1 Department of Epidemiology, Michigan State University, 4660 S. Hagadorn Road, Suite 600, East Lansing, MI 48823, USA
2 To whom correspondence should be addressed. e-mail: karmaus{at}msu.edu
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Abstract |
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Key words: DDE/in utero/menarche/offspring/PCB
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Introduction |
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Previous studies indicate that PCBs and DDE may exert endocrine-disruptive effects (McKinney and Waller, 1994; Kelce and Wilson, 1997
; Sonnenschein and Soto, 1998
; Yu et al., 2000
; Aoki, 2001
; Bonefeld-Jorgensen et al., 2001
). A number of studies have investigated the potential impact of organochlorine compounds on sexual maturation (Gladen et al., 2000
; Krstevska-Konstantinova et al., 2001
; Staessen et al., 2001
), but to our knowledge only two reported age at menarche. In 120 girls from three Belgian villages with different PCB exposure levels, no regional differences were detected (13.1 ± 1.2 years) (Den Hond et al.. 2002
). Blanck et al. (2000
) reported that prenatal exposure to polybrominated biphenyls (PBBs) was associated with a lower age at menarche. PBBs have the same chemical structure as PCBs, but have a different halogen component (bromine instead of chlorine).
To the best of our knowledge, no study has investigated the association between prenatal DDE exposure and age at menarche in the offspring as a marker of an endocrine effect.
Contamination of fish in the Great Lakes led to three successive surveys conducted to assess the PCBs and DDE burden in Michigan anglers and fish eaters. The surveys took place between 1973 and 1991. To test the hypothesis that women exposed prenatally to PCBs and DDE have an early age at menarche, we contacted the female offspring of this cohort.
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Materials and methods |
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In 2000, we approached this cohort (first generation) again; the details are described elsewhere (Karmaus et al., 2002a). The review boards on human subjects for Michigan State University and the Michigan Department of Community Health approved the study. A total of 391 women who were capable of having children between 1950 and 1980 and had recorded organochlorine measurements were included in these studies. Of these 391 potential participants, seven were deceased, 115 could not be contacted, and 10 did not give consent. The remaining 259 women (66.2%) provided information about 213 daughters 2050 years of age (second generation). We focused on daughters in this age range for the purpose of studying reproductive health effects. The Michigan State University committee on research involving human subjects also approved the offspring study. The female offspring were then contacted and, after written consent was obtained, trained staff conducted telephone interviews on their reproductive history.
PCB and DDE determinations in the parent generation
Subjects of the three surveys, conducted between 1973 and 1991, provided non-fasting blood samples for serum determinations of PCBs, DDE and other organochlorine compounds. All serum samples were analysed at the Health Risk Assessment Laboratory of the Michigan Department of Community Health in Lansing. A modification to the Association of the Official Analytical Chemists-approved Webb-McCall packed column gas chromatography technique was used to determine PCB and DDE levels. The analytical methods used are described in detail elsewhere (Needham et al., 1981; Price et al., 1986
). In brief, the procedure used methanolether/hexane extraction, microflorisil column clean-up and a silicon gel separation technique before injection into a programmed electron detection chromatograph. In the first two surveys (19731974 and 19791982), the laboratory PCB determinations were based on Aroclor 1254 and 1260 standards. The third survey (19891991) used Aroclor 1016 and 1260 standards. For purposes of comparison, we used the serum PCB measurements based on the Aroclor 1260 standard, which were available for all samples. The specimens with values less than the detection limit for Aroclor 1260 (3 µg/kg) were reported as 1.5 µg/kg. For PCBs, <5% of all samples were below the detection limit for all three surveys. DDE was not determined in the first survey (19731974). The technical detection limit for DDE in the following surveys was 1 µg/kg.
Backward extrapolation
Having repeated PCB measurements and additional survey information (19731974, 19791982 and 19891991) for mothers, we conducted linear regression analyses and used the results to backward-extrapolate serum organochlorine levels (Karmaus et al., 2003). Each of the two regression models covers one period between two survey measurements. We estimated regression coefficients for the most parsimonious models (Table I), and tested how well the two equations predicted actual organochlorine measurement collected in the past. By means of intra-class correlation coefficients (ICCs), we compared estimated and measured past organochlorine exposures (Armstrong et al., 1992
). We identified two formulae that predicted past values with high reliability (ICC = 0.77 for the period 19911979, and ICC = 0.89 for the period 19821973, Table I). As we were able to derive our models from repeated measurements, our backward extrapolations more accurately estimated actual values than two other approaches regarding organochlorine contamination from fish consumption (Rylander et al., 1998
; Weisskopf et al., 2003
) that we additionally applied.
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Questionnaire
Information on potential confounders (date of birth, maternal age at birth, birth weight and breastfeeding) were acquired in the year 2000 from the parents. Maternal height and weight were retrieved from the 19891991 survey. In 20012002, we conducted telephone interviews with the female offspring regarding their reproductive health, and asked them to recall their age at menarche and also to state their highest level of education. In a separate questionnaire, women estimated their body size at menarche using a standardized series of drawings to determine body size on a scale of 19, with 1 representing the most slender and 9 the most corpulent body size (Veron-Guidry and Williamson, 1996).
Data analysis
We linked each child with its backward-extrapolated maternal DDE and PCB serum concentrations at birth. After linearity between the backward-estimated maternal DDE and PCB concentrations and age at menarche was confirmed, the exposures were treated as continuous variables. We used maternal height as a categorical variable with three levels (<155 cm, 155170 cm and >170 cm). The maternal body mass index (BMI) was calculated from height and weight (kg/m2). The childs birth year was divided into four categories (19501954, 19551964, 19651974 and 19741980). Maternal age at birth and birth weight were used as continuous predictors, and breastfeeding was considered as a categorical variable (yesno). Education of the offspring was classified as high school or less, some college, college graduate or graduate school.
In order to estimate the association between PCB and DDE levels and age at menarche for the female offspring, we conducted linear regression analysis controlling for birth year cohorts, maternal height and age, birth weight, breastfeeding, and educational status of the offspring. Additionally, we assessed a second model with estimated body size at menarche as an additional predictor for each exposure. The results of the linear regressions (GLM procedure) are presented as regression coefficient (estimate) and standard error. The data were analysed using SAS software version 8 (SAS Institute, 2002).
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Results |
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The study population consisted predominantly of non-Hispanic Caucasian women (99%). Age at menarche in the offspring ranged between 9 and 17 years (Figure 1). Both the extrapolated maternal PCB and DDE at birth were higher in women with a younger age at menarche. More women with age at menarche between 9 and 11 years belong to earlier birth cohorts (Table II).
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Discussion |
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The study subjects were identified from parents who were recruited in Michigan in three surveys between 1973 and 1991. Of the offspring identified, who had maternal DDE and/or PCB determinations (n = 213), 71% participated in our study. We assume that our findings did not result from selection biases.
We did not identify an effect of birth weight on age at menarche as suggested by Adair (2001). However, age at menarche was significantly associated with maternal height, which in turn may predict birth weight and length (Adair, 2001
). Since a higher maternal DDE level may be associated with a higher percentage of body fat, in a prior model, we also investigated maternal BMI (kg/m2). We detected a weak association between maternal BMI and DDE serum level (Spearmans r = 0.15, P = 0.07); however, maternal BMI was not a significant predictor of offspring age at menarche. The rank correlation coefficient between maternal BMI and age at menarche was Spearmans r = 0.10 (P = 0.21).
One strength of this study was the availability of repeated maternal serum DDE and PCB measurements conducted during three investigations. Of the mothers, 7.5% had three organochlorine determinations, 63.8% had two, and 28.9% had one. The individual serum DDE and PCB concentrations at each investigation were incorporated into the extrapolation models in order to provide the backward-estimated exposure of the offspring in utero. We additionally investigated whether results changed when we used DDE and PCB measurements that were closest to the date of delivery. This approach also showed a significantly lower age of menarche in offspring with higher maternal DDE levels. The reason is that the backward extrapolation did change the DDE concentrations but did not change their order significantly.
DDT was widely used after 1945, and maternal DDE levels are positively correlated with earlier year of birth (Spearmans r = 0.39). If it were the case that the association between DDE and early age at menarche may only be due to a presumed higher exposure between 1950 and 1964, we would assume that offspring born in this period would have a younger age at menarche. However, in this group of women, age at menarche did not vary significantly with calendar time: born 19501954, 12.7 years (n = 19); born 19551964, 12.8 years (n = 60); and born 1965 and later, 12.9 years (n = 72). Thus, higher historic exposure and calendar time cannot explain the DDE effect.
Frisch and colleagues have suggested that a critical percentage of body fat may be necessary for the onset of menses (Frisch, 1980, 1990; Rich-Edwards et al., 1994
) Furthermore, it has been suggested that body size during childhood and adolescence is associated with various pubertal stages (Duran-Tauleria et al., 1995
; Bini et al., 2000
; Luo et al. 2003
). For this reason, we additionally asked participants to rate their body size at menarche using drawings developed by Veron-Guidry and Williamson (1996
). Body size was significantly associated with age at menarche, and adjusting for body size reduced the effect and statistical significance of maternal DDE on age at menarche. However, since only 102 women provided these ratings, the statistical power to detect significant DDE differences in age at menarche was reduced when controlling for body size at menarche. In addition, a basic conceptual problem emerges when controlling for body size, since both age at menarche and body size are considered as responses to changes in the activity and metabolism of sex steroid hormones (Apter, 1980
; Danilovich et al., 2000
; Legro et al., 2000
; Meseguer et al., 2002
) Hence, endocrine disruption during the intrauterine development may simultaneously increase the risk for higher body mass and early menarche. In this case, we should not control for body size at menarche, since body size is not a cause, but just a different phenomenon potentially resulting from endocrine disruption. This view is supported by further analyses of our offspring cohort. We demonstrated that a higher intrauterine DDE exposure was also associated with increased adult weight (Karmaus and Eneli, manuscript submitted).
A limitation is the lack of information about individual PCB congeners. We had to use the total PCB concentration based on the Aroclor 1260 standard. This may be a problem because various PCB congeners may have different, sometimes antagonistic effects (Connor et al., 1997; Kodavanti et al., 2001
), which may have attenuated the observed association between total PCB and age at menarche. However, a strength is that the technique of organochlorine determination did not change over the three surveys in the parent generation (19731991), which facilitated the backward extrapolations. Our backward estimates were based on reliable predictions for the period of pregnancy (ICCs between 0.77 and 0.89). Nevertheless, we do not have information on DDE levels during childhood.
Since fish consumption is a relatively stable habit, an alternative possible explanation is that offspring with higher maternal DDE levels (higher fish consumption) (He et al., 2001) were also exposed to a higher fish consumption and higher DDE intake early in life. In this case, exposure during childhood rather than an interuterine exposure would be more critical. However, evidence provided through animal and human studies supports a fetal origin of altered adult reproductive function (Rabinovici and Jaffe 1990
; Jongbloet et al., 1994
, 2002), in particular estrogen suppression and changes in the expression of estrogen receptor genes (Pepe et al., 2002
; Zachos et al., 2002
, 2003). Changes in the expression of genes, regulating sex steroid activity and their metabolism, is also known to occur after exposure to endocrine disruptors (Chen et al., 1997
; Klotz et al., 1997
; Kaya et al., 2002
).
Age at menarche was reported in years as it was recalled, which is likely to introduce a non-differential misclassification. Additionally, women had to recall over a median period of 24 years (range 7.740 years). However, other studies showed a good agreement between actual age at menarche and recalled menarcheal age, for both short- and long-term recollections (Damon et al., 1969; Bergsten-Brucefors, 1976
; Damon and Bajema, 1974
; Casey et al., 1991
; Koprowski et al., 2001
; Must et al., 2002
).
It is of importance that different markers of sexual development may be dissociated. For instance, Den Hond et al. (2002) reported that age at menarche was significantly associated with breast development but not with pubic hair growth. Hence, studies on pubertal development are not directly comparable with investigations of age at menarche. For instance, Gladen et al. (2000
) reported no association between DDE exposure and pubertal stages, but did not report the association with age at menarche. Staessen et al. (2001
) reported for girls that a delay in adult breast development was associated with the estimated concentrations of dioxin-like compounds in serum samples of participants. Krstevska-Konstantinova et al. (2001
) suggested that precocious puberty and DDT/DDE exposure may be related. To our knowledge, there are only two reports on age at menarche: one identified an earlier age associated with PBB exposure; one found no difference with regard to PCB exposure (Blanck et al., 2000
; Den Hond et al., 2002
). However, a different endocrine activity may be ascribed to different halogenated compounds.
Menarche is linked to elevated estrogen production (Apter, 1980; Apter and Vihko, 1985
; Legro et al., 2000
). Our findings suggest that DDE may exert such an estrogenic effect. In rats, DDE exposure significantly increased circulating levels of 17
-estradiol (OConnor et al., 1999
). Proposed mechanisms of DDE include androgen blocking, binding to estrogen receptors, a weakly estrogen-mimicking effect (Kelce et al., 1995a
,b; Sonnenschein and Soto, 1998
) or aromatase induction (You et al., 2001
). Aromatase is an enzyme that catalyses the conversion of C19 steroids (e.g. testosterone, androstenedione) to estrogens. Krstevska-Konstantinova et al. (2001
) discussed the pros and cons of central mechanisms (e.g. involvement of the hypothalamus) versus peripheral activities and leaned toward the former. Thus, more research is necessary to identify possible mechanisms.
Our results support an intrauterine programming of age at menarche as suggested by Adair (2001). The assumption of in utero programming is supported further by findings showing that girls who had been exposed to male co-twins had a significantly higher age at menarche than like-sex dizygotic female twins (Kaprio et al., 1995
). Thus, we hypothesize that in utero exposure to the estrogenic effect of DDE may result in earlier age at menarche.
Further research is necessary to understand the mosaic of possible endocrine effects of DDE that includes reduced growth in females (Karmaus et al., 2002b), younger age at menarche in the present report, reduction of breastfeeding (Gladen and Rogan, 1995
) and earlier age at menopause (Cooper et al., 2002
).
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Acknowledgements |
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Submitted on December 5, 2003; accepted on April 7, 2004.