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BOR - Papers in Press, published online ahead of print September 21, 2005.
Biol Reprod 2005, 10.1095/biolreprod.105.044396
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BIOLOGY OF REPRODUCTION 74, 125–130 (2006)
DOI: 10.1095/biolreprod.105.044396
© 2006 by the Society for the Study of Reproduction, Inc.

Research Article

Effects of Acute and Chronic Exposure to the Aryl Hydrocarbon Receptor Agonist 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the Transition to Reproductive Senescence in Female Sprague-Dawley Rats1

Anita Franczak 345  , Anna Nynca 5, Kelli E. Valdez 34 , Kemmy M. Mizinga 6, and Brian K. Petroff 2 34 

Center for Reproductive Sciences3 Department of Internal Medicine,4 University of Kansas Medical Center, Kansas City, Kansas 66160 Department of Animal Physiology,5 University of Warmia and Mazury, 10-718 Olsztyn, Poland Department of Pharmacology,6 Kansas City University of Medicine and Biosciences, Kansas City, Missouri 64106

ABSTRACT

Activation of the aryl hydrocarbon receptor (AHR) can occur in polluted environments, either from smoking-related toxicants or from endogenous ligands. We tested whether acute or chronic exposure to the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the transition to reproductive senescence in female Sprague-Dawley rats. In experiment 1, rats (n = 6 per experimental group) received a single dose of 0 or 10 µg/kg of TCDD orally (p.o.) on Postnatal Day 29. Vaginal cytology was monitored for 1 wk each month until rats were killed at 1 yr of age. The single prepubertal exposure to TCDD hastened the transition to reproductive senescence in female rats and was associated with delayed puberty, abnormal cyclicity, and premature reproductive senescence. In a second experiment, rats were exposed to TCDD chronically through weekly dosing (0, 50, or 200 ng kg–1 wk–1 p.o., n = 7 each dose) beginning in utero. Lifelong exposure to these lower doses of TCDD induced a dose- and time-dependent loss of normal cyclicity and significantly hastened the onset of the transition to reproductive senescence (P < 0.05). This premature transition to reproductive senescence was associated with prolonged estrous cycles and, at the highest dose of TCDD, persistent estrus or diestrus. The number and size of ovarian follicles were not altered by TCDD. Diestrous concentrations of LH in rats exposed chronically to TCDD were similar to those in controls, whereas progesterone tended to be elevated at both doses of the dioxin (P < 0.08). Serum FSH was elevated in the group exposed to 50 ng/kg of TCDD (P < 0.02), whereas estradiol was decreased at both doses of dioxin (P < 0.01). Data thus far support endocrine disruption rather than depletion of follicular reserves as a primary mechanism of the premature transition to reproductive senescence following activation of the AHR pathway by TCDD in female rats.

aging, environment, estradiol, ovulatory cycle, toxicology

INTRODUCTION

Normal reproductive senescence involves a loss of ovarian and hypothalamic function and is not pathological [1]. The end of ovarian activity is preceded by a period of irregular reproductive cycles of suboptimal fertility in both women and laboratory rodents [2–7]. Neuroendocrine changes common to middle-aged females include elevated FSH, increased duration and decreased frequency of LH pulses, and variability in duration of the reproductive cycle [8]. Whereas the responsiveness of the pituitary gland to GnRH appears to remain unchanged initially during the loss of reproductive function with age in the rat [9], GnRH neuronal activation during the normal cycle [9–11] and following stimulation with estradiol [12] are markedly reduced in middle-aged animals. The transition to reproductive senescence in the female also is accompanied by a blunting or loss of circadian rhythmicity in the primary neuroendocrine pacemaker, the suprachiasmatic nucleus [8, 13]. Depletion of follicular reserves causes the final loss of cyclicity at menopause in women [2, 7].

Reproductive senescence is normal, but premature reproductive senescence is pathological and undesirable because of health effects, such as osteoporosis and prolonged perimenopausal symptoms [14]. Loss of oocytes as a result of autoimmune disease is thought to be a central mechanism of human premature ovarian failure, leading to accelerated menopause [15]. Exposure to smoking-related toxicants, including some aryl hydrocarbon receptor (AHR) ligands, accelerates reproductive aging, inducing early menopause [16] through depletion of follicular reserves [14, 16–19] and disruption of neuroendocrine function [20]. Epidemiological examination of the female population exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) following the Seveso, Italy, accident revealed premature menopause associated with dioxin exposure, although this effect was not correlated with estimated dose [21].

The most toxic dioxin, and one of the most potent environmental toxicants, is TCDD, the prototypic AHR-specific ligand [22, 23]. Short-term AHR activation with TCDD in laboratory animals causes male and female endocrine disruption, altered sexual behavior, decreased spermatogenesis, diminished fertility, endometriosis-like symptoms, teratogenesis, and abortion [24–27]. We conducted the present study to determine if acute prepubertal or chronic lifelong activation of the AHR pathway alters the transition to reproductive senescence in the female rat.

MATERIALS AND METHODS

Animals

Female Sprague-Dawley rats (Charles River Laboratories) were housed under a 12L:12D photoperiod at an ambient temperature of 23 ± 2°C. Rats were provided with food (Purina Rat Chow; Ralston Purina Co.) and water ad libitum. The TCDD (CAS 1746–01–6; MW, 321.9; purity, >99%) was obtained from Cambridge Isotope Laboratories, Inc. All procedures were approved by the University of Kansas Medical Center Institutional Animal Care and Use Committee.

In experiment 1, prepubertal female Sprague-Dawley rats received a single oral dose of TCDD or corn oil vehicle (0 or 10 µg/kg; n = 6 each dose) at 29 days of age. This dose of TCDD mimics accidental and occupational exposure in humans and blocks ovulation acutely in rats [22]. Vaginal cytology was monitored for 1 wk each month until rats were killed at 1 yr of age [28]. The normal estrous cycle of the rat has a 4- to 5-day duration and a characteristic cyclic pattern and sequence of vaginal cytologic changes [28].

In experiment 2, female Sprague-Dawley rats were housed as described above and exposed chronically to TCDD beginning in utero. Pregnant dams (n = 2–3 per experimental group) received TCDD (50 or 200 ng/kg orally [p.o.]) or corn oil vehicle (4 ml/kg) on Gestational Days 14 and 21 and Postnatal Days 7 and 14 to provide in utero and lactational exposure of pups to the dioxin. The TCDD has a long half-life in the rat (3 wk) [29], and weekly dosing has been used commonly in past studies [30, 31]. On Postnatal Day 21, female pups (n = 7 per experimental group) were weaned and dosed directly with TCDD (50 or 200 ng/kg p.o.) or vehicle (corn oil, 4 ml/kg) each week thereafter. Estrous cycles were monitored by vaginal cytology for 7–10 days at 4, 6, and 8 mo of age as described previously (Figs. 1 and 2) [28]. A normally cycling animal was defined as having 4- to 5-day interestrous intervals, as confirmed by vaginal cytology. Persistent estrus or persistent diestrus was defined as at least five consecutive days of cornified or diestrous smears during a 7- to 10-day sampling period, respectively. Animals with interestrous intervals greater than 5 days (even if followed or preceded by normal cycles) but not persistent estrus or persistent diestrus were classified as having prolonged estrous cycles. The first occurrence of a prolonged (≥6 days) interestrous interval was considered to be evidence of the transition to reproductive senescence. Rats (other than those in constant estrus) were killed on the morning of diestrus at 8 mo of age once TCDD-treated animals had entered the transition to reproductive senescence. Diestrous concentrations of serum LH, FSH, progesterone, and estradiol were measured. Ovaries were collected and fixed for light microscopy [32].


Figure 1
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  		FIG. 1. Lifetime estrous cyclicity in control and TCDD-treated rats (10 µg/kg p.o. on Postnatal Day 29). The TCDD significantly accelerated the onset of abnormal or absent cyclicity with age. Vaginal cytology was monitored for 1 wk each month to 1 yr of age. Open circles and dark circles denote control vs. TCDD-treated rats, respectively. The plot for each animal is a three-level depiction of the estrous cycle; data points on the lower, middle, and top level represent a day of diestrus, proestrus, and estrus, respectively


Figure 2
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  		FIG. 2. Incidence of normal estrous cyclicity in female Sprague-Dawley rats dosed chronically with TCDD (50 or 200 ng kg–1 wk–1 p.o.) or corn oil vehicle from fetal life until 8 mo of age. Asterisks denote significant (P < 0.05) difference from corresponding control animals for that age. Because analysis considered each group as a whole, no measure of individual variation (i.e., error bar) is presented

Evaluation of Follicle Numbers

One ovary per rat was fixed in 4% paraformaldehyde (Electron Microscopy Sciences). Fixed tissues were dehydrated through graded ethanols, embedded in paraffin, serially sectioned (thickness, 8 µm), and stained with hematoxylin-eosin. Follicles with one incomplete layer, one layer, two layers, and three to five layers of granulosa cells, as well as early antral and mature antral follicles, were counted in every 20th section, and the number of follicles at each developmental category per ovary was estimated from this subsample [32, 33]. Only follicles bearing an oocyte with a visible nucleolus were counted [32, 33]. Approximately 15 (14.8 ± 0.37) sections per ovary were evaluated.

Hormone Assays

Serum concentrations of LH, FSH, progesterone, and estradiol were measured by The Ligand Assay and Analysis Core in the Center for Research in Reproduction at the University of Virginia. The LH was measured by a modified two-site sandwich ELISA, with an assay sensitivity of 0.07 ng/ml and an intra-assay coefficient of variation of 4.7%. The FSH was measured by RIA using primary anti-rat FSH (Dr. A. F. Parlow, NIDDK) diluted to a final concentration of 1:46000. The assay sensitivity was 1.5 ng/ml, with less than 0.5% cross-reactivity with other pituitary hormones. The intra-assay coefficient of variation was 4.6%. Serum concentrations of estradiol and progesterone were measured by RIA. Assay sensitivity was 1.5 pg/ml for estradiol and 0.05 ng/ml for progesterone. The intra-assay coefficients of variation were 5% for estradiol and 4.3% for progesterone. All samples were run in duplicate within a single assay for each hormone.

Statistical Analysis

To detect early effects of TCDD on hormones before abnormal cyclicity, hormonal data from rats in constant estrus or constant diestrus were excluded from analysis, leaving seven, five, and three animals from the control, 50 ng/kg, and 200 ng/kg TCDD groups, respectively. Effects of TCDD on the onset of puberty (as indicated by vaginal opening), the onset of abnormal or absent cyclicity with age, and the duration of reproductive life span in TCDD-treated and control animals were evaluated by Student t-test, with statistical significance assigned at P ≤ 0.05. Effects of TCDD on the proportion of animals cycling normally at 4, 6, and 8 mo of age and the incidence of prolonged cycles and persistent estrus or diestrus were tested by chi-square analysis. Differences between mean numbers of follicles and serum concentrations of LH, FSH, estradiol, and progesterone in TCDD-treated and control animals were evaluated by one-way ANOVA. When significant main effects were found, individual means were compared using the Tukey test in post hoc analyses. All values are mean ± SEM.

RESULTS

Effect of Acute Prepubertal Exposure to TCDD

Control animals reached puberty (defined as vaginal opening) at Day 33.2 ± 1.0 of age and exhibited normal 4- to 5-day estrous cycles until approximately 1 yr of age (Table 1 and Fig. 1). A single prepubertal dose of TCDD accelerated the onset of abnormal or absent estrous cyclicity with age. The combination of delayed puberty (P < 0.05) and a premature onset of abnormal cyclicity shortened the reproductive life span (P < 0.05) of rats exposed to the dioxin. The TCDD-treated rats also exhibited subtle differences in normal reproductive cycles throughout the reproductive life span, with a greater proportion of time spent in diestrus compared to controls.


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  		TABLE 1. Summary of effects of a single prepubertal exposure to TCDD on estrous cyclicity in female rats

Effect of Lifelong Exposure to TCDD

Control animals exhibited estrous cycles (as assessed by vaginal cytology) of normal progression and duration until the end of the experiment at 8 mo of age (Fig. 2). More than 80% of rats in all groups exhibited normal estrous cycles at 4 mo of age, but by 6 mo, a tendency (P < 0.1) toward a loss of normal cyclicity was observed in TCDD-treated animals. Compared to controls, TCDD-treated rats had a loss of normal cyclicity at 8 mo of age for both doses of the dioxin (50 and 200 ng TCDD/wk p.o. and 1.7 and 8 µg TCDD/kg of cumulative exposure, respectively). This trend is reflected in an interaction between TCDD and time in the chi-square analysis. The effect of TCDD by 8 mo of age varied with dose (Fig. 3). Approximately 50% of rats receiving the highest dose of TCDD exhibited a loss of any cyclicity, as evidenced by persistent estrous or diestrous vaginal cytology. Notably, while the low dose of TCDD increased the prevalence of prolonged cycles, persistent estrus or diestrus only occurred in approximately 10% of rats.


Figure 3
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  		FIG. 3. Incidence of normal cyclicity and animals with prolonged cycles, persistent diestrus, or persistent estrus by vaginal cytology at 8 mo of age. Rats were dosed chronically with corn oil vehicle or TCDD (50 or 200 ng kg–1 wk–1 p.o., n = 6–8 per group). Asterisks denote a significantly different (P < 0.05) incidence distribution in comparison with that of the control population. Because analysis considered each group as a whole, no measure of individual variation (i.e., error bar) is presented

The number and size distribution of ovarian follicles, as well as the number of corpora lutea, were not altered by chronic exposure to TCDD at either of the doses tested (Table 2).


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  		TABLE 2. Effect of chronic exposure to TCDD on populations of ovarian follicles and corpora lutea.a

Hormonal data (Figs. 4 and 5) reflect diestrous concentrations in sera from control and TCDD-treated rats still exhibiting reproductive cyclicity to exclude secondary effects of loss of cyclicity. Diestrous concentrations of progesterone tended to be elevated (P < 0.08) in animals receiving either of the two doses of the dioxin compared to controls. The TCDD decreased serum estradiol concentrations (P < 0.03) (Fig. 4) but had no effect on serum LH at diestrus (Fig. 5). The FSH was elevated in rats receiving the lower dose of TCDD (P < 0.01) (Fig. 5), but no effect of the higher dose was observed.


Figure 4
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  		FIG. 4. Diestrous concentrations (mean ± SEM) of progesterone and 17ß-estradiol in the serum of Sprague-Dawley rats exposed chronically to increasing doses of TCDD (50 or 200 ng kg–1 wk–1 p.o.) or corn oil vehicle (control) from fetal life until 8 mo of age. Bars bearing different letters denote a significant difference (P < 0.05) between individual treatment means


Figure 5
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  		FIG. 5. Diestrous concentrations (mean ± SEM) of LH and FSH in the serum of Sprague-Dawley rats exposed chronically to increasing doses of TCDD (50 or 200 ng kg–1 wk–1 p.o.) or vehicle (control) from fetal life until 8 mo of age. Bars bearing different letters denote a significant difference (P < 0.05) between individual treatment means

DISCUSSION

Short-term activation of the AHR in prepubertal laboratory animals causes endocrine disruption and diminished fertility [27, 34]. In the present study, a single prepubertal exposure to TCDD had both immediate and persistent effects on female reproductive function in the rat, leading to a premature transition to reproductive senescence. This is in agreement with previous studies that demonstrated a premature onset of constant estrus [25] with premature senescence following a single dose of TCDD delivered during gestation. Eskenazi et al. [21] also recently reported premature menopause in human populations accidentally exposed to TCDD, although this effect was not seen at the highest estimated exposures.

Earlier studies have shown that exposure to high doses of TCDD is associated with an early onset of constant estrus and a loss of fertility with age [25], but the effect of chronic low-dose exposure on the characteristics of normal estrous cycles, hormone profiles, and follicular reserves in middle aged rats were unknown previously. The present study reveals a dose-dependent acceleration of the onset and progression of reproductive senescence following chronic exposure to TCDD, including a low dose of 50 ng kg–1 wk–1. While the doses used for this chronic exposure to TCDD are directly relevant only to human populations exposed to high levels of AHR ligands and not to the general population, these data indicate a need to assess further the sensitivity of the developing and aging female reproductive system to AHR ligands.

At the level of the ovary, activation of the AHR system by polyaromatic hydrocarbons other than TCDD has been shown to induce germ cell apoptosis and diminish ovarian follicular reserves [2, 18, 19, 35, 36]. Previous work from our group showed that TCDD blocks ovulation following direct ovarian treatment and in gonadotropin-primed, hypophysectomized rats, both suggesting direct ovarian effects [34, 37]. Transgenic or chemical blockade of AHR appears to protect against toxicant-mediated follicular depletion, resulting in expanded follicular reserves and a prolonged reproductive life span [38]. Additionally, TCDD is suggested to act on the ovarian AHR in a manner distinct from that of other polyaromatic hydrocarbons and does not promote fetal follicular apoptosis in vitro [39]. In previous studies using higher doses, TCDD appeared to attenuate follicular maturation acutely by reducing the number of antral and preantral follicles without inducing apoptotic cell death in rat offspring exposed in utero and during lactation [40]. In the present study, the number and size distribution of ovarian follicles were not altered after chronic exposure to TCDD. Similarly, Flaws et al. [17] also found little effect of exposure to TCDD in utero on follicular populations in rats during a 6-day study. A plausible explanation is that these direct ovarian effects of TCDD may be dose dependent and, therefore, not seen with low-dose regimens.

While direct effects of TCDD on the vagina may contribute to changes in the cycle of the vaginal epithelium in the present study, the doses used make this unlikely [17], particularly for the chronic dosing study. When given in utero, however, TCDD does cause vaginal thread formation [17]. Nonetheless, the endocrine changes that we observed probably are sufficient in themselves to disrupt cyclicity and, secondarily, vaginal smears. Additionally, direct actions of TCDD on the vaginal epithelium, in the absence of other effects, would be expected to cause vaginal epithelial cycles of normal duration but abnormal cytology rather than the prolonged cycles and persistent estrus or diestrus observed in the present study.

Acute exposure to TCDD blocks ovulation; however, this occurs at much higher doses (median effective dose, 7.5 µg/kg p.o.) than those used during the present chronic dosing study in which ovarian morphology was examined [34, 37]. The lack of effect of TCDD on number of corpora lutea in the present study is an interesting phenomenon, and it probably reflects the presence of retained corpora lutea following disrupted cyclicity. This seems to suggest that the ovulation number in the disrupted and prolonged reproductive cycles is similar to that of a normal cycle. Thus, the chronic effect of TCDD may be primarily on cycle length (i.e., the days between gonadotropin surges) rather than on the magnitude of, and ovarian response to, the preovulatory gonadotropin surge. This may reflect actions on the circadian drive and daily neural signal for ovulation with aging [13], although we did see effects on diestrous estradiol and FSH in the present study.

The transition to reproductive senescence often is accompanied by elevated FSH concentrations, delayed LH surges with altered pulse frequencies, and decreased serum estradiol [1, 10]. In acute studies of ovulation in the rat, TCDD accelerates and intensifies similar changes in gonadotropin and steroid profiles in a manner paralleling reproductive aging in the female [20]. TCDD induces a premature LH and FSH surge and antagonizes the hypothalamic actions of estradiol on proestrus [41]. Intrauterine and lactational exposure of female rats to TCDD alters estrogen concentrations and gonadotropin synthesis [42–45]. In the present study, we observed elevated serum FSH and progesterone concentrations and decreased estradiol on the morning of diestrus in rats treated chronically with TCDD. Such preferential disruption of FSH without a significant effect on LH is in agreement with the results of previous short-term studies [27], although this effect was significant only at one dose in the present study. Selective disruption of FSH following AHR activation may reflect an alteration in GnRH pulse frequency to favor FSH secretion or indicate decreased inhibin release or action. We were unable to detect alterations in serum or ovarian inhibin, however, following acute exposure of rats to TCDD during follicular development in a previous study [34], which argues against decreased inhibin as a mechanism for elevated FSH in the present work.

A number of studies have addressed the effects of TCDD on steroidogenesis in vitro and in vivo, with variable results. In some rat studies, TCDD has altered ovarian steroid synthesis [40, 46, 47]. On the other hand, although TCDD blocks ovulation in the rat at high doses, the lack of a direct action on ovarian granulosa and thecal-intestinal cell steroidogenesis was reported [48]. In the present study, TCDD decreased serum estradiol without changes in follicle numbers. Theoretically, this might be the influence of TCDD on distribution, metabolism, and elimination of steroids, although we failed to find an acute effect of TCDD on the pharmacokinetics of estradiol and progesterone previously [49]. Roby [50] did find a reduction in ovarian gonadotropin receptor expression following exposure of rats to TCDD, possibly explaining the decreased estradiol in the present study. Future studies are needed to address hormonal changes throughout the reproductive cycle induced by chronic AHR activation and accompanying premature reproductive aging.

The rule of Haber [51] supports the notion that chronic exposure to low doses of a toxicant exerts effects similar to those from acute high-dose exposure provided that the areas under the respective dose-time curves are equivalent. In the present study, we have data from a single high-dose (10 µg/kg), prepubertal exposure to TCDD and chronic low-dose (50 and 200 ng/wk p.o. and 1.7 and 8 µg/kg of cumulative exposure, respectively) exposure to TCDD beginning in prenatal life. The doses chosen for the chronic study are equivalent to a daily exposure of approximately 7500–30000 pg kg–1 day–1 or a cumulative exposure of roughly 50–10000 ng/kg in total across the normal reproductive life span (1 yr) [7]. These doses mimic the exposure of high-risk populations to dioxin-like compounds [52] and have been well characterized for other endpoints in previous chronic studies [53]. Interestingly, chronically treated rats began the premature transition to reproductive senescence much sooner (8 vs. 10 mo of age) than the group receiving a single prepubertal exposure that was approximately sixfold greater than the low-dose, chronic exposure regimen. This may reflect an increased sensitivity of the developing reproductive axis to TCDD during fetal and early postnatal life, because the chronic exposure model began in utero and the acute exposure occurred just before puberty. Alternatively, a single high dose of TCDD may only saturate the AHR pathway briefly, whereas the chronic low-dose exposure persistently stimulates the AHR gene battery.

In conclusion, a single prepubertal exposure to the AHR agonist (TCDD) resulted in a shortened reproductive life span with delayed puberty, abnormal cyclicity, and premature reproductive senescence in the female rat. Chronic exposure to low doses of TCDD hastened the process of reproductive aging in female rats by endocrine disruption rather than by depletion of follicle reserves. Future work is needed to determine the sensitivity of the aging female reproductive axis to AHR ligands and to discover that developmental processes and neuroendocrine pathways that are particular targets of AHR-mediated toxicity, resulting in premature reproductive senescence.

ACKNOWLEDGMENTS

We thank Dr. Karl Rozman, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, for donating the TCDD. We also would like to acknowledge Dr. Rozman and Dr. Paul Terranova for critical discussions during the planning and conduct of these experiments. Thanks go to Dr. Xin Gao and Margitta Lebofsky for technical assistance.

FOOTNOTES

1 Supported in part by the Kansas City Area Life Sciences Initiative, NICHD HD28934 and NIEHS ES012916. Back

2 Correspondence: Brian K. Petroff, Center for Reproductive Sciences, Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. FAX: 913 588 7180; bpetroff{at}kumc.edu Back

Received: 2 June 2005.

First decision: 20 June 2005.

Accepted: 15 September 2005.

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