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. 2020 Aug 24;4(5):e111.
doi: 10.1097/EE9.0000000000000111. eCollection 2020 Oct.

Age at menarche in Seveso daughters exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Marcella Warner  1 , Stephen Rauch  1 , Jennifer Ames  1 , Paolo Mocarelli  2 , Paolo Brambilla  2 , Brenda Eskenazi  1
Affiliations

Age at menarche in Seveso daughters exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin

Marcella Warner et al. Environ Epidemiol. .

Abstract

In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with delayed pubertal development in animal studies. No epidemiologic study has investigated this association. We examined the relationship of in utero exposure to TCDD with reported age at onset of menarche in female children born to a unique cohort of TCDD-exposed women resulting from an explosion in Seveso, Italy, on 10 July 1976.

Methods: In 2014, nearly 40 years after the explosion, we enrolled postexplosion offspring, 2 to 39 years of age, in the Seveso Second Generation Study. Age at onset of menarche (years) was collected for 316 daughters by maternal report or self-report at interview. In utero TCDD exposure was defined by maternal TCDD serum concentrations extrapolated to the pregnancy.

Results: At interview, 287 daughters were postmenarche and reported age at menarche averaged 12.1 years (±1.3 years). Overall, we found no change in risk of menarche onset with a 10-fold increase in in utero TCDD exposure (hazard ratio [HR] = 0.86; 95% confidence interval [CI] = 0.71, 1.04). When we considered maternal menarche status in 1976 as a potentially sensitive developmental exposure window, in utero TCDD (log10) was associated with later age at menarche among daughters whose mothers were premenarche (HR = 0.71; 95% CI = 0.52, 0.97) but not postmenarche (HR = 0.89; 95% CI = 0.71, 1.12) at the time of the explosion (P int = 0.24).

Conclusions: These results suggest that in utero TCDD exposure may alter pubertal timing among daughters of women who were prepubescent at the time of the Seveso accident.

Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin; Dioxin; In utero exposure; Menarche; Seveso.

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Conflict of interest statement

The authors declare that they have no conflicts of interest with regard to the content of this report. The results reported herein correspond to specific aims of grant R01ES07171 to investigator B.E. from National Institute of Environmental Health Sciences. This work was also supported by grants F06TW02075-01 and F31ES026488 from the National Institutes of Health, 2P30-ESO01896-17 from the National Institute of Environmental Health Sciences, R82471 from the U.S. Environmental Protection Agency, and #2896 from Regione Lombardia and Fondazione Lombardia Ambiente, Milan, Italy.Sponsorships or competing interests that may be relevant to content are disclosed at the end of the article.

Figures

Figure 1.
Figure 1.
Adjusted hazard ratios from Cox proportional hazard models for age at menarche in Seveso daughters by in utero TCDD exposure (log10) overall and by maternal menarche status in 1976, Seveso Second Generation Study, Italy, 1976–2016. Adjusted for maternal age at menarche and primary wage earner education.
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