Study of the relation between the incidence of uterine leiomyomas and the concentrations of PCB and DDT in Baltic gray seals
Introduction
Earlier studies on Baltic gray seals (Halichoerus grypus) have revealed a high incidence of lesions such as adrenocortical hyperplasia, osteoporosis, intestinal ulcers, renal lesions, uterine stenosis and occlusions, and uterine leiomyomas, often occurring in combination [1]. The different types of lesions indicate hormonal imbalance, metabolic disorder and immunosuppression. These observations have been associated with findings of organochlorine contaminants and especially of high levels of dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) in the seals [2]. The results of an experimental study in The Netherlands, in which harbor seals (Phoca vitulina) feeding on fish from PCB-polluted coastal waters failed to reproduce [3], indicate that PCB can disturb reproductive processes. Organochlorine pollution might also be involved in the development of renal lesions in Baltic gray seals [4].
In mink (Mustela vison), the litter size was reduced by dietary PCB [5], [6], but was not affected by dietary DDT [5]. Further, PCB-treated animals showed a reduced uterine glandular diameter, a peak plasma estrone sulfate concentration that was not found in the control groups, and under-developed placentas [6]. PCB exposure also caused placental lesions such as degenerate endothelial cells, loss of endothelial cells, and thrombi in the maternal vessels [7], suggesting that placental lesions may be a causative factor in fetal death after PCB exposure in mink. There are also other examples of species in which reproductive effects have been reported after PCB exposure, as reviewed by Vos et al. [8].
A time-trend pathological study between 1977 and 1986 revealed that 42% of collected Baltic gray seal females had uterine occlusions and/or stenosis, and that 53% of the gray seal females older than 4 years had uterine leiomyomas [9]. During the 1970s, the levels of PCB and DDT in Baltic biota began to decrease [10]. The prevalence of uterine occlusions and stenoses among Baltic gray seal females older than 4 years decreased to 11% in animals examined between 1987 and 1996 [9]. During the same time period, the leiomyoma prevalence decreased to 43% and the pregnancy rate increased from 9 to 60% in females older than 4 years.
The etiology and pathogenesis of uterine leiomyoma are not clear but once developed, these tumors in humans seem to be ovarian steroid-dependent, as evidenced by their growth during the reproductive years and increase in size during pregnancy, as well as regression following the menopause [11], [12]. Further, treatment with a progesterone antagonist causes leiomyoma regression [13]. Accordingly, it is possible that endocrine-disrupting environmental pollutants such as DDT and PCB may have an influence on the proliferation rate in existing leiomyomas. There are no reports of general occurrence of uterine leiomyomas in seal populations outside the Baltic Sea and it thus seems as if the lesions are associated with the Baltic Sea environment.
DDT and some PCBs, and their metabolites, are anti-estrogenic or estrogenic [14], [15], [16], [17], [18]. Some hydroxylated PCB metabolites bind the α and β estrogen receptors [17], [19], stimulate transcriptional activity from both receptors in vitro [19] and increase the uterine weight in mice in vivo [17]. Estrogenic effects might also be mediated by inhibition of the estrogen-inactivating enzyme estrogen sulfotransferase, resulting in increased estrogen bioavailability in target tissues [14]. Further, some hydroxylated PCB metabolites reduce cell viability [15] and bind weakly to the transmembrane estrogen receptor GPR30 [20].
It has been reported that o,p′-DDT binds to estrogen receptor α [19], [21] and β [19]. Further, o,p′-DDT stimulates transcriptional activity from both estrogen receptors [19], has estrogenic effects in the female reproductive tract of rats [18], [22], [23], chicken and quail [18], inhibits uterine uptake of estradiol in rats [22], and is inhibited by substances that also block estrogenic effects [23]. In ovo exposure to o,p′-DDT and other xenoestrogens may disturb gonadal development [24], [25] and male sexual behavior in adult birds [26], [27]. p,p′-DDT and the DDT metabolite o,p′-dichlorodiphenyldichloroethylene (DDE) also bind weakly to GPR30 [20]. DDE causes reproductive failure due to eggshell thinning and broken eggs in avian wildlife [28], [29]. In male rats the DDT metabolite p,p′-DDE exerts anti-androgenic effects both in vitro and in vivo by inhibition of androgen binding to the androgen receptor, androgen-induced transcription, and androgenic action [30]. Furthermore, developmental abnormalities of the gonads, and altered sex steroid concentrations in hatching alligators from the DDT-contaminated Lake Apopka in Florida have been reported [31], and alligator eggs from the same lake contain high levels of the metabolite p,p′-DDE [32].
Taken together, PCB and DDT and their metabolites seem to be involved in reproductive disturbances of several species, including mink and Baltic seals. The aims of this study were (1) to investigate whether there is an association between the concentrations of PCB and DDT in Baltic biota and the occurrence of uterine leiomyomas in Baltic gray seals examined between 1973 and July 2007, and (2) to measure the blubber concentrations of PCB and DDT in a subset of gray seal females aged 22 years or older with uterine leiomyomas as compared to those in a corresponding subset of females without these tumors. A further objective was to study the proliferative activity of leiomyomas in a subset of females without corpora lutea in the ovaries, since, if present, proliferative activity of the leiomyomas in these females might be dependent on other stimulants of proliferation than ovarian hormones. We hypothesized that higher contaminant levels of PCB and DDT could be associated with a higher incidence of uterine leiomyomas and possibly also with higher proliferative activity in the leiomyomas.
Section snippets
Materials and methods
Hunting of gray seals was prohibited in Sweden between 1974 and 2000. Therefore, most seals included in this investigation were found dead in fishing gear (accidentally caught) or on beaches.
Occurrence of Baltic gray seal uterine leiomyomas and concentrations of PCB and DDT in Baltic biota
Uterine leiomyomas were only present in seals between 22 and 41 years of age (Fig. 2). The prevalence of uterine leiomyomas in this age group was 65% and in the total study population 15%. Among all investigated seals of ages 22–41 years, the leiomyoma-bearing seals (n = 39) had an earlier mean birth year (1954) than the seals without leiomyomas (n = 21, mean birth year 1961), and the leiomyoma-bearing seals were older (mean age 33 years) than the control seals (mean age 26 years).
The levels of
Discussion
The reproductive rate of the Baltic gray seals was low during the 1960s and 1970s, but began to recover in the middle of the 1980s [9]. By that time, the levels of PCB and DDT in the Baltic environment had begun to decrease [10], but the prevalence of lesions, such as uterine leiomyomas, in the reproductive tract was still high among the gray seal females [9]. Reports have been published indicating that PCB and DDT might be involved in disturbances of reproductive functions in several species
Acknowledgements
The authors would like to acknowledge Euro Chlor, CEFIC-EMSG in Brussels, Belgium, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS), and the Swedish Animal Welfare Agency for financing the project. We also want to express our sincere gratitude towards Veterinary Anders Bergman, Department of Contamination Research, Swedish Museum of Natural History, who performed many of the gray seal dissections, Erik Greyerz, Laboratory assistant, Department of
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