Serum Dioxin Concentrations and Age at Menopause

Abstract

2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD), a halogenated compound that binds the aryl hydrocarbon receptor, is a by-product of numerous industrial processes including waste incineration. Studies in rats and monkeys suggest that TCDD may affect ovarian function. We examined the relationship of TCDD and age at menopause in a population of women residing near Seveso, Italy, in 1976, at the time of a chemical plant explosion. We included 616 of the women who participated 20 years later in the Seveso Women’s Health Study. All women were premenopausal at the time of the explosion, had TCDD levels measured in serum collected soon after the explosion, and were ≥ 35 years of age at interview. Using proportional hazards modeling, we found a 6% nonsignificant increase in risk of early menopause with a 10-fold increase in serum TCDD. When TCDD levels were categorized, compared with women in the lowest quintile (< 20.4 ppt), women in quintile 2 (20.4–34.2 ppt) had a hazard ratio (HR) of 1.1 (p = 0.77), quintile 3 (34.3–54.1 ppt) had an HR of 1.4 (p = 0.14), quintile 4 (54.2–118 ppt) had an HR of 1.6 (p = 0.10), and quintile 5 (> 118 ppt) had an HR of 1.1 (p = 0.82) for risk of earlier menopause. The trend toward earlier menopause across the first four quintiles is statistically significant (p = 0.04). These results suggest a nonmonotonic dose-related association with increasing risk of earlier menopause up to about 100 ppt TCDD, but not above.

Internal exposure to pollutants and sexual maturation in Flemish adolescents

“…Further on, a growing number of observations indicate that the biological and health effects of pollutants capable of binding to receptors show complex dose-response relationships. Even non-monotonic associations have been described (Bonefeld-Jorgensen et al, 2001;Endo et al, 2003;Gregoraszczuk et al, 2003;Eskenazi et al, 2005). The positive association found by Dhooge et al (2010) between serum marker PCB levels and sex hormone levels for male adolescents in our study was much stronger at serum PCB concentrations below the median concentration of 0.92 nmol/l.…”

Internal exposure to pollutants and sex hormone levels in Flemish male adolescents in a cross-sectional study: associations and dose–response relationships

“…For most exposureresponse associations in our study, a supra-linear relationship was observed, with relatively more intense responses (steeper dose-response curves) at exposures below the median. Others have made similar observations, for instance regarding dioxins in humans (Eskenazi et al, 2005) or HCB in animals (Ralph et al, 2003). Hence, one might speculate that the observed biological and health effects result from interactions with receptors, constituting a xeno-hormonal rather than a less-specific toxic effect.…”

“…Hence, one might speculate that the observed biological and health effects result from interactions with receptors, constituting a xeno-hormonal rather than a less-specific toxic effect. Biological and health effects of pollutants capable of binding to receptors show complex dose-response relationships including non-monotonic associations (Bonefeld-Jorgensen et al, 2001;Endo et al, 2003;Gregoraszczuk et al, 2003;Eskenazi et al, 2005;Lilienthal et al, 2006). Using an ordinary differential equation-based computational model, Li et al (2007) showed that nonmonotonic dose-responses in gene expression can arise for exogenous ligands of steroid hormone receptors in an endogenous hormonal background.…”

Dioxin Induces an Estrogen-Like, Estrogen Receptor-Dependent Gene Expression Response in the Murine Uterus

“…Despite the inability to induce uterine weight alterations, TCDD may alter physiological thresholds for estrogenic responses that could affect other functions. For example, the antiestrogenic properties may be a contributing factor in compromised reproduction, breast cancer incidence, and earlier onset of menopause (Bertazzi et al, 2001;Jongbloet et al, 2002;Safe and Wormke, 2003;Eskenazi et al, 2005). In contrast, the subtle estrogen-like properties in the absence of estrogen may alter thresholds for estrogen-mediated responses, which could contribute to the earlier onset of puberty associated with TCDD exposure (Warner et al, 2004;Warner and Eskenazi, 2005;Wolff et al, 2005).…”