A Single Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Disrupts the Adult Uterine Response to Estradiol in Mice

Toxicological Sciences, Dec 2013

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) given as a cotreatment with estrogen exhibits antiestrogenic properties on the rodent adult uterus, but less is understood regarding hormonal responsiveness of the adult uterus from animals having been exposed to TCDD during critical periods of development. We characterized the inhibitory effects of TCDD (T) exposure at gestational day 15 (GD15), 4 weeks, and 9 weeks of age (TTT) on the adult uterus following hormone treatment. TTT-exposed mice in response to hormone treatment exhibited a blunted weight increase, had fewer uterine glands, displayed morphological anomalies, and had marked decreases in the hormonal regulation of genes involved in fluid transport (Aqp3 and Aqp5), cytoarchitectural (Dsc2 and Sprr2A), and immune (Lcn2 and Ltf) regulation. To determine if the 9-week exposure was responsible for the blunted uterine response, due to the 7- to 11-day half-life of TCDD in mice, a second set of experiments was performed to examine exposure to TCDD given at GD15, GD15 only (cross-fostered at birth), only during lactation (cross-fostered at birth), or at GD15 and 4 weeks of age. Our studies demonstrate that a single developmental TCDD exposure at GD15 is sufficient to elicit a blunted adult uterine response to estradiol and is due in part to fewer gland numbers and the reduced expression of forkhead box A2 (FoxA2), a gene involved in gland development. Together, these results provide insight regarding the critical nature of in utero exposure and the potential impact on ensuing uterine biology and reproductive health later in life.

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A Single Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Disrupts the Adult Uterine Response to Estradiol in Mice

Advance Access publication September A Single Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Disrupts the Adult Uterine Response to Estradiol in Mice Katherine A. Burns L 2 eah M. Zorrilla 0 Katherine J. HamiltoCna s 2 ey E. Reed 1 Linda S. Birnbaum 3 Kenneth S. Korac h 0 Investigative Toxicology Division, Integrated Laboratory Systems, Inc. , Research Triangle Park, North Carolina 27709 1 Reproductive Endocrinology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, North Carolina 27709 2 Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, North Carolina 27709 3 National Cancer Institute at National Institute of Environmental Health Sciences , Research Triangle Park, North Carolina 27709 Received July 18, 2013; accepted September 4, 2013 laod Published by Oxford University Press on behalf of the Society of Toxicology 2013. This work is written by (a) US Government employee(s) and is in the public domain in the US. et al. (2008) acutely cotreated mice with ethynyl estradiolaCanacnreedowfiAthnitmhaelNsaantidownaitlh IanpsptriotvuetdesNoaftiHoenaalltIhnsGtuitiduetleinofesEnfovrirHonummeannteaUlsHeeaanl respective control) was performed for the second study using General Linear Model procedures (SAS). Statistical significance is denoted when p < .05. With hormone treatment postovariectomy in OOO animals (E2 or E2+P4), the uteri develop more glandular structures. In contrast, in the TTT group, hormone treatment postovariectomy (E2 or E2+P4) does not alter the number of glandular structures an the decreases are significantly reduced compared with control uteri. These data reveal that TTT exposure affects uterin-e mor phology and the formation of uterine glands. Uteri From Mice Exposed to TCDD at GD15, 4 Weeks, and 9 Weeks of Age (TTT) Have Minimal Levels of Apoptosis foriolm), OE2O O(0(.5cmorgn, o21il-)d,aoyr TreTlTea(TseC/mDoDu)s-eex),poorseEd2(+1µP0g 4/k(0g.m)5mg,ic2e1a-dftaeyr roeille(acsoer/n determine if an increase in apoptosis was mediating the Fi G. 3. Exposure to TCDD at GD15, 4 weeks, and 9 weeks of age results in blunted E2-mediated uterine gene responses. Genes involved in (A) tissue fluid uptake (Aqp3 and Aqp5), (B) cytoarchitectural regulation (Dsc2 and Sprr2a), (C) immune regulation (Lcn2 and Ltf), and (D) Cyp1A1 were examined in OOO and TTT-exposed mice treated postovariectomy with oil (corn oil), Em2g(,02.51-day release/mouse), or E2+P4 (0.m5g, 21-day release/mouse +m1 g/mouse). Data are expressed relative to the pL7. Mean ± SD, letters different from each other represent statistical differences (p < .05). D o w n l o Fi G. 6. Experimental design for study 2 exposure to TCDD at GD15, lactation, and 4 weeks of age. C57BL/6J mice were time mated/copulation plug poadsitiv (GD 0.5). A, At GD15, pregnant dams were orally administered vehicle (corn oilµ)go/krg10o f TCDD in corn oil. Animals were weaned at 3 weeks of age. At fed weaning, pups in group T(G)O were cross-fostered to dams that were not exposed to TCDD. Pups in group T(L)O were cross-fostered to dams that were exporomsed to TCDD during pregnancy at GD15. Groups TO and TT were not cross-fostered. Groups OT and TT additionally recµegiv/kegd o1f0 TCDD in corn oil at 4 h weeks of age. Mice were ovariectomized at 12 weeks of age and a placebo or E2 pelmlegt, 2(01.-5day release/mouse) was implanted and mice were sacrificed :ttp 11 days later. B, Table showing schematic of pup exposure to TCDD. Gray boxes denote when pups were exposed to TCDD. Group exposure is as follow/t s: / o OO—corn oil at GD15 and PND 28; OT—corn oil at GD15, TCDD at PND 28; TO—TCDD at GD15/throughout lactation, corn oil at PND 28; T(G)O—TC DsxD c at GD15, no lactational exposure, and corn oil at PND 28; T(L)O—corn oil GD15, lactational exposure from dams given TCDD at GD15, and corn oil at P.ioND TT—TCDD at GD15, throughout lactation, and at PND 28. fox r d j o u r gland counts. Interestingly, FoxA2 was not detectable in thane l s TT-E2 samples. TheFoxA2 levels were reduced in the T(G) .ro g O groups but did not reach statistical significance. Groups OT /b y and T(L)O were not different than the OO-Oil control groupgu correlating to the gland numbers. Additionally, we confirmed atse decrease in FoxA2 in the TTT animals from the first experiment no O (Supplementary Figure 1C). These data suggest that the expres- tc o sion of Foxa2 is blunted (TO-Oil, TT-Oil, TO-E2) or inhibited reb (TT-E2) by early-life exposure to TCDD. ,9 2 0 1 6 Dis Cussi On FiG. 8. Exposure to TCDD at GD15 does not consistently alter the adult uterine gene expression response to E2. Genes involved in (A) tissue fluid (Aqp3 and Aqp5), (B) cytoarchitectural regulation (Dsc2 and Sprr2a), and (C) immune regulation (Lcn2 and Ltf) were exam (...truncated)


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Katherine A. Burns, Leah M. Zorrilla, Katherine J. Hamilton, Casey E. Reed, Linda S. Birnbaum, Kenneth S. Korach. A Single Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Disrupts the Adult Uterine Response to Estradiol in Mice, Toxicological Sciences, 2013, pp. 514-526, 136/2, DOI: 10.1093/toxsci/kft208