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BOR - Papers in Press, published online ahead of print October 4, 2002.
Biol Reprod 2002, 10.1095/biolreprod.101.002006
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Biology of Reproduction 67, 1734-1740 (2002)
DOI: 10.1095/biolreprod.101.002006 © 2002 Society for the Study of Reproduction, Inc.

Ovary

Effect of Maternal Exposure to the Environmental Estrogen, Octylphenol, During Fetal and/or Postnatal Life on Onset of Puberty, Endocrine Status, and Ovarian Follicular Dynamics in Ewe Lambs

C. Wrighta,b, A.C.O. Evansa, N.P. Evansc, P. Duffya, J. Foxb, M.P. Bolanda, J.F. Rocheb, and T. Sweeney1,b

a Faculties of Agriculture b Veterinary Medicine, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland c Department of Veterinary Preclinical Studies, University of Glasgow Veterinary School,Glasgow G61 1QH, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Octylphenol (OP) is one of a number of compounds found in the environment that has estrogen-mimicking actions in vivo. Our objective was to determine if maternal exposure to octylphenol during fetal and/or postnatal life would affect the onset of puberty, endocrine status, and subsequent ovarian follicular dynamics of ewe lambs. Lambs were born in March to ewes that received twice weekly s.c. injections of octylphenol (1000 µg/kg/day) from Day 70 of gestation to weaning (n = 6); Day 70 of gestation to birth (n = 3); birth to weaning (n = 5; gestation = 145 days); or corn oil from Day 70 of gestation to weaning (control; n = 5). Blood samples were collected twice weekly to determine progesterone and FSH concentrations from 20 wk of age throughout the first breeding season. Onset of puberty and interestrous intervals were determined from 20 wk of age by twice daily observation for estrus in the presence of a vasectomized ram. During January the ovaries of each lamb were examined using transrectal ultrasonography from the day of estrus for 15 days. Blood samples were collected every 8 h to examine FSH concentrations and every 2 h to detect the preovulatory gonadotropin surge throughout this estrous cycle. The onset of puberty and first progesterone rise was advanced and the FSH preovulatory surge was elevated for longer in the OP-treated lambs compared with the control lambs (P < 0.05). Interestrous intervals, FSH profiles, and ovarian follicular dynamics were not affected (P > 0.05) by exposure to octylphenol. In conclusion, octylphenol exposure advanced the onset of puberty but it did not disrupt FSH concentrations or the dynamics of ovarian follicular growth.

environment, follicle, follicle-stimulating hormone, ovulatory cycle, puberty


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Widespread international concern has intensified over the deleterious effects of endocrine disrupting compounds (EDCs) found ubiquitously in the environment [1–5]. Possible human end points affected by EDCs may include an increase in estrogen-sensitive cancers (breast and testicular) [2, 6], declining sperm quality in men [7–10], a rise in endometriosis [11], and precocious puberty in women [12, 13]. In addition, many chemicals released into the environment can disrupt normal endocrine and reproductive function in a variety of wildlife and domestic animals [14–18].

Estrogen is essential for growth and development of the reproductive tract, regulation of estrous cyclicity, and the development of secondary sex characteristics [19]. To elicit these actions, estrogen binds to specific intracellular estrogen receptors. Chemicals found in the environment have several mechanisms through which they may disrupt the endocrine and reproductive systems. Chemicals such as alkylphenol polyethoxylates (APEOs) used in the manufacture of detergents and pesticides are prevalent in the environment as pollutants found in sewage and rivers [20, 21]. APEOs and their breakdown products, such as octylphenol (OP), mimic steroid hormone action by competing with estradiol and binding to estrogen receptors [20] and initiate transcription of estrogen-receptor-regulated genes in vitro [22–24]. OP can also stimulate estrogen receptor-mediated physiologic responses in vivo [25, 26]. Although OP and other EDCs may only be weakly estrogenic, they potentially pose a threat to living organisms because of their persistency and ability to bioaccumulate in adipose tissue [27, 28].

Studies in rats have demonstrated that exposure to OP disrupts puberty onset, estrous cycles, gonadotropin, and steroid secretion [26, 29–31]. Recent studies in sheep, examining the effect of fetal exposure to OP, have identified altered FSH concentrations [32] and folliculogenesis [33] in newborn lambs. Our objective was to investigate the effects of exposure to the environmental estrogen OP during fetal and/or postnatal life on the onset of puberty, endocrine status, and ovarian follicular growth characteristics in ewe lambs.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Treatment

Nineteen Suffolk cross ewe lambs were born in March to ewes that had received 1000 µg/kg of OP in twice weekly s.c. injections during gestation and lactation. These ewe lambs were exposed to OP from Day 70 of gestation to weaning (treatment 1; n = 6); Day 70 of gestation to birth (treatment 2; n = 3); birth to weaning (treatment 3; n = 5); or corn oil from Day 70 of gestation to weaning (treatment 4; n = 5). The 4-(tert-octyl)phenol ((CH3)3 CCH2C(CH3)2 C6H4OH) (Aldrich Chemical Company, Inc., Milwaukee, WI) had a purity value of 97%. It was dissolved in corn oil on the day of application. The lambs were maintained outdoors with their mothers and were weaned at 5 mo of age. At 6 mo of age the animals were housed with free access to water and were each fed 0.45 kg/day of 19% protein ration and 0.5 kg/day of hay. Animals were penned according to treatment. All procedures were in accordance with the cruelty to animals act 1876 (European Community Directive 86/609/EC) licensed by the Department of Health and Children, Ireland.

Endocrine Status and Ovarian Estrous Cycles Throughout the First Breeding Season

Blood samples were collected twice weekly by jugular venepuncture from 20 wk of age throughout the breeding season for FSH and progesterone analyses. Blood samples were stored at room temperature for 1 h, placed in a refrigerator (4°C) for 24 h, and centrifuged at 4°C for 20 min. The serum was decanted and stored at -20°C until required for assay.

First behavioral estrus (identified as the first date the female stood to be mounted), interestrous interval, duration of estrus, and end of breeding season were determined from 20 wk of age by twice daily observation of ewes in the presence of a vasectomized ram. The end of the breeding season was determined by transrectal scanning of the ovaries and 2 times daily heat checking. Onset of puberty was defined as the first progesterone rise (defined as the date the progesterone concentration first reached >=0.4 ng/ml for two consecutive samples), followed by the first behavioral estrus. The weight of each animal was recorded at 3-wk intervals.

Endocrine Status and Follicular Dynamics

To determine if pre- and/or postnatal exposure to OP had disrupted folliculogenesis and/or endocrine status, hormone concentrations and follicle growth patterns were monitored over 15 days during a synchronized estrous cycle toward the end of the breeding season (January). A catheter was inserted into the jugular vein of each ewe to facilitate collection of blood. Throughout this period blood samples were taken every 8 h for FSH concentration and blood samples were collected every 2 h (commenced 24 h postprostaglandin injection) to detect the preovulatory gonadotropin (FSH and LH) surge. A vasectomized ram was introduced into the pen every 8 h to check for estrus activity.

Ovarian Function

Ovarian cycles were synchronized by two i.m. injections of Prostaglandin F2{alpha} (0.5 ml Estrumate) 24 h apart. Ovarian follicular activity was studied for 15 days from estrus by transrectal ultrasonography. During examination periods (5 min) the animals were housed in darkened conditions and were restrained in a fostering crate. Scanning was conducted using a rigid 7.5 MHz linear array transducer (Concept 500; Dynamic Imaging Ltd., Livingston, Scotland) as previously described [34]. The transducer was covered with a lubricant gel, inserted into the rectum, and manipulated externally using the landmark of the bladder and uterine horns to locate the ovaries. The position and diameter of each follicle >=2 mm in diameter and of each corpus luteum was recorded daily as previously validated for ewes [35]. Individual follicles that reached 4 mm in diameter and that were >=3 mm for >=3 days were retrospectively defined as identified follicles. Emergence was defined as the synchronous growth of a cohort of identified and unidentified follicles, which were 2 or 3 mm in diameter. The day of ovulation was determined by the collapse of the large antral follicle and formation of a corpus luteum in its place and confirmed by detection of estrus using a vasectomized ram.

RIA Analyses

Luteinizing hormone Serum concentrations were determined by radioimmunoassay using a modification of the method described by Sweeney [35]. Briefly, on Day 1, 200-µl aliquots of serum or standard (NIDDK oLH—AFP 9598B), 100 µl of monoclonal antibody (518B7 mcAby), and 100 µl of I125-labeled radioligand (NIDDK oLH—I—3 AFP 9598B) were added to tubes. The tubes were vortexed and incubated at room temperature for 24 h. On Day 2, 50 µl of secondary antibody (donkey antimouse, SAC-CELL, A-SAC 4, IDS, Boldon, Tyne and Wear, U.K.) was added to the tubes, vortexed, and incubated for 30 min at room temperature. Distilled water (250 µl) was added and the tubes were centrifuged at 2500 rpm for 5 min. The supernatant was aspirated and the amount of radioactivity in the pellet was determined using a gamma counter.

The sensitivity of the assay was 0.1 ng/ml with 95% binding. Interassay coefficient of variations (CVs) at 0.3, 1.7, and 3.6 ng/ml (n = 10) were 9.3%, 9.7%, and 11.7%, respectively, and intraassay values were 27.6%, 14.8%, and 17.7%, respectively (n = 6).

Follicle-stimulating hormone The circulating concentrations of FSH were measured in duplicate aliquots of plasma using an anti-ovine antibody (NIDDK oFSH AFP 5288113) and an iodinated antigen (NIDDK oFSH–I–SIAFP–21 AFP 7571A), with a modification to the ovine standards (USDA–oFSH–SIAFP–RP–2) described by Evans et al. [36]. The sensitivity of the assay defined by 95% binding was 0.06 ng/ml. Interassay CVs for the three serum pools with values of 0.3, 1.3, and 3.4 ng/ml (n = 15) were 15.2, 15.2, and 18.2%, respectively. Intraassay CVs were 28.85, 15.4, and 11.9%, respectively (n = 6).

Progesterone Serum progesterone concentrations were determined using a modification of the time resolved solid phase fluoroimmunoassay DELFIA progesterone kit (EG&G Wallac, Turku, Finland) [34]. The standard supplied with the kit was replaced by progesterone (Sigma P0130) standard, which was added to prepared progesterone-free ovine serum. Interassay CVs at 0.2, 1.1, and 2.3 ng/ml (n = 10) were 20.3%, 13.6%, and 7.5%, respectively. Intraassay values were 14.8%, 5.78%, and 10.8%, respectively (n = 6).

Statistics

Differences in the onset of puberty; first progesterone rise; interestrous interval; and body weight throughout the first breeding season and at the onset of puberty, end, and duration of the breeding season were analyzed using ANOVA (repeated measures where relevant) and Duncan t-test. The onset of puberty data was further analyzed with body weight as a covariate using the General Linear Models procedure of SAS (SAS version 6.12, Cary, NC) [37]. Twice-weekly endocrine profiles, FSH, and progesterone were analyzed by repeated-measures ANOVA using SAS.

Data from both ovaries were combined and the following parameters were examined by ANOVA in SPSS, version 8.02 (Chicago, IL) [38]: The number of waves; interwave interval; number of identified follicles per wave; ovulatory and maximum follicle diameter; the total number of follicles (small, medium, and large follicles combined); and the mean 8 hourly FSH concentrations. The characteristics of the preovulatory gonadotropin surges were compared across groups by ANOVA in SAS.

Before ANOVA, logarithmic transformations were carried out where necessary to yield homogeneity of variance. All values are given as the mean ± SEM.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Animals exposed to OP had an earlier (P < 0.05) onset of puberty in comparison to control animals, as determined by the first progesterone rise and first behavioral estrus (Table 1). In contrast, maternal exposure to OP had no effect (P > 0.05) on the date at which the breeding season ended in these animals (Table 1). All animals became anestrus at a similar time, hence the duration of the breeding season was shorter in control ewes (58 ± 10 days) than in OP-treated animals (85 ± 7, 93 ± 10, 86 ± 9 days; P < 0.05). Treatment with OP did not affect (P > 0.05) the interestrous interval (Table 1) or progesterone (5 wk before, 2 wk after) concentration around the time of onset of puberty (Fig. 1).


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  		TABLE 1. Mean (±SEM) reproductive parameters and weight at puberty in ewes treated with octylphenol from Day 70 of gestation to weaning, Day 70 of gestation to birth, birth to weaning, or corn oil alone (control).a



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  		FIG. 1. Mean progesterone concentrations during the 5 wk before and 2 wk after the first estrus in ewe lambs treated with octylphenol from Day 70 of gestation to weaning (open diamond: n = 6), Day 70 to birth (open square: n = 3), birth to weaning (open triangle: n = 5), or corn oil (filled circle: control n = 5)

At the onset of puberty no differences were noted in body weight between any of the OP-treated or control animals (Table 1). The animals treated with OP were significantly heavier in November (Day 70 to weaning, 47 ± 1.6 kg; Day 70 to birth, 49 ± 1.9 kg; birth to weaning, 49 ± 2.3 kg) and December (Day 70 to weaning, 49 ± 1.7 kg; Day 70 to birth, 51 ± 1.0 kg; and birth to weaning, 49 ± 2.3 kg) than the control ewes (41.4 ± 1.4 kg and 42.9 ± 1.5 kg, respectively; Fig. 2). However, there were no differences (P > 0.05) among groups for animal weights in October or January.



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  		FIG. 2. Schematic representation of the correlation between onset of puberty and weight for each group: the progeny of ewes treated with octylphenol from Day 70 of gestation to weaning (open diamond: n = 6), Day 70 to birth (open square: n = 3), birth to weaning (open triangle: n = 5), or corn oil (filled circle: control n = 5). Each individual symbol represents the date of onset of puberty of an animal grouped by treatment. The lines represent the mean body weight in each group from October to January. Significant differences in body weight observed in November and December are indicated by a star symbol

Gonadotropin secretion was monitored at 2-h intervals around the time of the expected preovulatory surge during the study. A FSH surge was only detected in one animal in Day 70 of gestation to birth group (n = 1), and as a result this group was omitted from the analysis. No significant differences were noted between groups in the amplitude of the LH surge. However, when the FSH concentrations were aligned relative to the peak LH preovulatory surge, FSH was elevated for longer in control rather than OP-treated animals (Fig. 3). In contrast, mean FSH concentrations as assessed in twice-weekly blood samples prior to and during the first breeding season and the mean FSH concentrations across the study cycle were unaffected by treatment (P > 0.05; Table 2). Waves of ovarian follicle growth were noted in all animals but no differences (P > 0.05) were seen among groups in the proportion of ewes having two or three follicle waves per cycles or the interval between waves (Fig. 4). The mean number of identified follicles per wave, the mean diameter of the ovulatory follicle, and the diameter of the largest follicle were also unaffected by treatment (P > 0.05). There were no differences (P > 0.05) detected in the number of small, medium, or large follicles, or combined numbers of follicles.



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  		FIG. 3. Mean (±SEM) FSH concentrations in 2-h samples during the preovulatory surge in ewe lambs plotted aligned to the peak of the LH surge: treated with octylphenol from Day 70 of gestation to weaning (open diamond: n = 6), birth to weaning (open triangle: n = 5), or corn oil (filled circle: control n = 4). A star identifies significant differences in FSH concentrations among groups


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  		TABLE 2. Mean (±SEM) ovarian follicular dynamics and FSH concentrations during 15 days from estrus in ewes treated with octylphenol from Day 70 of gestation to weaning, Day 70 of gestation to birth, birth to weaning, or corn oil alone (control). There were no significant differences (P > 0.05) among groups.a



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  		FIG. 4. Growth patterns of identified ovarian follicles in wave 1 (filled circle), wave 2 (filled triangle), and wave 3 (filled square) in individual animals treated from Day 70 of gestation to weaning (A and E, n = 6); Day 70 of gestation to birth (B and F, n = 3); birth to weaning (C and G, n = 5); or corn oil (D and H, control n = 5). A–D) Animals with two follicle waves per cycle; E–H) animals with three follicle waves per ovarian estrous cycle. Mean (±SEM) FSH (filled diamonds) concentrations in 8-h samples are located at the lower portion of the graph. Arrows indicate time of ovulation


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Advancing the onset of puberty without affecting interestrous intervals, endocrine profiles throughout the first breeding season, or ovarian follicular dynamics demonstrates that OP did not exert a general overt effect, but rather acted as a specific and discrete endocrine disrupter at critical time periods during the development of ewe lambs and the estrous cycle. The noted effects on puberty mirror a trend in the human population where young girls are developing pubertal characteristics at a significantly younger age [39], and there is concern that this may be partially due to exposure to EDCs. Advancement of puberty in rats exposed to chemicals with estrogenic action was discovered 30 yr ago in a number of trials [40–42]. Our data supports recent animal studies where pre- [43] and postnatal exposure [29, 30] to various known endocrine disrupters, including OP, advances the age of vaginal opening in rats.

This study examined both the long-term changes in gonadotropin secretion (20–46 wk) and acute changes over the course of an estrous cycle. No significant changes were detected in mean FSH concentrations from 20 wk of age or at 8-h intervals during the estrous cycle. However, when FSH concentrations during the preovulatory gonadotropin surge were aligned to the peak of the LH surge, suppression in FSH concentrations was detected in OP-treated lambs both before and after the surge. A similar differential effect of OP on FSH and LH secretion has been described in male and female lambs exposed during fetal life where maternal exposure to OP suppressed FSH concentration without any effect on LH [32]. Hence OP may induce effects on the systems that regulate gonadotropin secretion, which result in the observable effects in utero and at specific times during the first year of life. There are conflicting reports on the effects of environmental chemicals on endocrine profiles in males and females. Postnatal exposure to endocrine-disrupting compounds (OP and pesticide) has been shown to decrease or increase serum LH and FSH concentrations in male rats and rams [44–46]. In female rats, postnatal and adult exposure to xenoestrogen had a suppressive effect on serum concentrations of LH, FSH, and progesterone [29, 47, 48].

There are varying reports on the effects of endocrine-disrupting compounds on body weight. Laws et al. [29] reported that none of the environmental estrogens examined had any significant effects on body weight in rats exposed as adults or during neonatal life, whereas Yoshida et al. [31] reported that female adult rats exposed to high doses of OP showed a significant suppression of body weight. However, our results support the findings of Howedshell et al. [43] who found that exposure to an EDC increased postnatal body weight and advanced puberty in female mice. Therefore, from these results we can suggest that OP may be exerting an anabolic estrogenic effect promoting growth in sheep.

It is recognized that neither the gonad nor the anterior pituitary of the immature sheep limit sexual development [49–51], and a previous study has demonstrated that delivery of exogenous GnRH during neonatal life was effective in inducing precocious puberty in ewe lambs. The pituitary LH release system in prepubertal ewe lambs is capable of responding when exposed to exogenous estradiol [52, 53]. Nass et al. [53] discovered altered reproductive function and gonadotropin response in rats treated with estrogen before puberty and hypothesized that it was due to an alteration in hypothalamic GnRH release [51]. In addition, estrogenic mimics present in the environment can disrupt hypothalamic control of pituitary-ovarian function in the rat [47, 54]. Combining the information from these studies and our results, we hypothesize that exogenous treatment with OP may have altered GnRH secretory patterns by advancing the lambs' sensitivity to the stimulatory effects of estradiol.

Development of the full complement of oocytes available in adult life occurs during fetal development in the sheep under the influence of high concentrations of FSH between Days 100 and 130 of gestation [55]. Exposure to OP during this critical period of development has been shown to alter adult follicle populations and promote early follicle growth in sheep [33]. We therefore hypothesized that the earlier onset of puberty may be associated with a disruption in the characteristics of follicle development. Studies in rats have demonstrated that postnatal exposure to a range of environmental estrogens can disrupt estrous cyclicity [29, 31, 44, 53, 56] and block ovulation [49]. Endocrine disrupters could affect follicle wave dynamics by altering steroid receptor function [29] or hypothalamic GnRH release [53]. In contrast, the data in the present study suggest that exposure to OP during fetal and/or postnatal life does not have any adverse effect on follicle wave dynamics toward the end of the first breeding season. All ewes had two to three waves of follicle growth during an estrous cycle, which is in agreement with previous studies [34, 57, 58]. In addition, the duration of estrus of ewes in this trial was normal according to the classic study of McKinszie and Terrill [58].

OP altered physiological processes by advancing the onset of puberty and first progesterone rise, yet once the ewes reached puberty the xenoestrogen appeared to no longer exert a disrupting effect and the ewes underwent normal follicle wave development. This pattern is not without precedence as neonatal exposure of male rats to OP has been shown to advance aspects of pubertal spermatogenesis [59] and disrupt development of excurrent ducts in the testis [60], but by adulthood these effects were no longer evident. There are two possible explanations for this. First, Stoker et al. [54] has shown that continued exposure to a xenoestrogen is without apparent effect on female reproductive capacity, indicating that the female may become tolerant to such adverse effects. Second, effects of chronic exposure may not be obvious until the offspring is well into adulthood. Data by Picton et al. [33] would suggest that if the ewe lambs in this study were maintained until later in adult life they may have had a shorter reproductive life span. The reproductive consequences of advancing puberty seen in this study raises a serious health concern, as evidence is available that suggests that women who attain puberty at significantly earlier ages are at greater risk of developing breast cancer in later life [12].

In conclusion, maternal exposure to OP during pre- and/or postnatal life advanced the onset of puberty and first progesterone rise but did not disrupt the interestrous interval or endocrine profiles throughout the first breeding season or the pattern of ovarian follicular dynamics.


   ACKNOWLEDGMENTS
 
We thank Tony Harte, Pat Brophy, Gerry Connellan, and the staff at Lyons for their assistance and maintenance of animals throughout the trial. They also wish to thank Denis Flynn, Liz Lane, Jose Maria Lozano, Fabian Ward, Brian Enright, and David Nation for their assistance during the experiment. We are also grateful to Niamh Hynes and staff at the Animal Husbandry and Production laboratories for assisting with hormone assays. We would like to express our thanks to A.F. Parlow (NIDDK National Hormone and Pituitary Programme) and J.F. Roser, University of California, Los Angeles (UCLA), for their gifts of hormone preparations. Further thanks to John Dardis and Sylvie Snjieders for their statistical assistance.


   FOOTNOTES
 
1 Correspondence: Torres Sweeney, Department of Animal Husbandry and Production, Faculty of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland. FAX: 353 1 6600883; tsweeney{at}vetmed.ucd.ie Back

Received: 29 November 2001.

First decision: 27 December 2001.

Accepted: 28 May 2002.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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K. D. Malcolm, L. M. Jackson, C. Bergeon, T. M. Lee, V. Padmanabhan, and D. L. Foster
Long-Term Exposure of Female Sheep to Physiologic Concentrations of Estradiol: Effects on the Onset and Maintenance of Reproductive Function, Pregnancy, and Social Development in Female Offspring
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