addressed at Endocrine Disruptors and Dioxin Research Project, National Institute for Environmental Studies, Tsukuba 305-8506, Japan. E-mail: nishimura.noriko{at}nies.go.jp
Received November 16, 2004; accepted February 15, 2005
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ABSTRACT |
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Key Words: hypothyroxinemia; lactational exposure; TCDD; thyroxin.
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INTRODUCTION |
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Thyroid hormone has been reported to play a crucial role in development of the fetal brain in laboratory animals and humans. During fetal and early neonatal periods, disorders of thyroid hormone may lead to the development of motor and cognitive disorders (Sher et al., 1998). While the neuronal defects related to thyroid function could be readily reversed with appropriate medical treatment in adults, effects on the developing brain are irreversible if damage due to thyroid malfunction occurs early in life (Porterfield, 1994
).
The major source of human exposure to dioxins is through the diet (Porterfield, 1994). Dioxins have been shown to accumulate in human tissues rich in fat such as adipose tissues, blood lipids, and milk fat. The human fetus is exposed to dioxins through placental transport, and larger quantities of dioxins are transferred to the infant via breast milk. A Dutch cohort study investigated the adverse effects of background exposure to polychlorinated biphenyls (PCBs) and dioxins on growth and development of healthy full-term infants. While lower total serum thyroxin (TT4) levels and higher thyroid stimulating hormone (TSH) levels of infants in the second week after birth were associated with higher PCB and dioxin levels in breast milk, delay in neuronal development and immune status, rather than lactational exposure, were associated with prenatal exposure to PCBs and dioxins (Huisman et al., 1995a
, 1995b
; Sauer et al., 1994
). Similarly, Dutch epidemiological studies suggest that in utero rather than lactational exposure to dioxins and/or PCBs is critical in the development of cognitive functions (Patandin et al., 1999
).
Using a cross-fostering protocol, Crofton et al. (Crofton et al., 2000) reported that lactation is the major route of Arochlor 1254, which is responsible for ototoxicity and hypothyroxinemia. A toxicokinetic study using 14C-labeled TCDD in pregnant and lactating rats demonstrated that TCDD was transferred to the livers of their fetuses predominantly through breast milk (Li et al., 1995
). However, in utero but not lactational TCDD exposure was mainly responsible for morphological alterations in the reproductive tissues of female rat offspring (Gray et al., 1997
) and for neurodevelopmental deficits after exposure to PCB (Lilienthal and Winneke, 1991
). According to the findings of cross-fostering studies (Bjerke and Peterson, 1994
; Gray et al., 1997
) functional disorders in male and female reproductive organs were caused by in utero exposure alone.
It is still uncertain, however, whether lactational exposure to TCDD is mainly responsible for the disruption of thyroid hormone homeostasis and morphological changes in the liver and thyroid during the early stages of development. In the present study, we used a cross-fostering protocol on newborn rats to investigate this aspect of TCDD toxicity.
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MATERIALS AND METHODS |
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After spontaneous delivery, pups were divided into the following four groups according to the cross-fostering protocol. The first group of pups was exposed to TCDD both in utero and via lactation and was designated T/T group. We switched the mothers of the second and third groups of pups on PND 1 so that they were exposed to TCDD either in utero only (T/C) or via lactation only (C/T). The fourth group of pups was born to dams and fostered by the same dams administered vehicle (C/C). Serum and tissues from each group of neonates (n = 6) were collected on postnatal day (PND) 21 and analyzed. Liver and thyroid glands with the trachea were excised, fixed in Zamboni's solution for 24 h at 4°C, and processed for immunohistochemical and histopathological examinations. For biochemical examination, tissues were snap-frozen in liquid nitrogen and stored at 80°C until analysis.
Male and female rats (n = 46) from each group were killed on PND 49 for histopathological examinations.
Thyroid hormone analysis.
Total thyroxin, free thyroxin (FT4), and total triiodothyronine (TT3) in the serum were determined with Amerlex radioimmunoassay kits (Amersham, Buckinghamshire, UK) according to the manufacturer's instructions. Serum TSH concentrations were quantified with a rat TSH enzyme immunoassay kit (Amersham) as described elsewhere (Nishimura et al., 2002).
Immunohistochemistry.
Cytochrome P450 (CYP) 1A1 and the UDP-glucuronosyltransferase 1-6 precursor UDP glycosyltransferase 1 family, polypeptide A6 (UGT1A6) in the liver were stained in tissue sections by an indirect immunohistochemical technique. Briefly, the deparaffinized and rehydrated sections were pretreated in 0.01 M sodium citrate buffer (pH 6.0) with microwave heating and washed in phosphate-buffered saline (PBS). To quench endogenous peroxidase activity, sections were covered with 0.3% H2O2 dissolved in 100% methanol. Goat polyclonal antibody against CYP1A1 (G-18; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was diluted 1:200 and rabbit antibody against rat UGT1A6-specific peptide (Ikushiro et al., 1995) was diluted 1:200 in phosphate buffered saline (PBS). The primary antibodies were incubated over the sections in a humidified chamber for 1 h at 37°C. Sections were subsequently washed with PBS, followed by incubation for 1 h with biotinylated rabbit anti-goat immunoglobin G (IgG) (BA-5000, Vector Laboratories, Vector, Burlingame, CA) or goat anti-rabbit IgG (BA-1000, Vector Laboratories), which were diluted 1:300 in PBS. They were incubated with an avidinbiotinylated peroxidase complex (PK-4000, Vector Laboratories). Immunoreactions were performed using hydrogen peroxideactivated 3,3'-diaminobenzidine-tetrahydrochloride (Sigma, St. Louis, MO). Sections were counterstained for 10 s in Mayer's hematoxylin. Negative controls, in which the primary antibody was replaced with normal rabbit IgG, did not show nonspecific staining.
RNA extraction and reverse transcriptasepolymerase chain reaction.
All enzymes and cofactors used for reverse transcription (RT) and polymerase chain reaction (PCR) were purchased from Takara (Otsu, Japan). All primers were purchased from Amersham Pharmacia Biotechnology (Piscataway, NJ). Sequences of PCR primers for amplification of CYP1A1, UGT1A6, UGT1A7, and ß-actin are summarized in Table 1. Total RNA was isolated from liver with Isogen (Nippon Gene, Tokyo, Japan) and reverse transcribed in a 20-µl reaction mixture containing 5.0 mM MgCl2, 1.0 mM dNTP, 0.25 U/µl AMV reverse transcriptase, 0.125 µM oligo dT-adaptor primer, 1 U/µl RNase inhibitor, and 1 µg of total RNA with the RNA LA PCR kit (Takara).
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Measurement of TCDD concentration.
The presence of TCDD in tissue specimens (serum, liver and milk) was determined by essentially the same method as described elsewhere (Nishimura et al., 2002). The TCDD concentrations were analyzed by high-resolution gas chromatographymass spectrometry procedures with selected ion monitoring. Quantified values were calculated by the internal standard method, as previously described.
Data analysis.
StatView for Windows (version 5.0, SAS Institute, Cary, NC) was used for statistical analyses. Data are expressed as mean ± S.E.M. Differences in means among the groups were analyzed by one-way analysis of variance (ANOVA) followed by Scheffe's test as a post-hoc comparison, and compared each treatment groups; p values < 0.05 were considered statistically significant.
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RESULTS |
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DISCUSSION |
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In the present study, a significant decrease in TT4 and FT4 levels of both sexes was accompanied by a concomitant increase in TSH levels in the circulation only in newborn rats exposed to TCDD lactationally (C/T and T/T groups) on PND 21. In contrast, controls (C/C group) and neonates exposed to TCDD only in utero (T/C group) were unaffected. The weights of thymus and liver, organs that are sensitive to TCDD toxicity, were decreased and increased, respectively, on PND 21 in the C/T and T/T groups, but not in the C/C and T/C groups. These effects of TCDD on the weight of these organs are in good agreement with previous studies indicating that TCDD toxicity occurred in offspring.
The most consistent effect of TCDD is a decrease in TT4 and FT4 in the blood circulation, an effect studied in adult mammals (Bastomsky, 1977), newborn animals (Seo et al., 1995
), and humans (Brucker-Davis, 1998
). Both chronic administration (Capen, 1992
; Sewall et al., 1995
) and a single dose of TCDD (Nishimura et al., 2002
; Seo et al., 1995
;) increased secretion of pituitary TSH, as a compensatory response to a lower concentration of circulating T4, which led to thyroid follicular cell hyperplasia and hypertrophy. In support of this observation, we showed that the proliferative changes of thyroid follicular cells on PND 49 were produced only via lactational exposure to TCDD (Fig. 6). These pathological lesions show a remarkable consistency with those observed in adult thyroids given a single dose of TCDD (Nishimura et al., 2002
) and in pup thyroids exposed to TCDD in utero and lactationally (Nishimura et al., 2003
).
In the present study, we observed a slight but statistically insignificant increase in serum TSH in female pups, in contrast to a significant increase in serum TSH levels in male pups in the C/T and T/T groups. The underlying mechanism of this sex difference in TSH response to TCDD is not clear at present. We observed previously (Nishimura et al., 2003) that the serum TSH levels were significantly elevated in both sexes in the highest TCDD dose group, and the concentrations of TSH in male rats tended to be higher than those in the female rats at all developmental stages examined. In fact, the presence of a sex difference in hypothalamic-pituitary-thyroid function was suggested by McClain et al. (1988)
. Phenobarbital, a hepatic microsomal enzyme inducer, promoted thyroid tumours more in male rats than in female rats, mediated via increased TSH secretion as a compensatory response to the T4 metabolism and excretion. Higher TSH responsiveness to thyrotropin releasing hormone (TRH) was observed in male rats but not in female rats, and the presence of testosterone was suggested to cause this difference (Christianson et al., 1981
). Therefore, one possible explanation for the difference in response to TCDD between male and female rats might be that male rats are more susceptible to TCDD than female rats in terms of TSH response.
Gene expression of CYP1A1 and UGT mRNAs in the liver was induced markedly in the C/T and T/T groups, in contrast to no induction in the C/C and T/C groups. Induction of these genes was also confirmed by immunohistochemical examinations, which showed that an expression of immunoreactivity was localized in centrilobular hepatocytes (Fig. 3). The finding that TCDD-induced expression of CYP1A1 was restricted to the centrilobular region is consistent with the observations of Tritscher et al. (1992) of the liver from a rat chronically exposed to TCDD for 30 weeks. The distribution pattern of UGT1A6 protein after TCDD treatment in the present study was in good agreement with that observed in an in situ hybridization study by Saarikoski et al. (1998)
, which revealed that UGT1A6 mRNA was induced in the restricted area of the central veins of rats after 3-methylcholanthrene (MC) treatment. The region-specific induction of CYP1A1 and UGT1A6 proteins in the liver might be related to differences in TCDD localization. As the concentration of TCDD was reported to be significantly higher in centrilobular cells than in periportal hepatocytes (Santostefano et al., 1999
), in the present study the differential expression of the genes observed might depend on the tissue concentration of TCDD.
To our knowledge, the present study provides the first evidence of localization of hepatic UGT1A6 protein in response to TCDD. In addition, TCDD did not affect gene induction of UGT1A1, whereas both UGT1A6 and UGT1A7 mRNAs were induced significantly. Extensive studies have suggested that UGTs are involved in glucuronidation of xenobiotics and endogeneous compounds, including T4 and T3. Mammalian UGT isoforms can be grouped into two major families, the UGT1 family and the UGT2 family, according to nucleotide and amino acid sequences. The UGT1 family is classified into the bilirubin cluster (UGT1A1 and UGT1A5) and the phenol cluster (UGT1A6 and UGT1A7) (Ikushiro et al., 1995; Luquita et al., 2001
). Thyroid hormones are likely to be glucuronidated by different UGT enzymes (Visser et al., 1993
). A member (or members) of the UGT1A subfamily is believed to glucuronidate T4, specifically UGT1A1 and UGT1A6, whereas the UGT2 subfamily is likely to glucuronidate T3 (Vansell and Klaassen, 2002
). Bank et al. (1989)
found that TCDD increased the UGT activity in rats. Among all rat UGT families, only UGT1A6 and UGT1A7 mRNA are known to be induced selectively by MC and PCB (Bank et al., 1989
; Emi et al., 1995
, 1996
). Furthermore, the possible involvement of UGT1A6 in glucuronidation of T4 is supported by evidence that UGT1A6 is responsible for T4 conjugation in cultured rat hepatocytes treated with MC (Jemnitz et al., 2000
). Our findings of a significant decline in serum levels of T4 with concomitant induction of UGT1A6 and UGT1A7, but not UGT1A1, strongly suggests a contribution of UGT1A6 and UGT1A7 in T4 glucuronidation. The role of UGT1A7 in addition to UGT1A6 in T4 glucuronidation needs further investigation.
A large amount of TCDD was detected in milk remaining in stomachs of newborn pups on PND 1 nursed by TCDD-exposed dams. Li et al. (1995) showed in a cross-fostering study that only 0.01% of total dose of TCDD given to the dams was transferred to fetal liver through the placenta. In our study, however, the concentration of hepatic and serum TCDD in the C/T and T/T groups was more than 25- to 30-fold higher as compared to the T/C group. Hepatic concentrations of TCDD in the rats from C/T and T/T group were 1461 and 2350 pg/g tissue, much higher than that of the T/C group value of 44 pg/g tissue. According to Dutch epidemiological cohort studies, the median dioxin toxicity equivalent (TEQ) concentration in breast milk specimens was reported to be 33.4 ng TEQ/kg fat. In comparison, the milk specimens in the stomach of male pups on PND 1 was 979 ± 136 (TCDD pg/wet-g), which is equal to approximately 30,000 ng TEQ/kg fat provided that the fat content in the milk is 3.3% (Patandin et al., 1999
). In contrast, in our study, dioxin TEQ levels in the serum from pups born to dams of the CT and TT groups on PND 21 ranged from 20 to 31 pg TEQ/g serum, which is approximately equal to 6,600 to 10,000 pg TEQ/g lipid, with the assumption that the serum contains approximately 0.3% fat. Although dioxin concentrations in the serum of infants and mothers were not available for the Dutch studies, some of the available data on average dioxin TEQ concentrations in the serum in adult humans without having known accidental dioxin exposure were reported to be approximately between 15 and 25 pg/g fat (Papke et al., 2003
). The comparison for these data would allow us to estimate that the margin of exposure for the disruption of thyroid effects ranges from 250 to 670 for serum and 900 for milk, respectively. Thus, from the public health point of view, the suggestion of nourishing breast milk is valid in terms of benefits of nutrition and skin contact between mothers and babies, at least for possible deleterious effects on thyroid hormone homeostasis by dioxins. Based on the present cross-fostering study, we conclude that exposure to TCDD via breast milk, not by placental transfer, was entirely responsible for disturbance of thyroid hormone homeostasis in pups.
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ACKNOWLEDGMENTS |
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