Effect-Based Analysis of Endocrine Disrupting Chemical Mixtures in Breast Milk and Possible Health Consequences for Human Infants.

Bérénice Constance Collet

Research output: PhD ThesisPhD Thesis - Research VU Amsterdam, graduation VU Amsterdam

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Abstract

The research described in this thesis investigated the amount and potential effects of EDCs present in human milk using samples derived from the Norwegian HUMIS cohort. This work focused on three main actors of the endocrine system, the estrogens, androgens, and thyroid hormones. The first aim of the thesis was to develop a suitable method to properly extract EDCs from human milk samples, focusing on both polar and apolar endocrine active contaminants. The second aim was to perform a pilot study on a limited number of breast milk samples, using the existing ERα and AR CALUX bioassays, in agonistic and antagonistic mode. This phase was also used to evaluate the nature and origin of the observed EDC activity, as well as the contribution of endogenous hormones to the measurements. The third goal was to measure the EDC activity in a larger set of human milk samples to evaluate the potential association between anti-androgenic EDCs and an androgen-dependent deformity: cryptorchidism. The last objective was the development and application of novel thyroid hormone-based bioassays, TRβ CALUX and TTR-TRβ CALUX assays. These bioassays were used to evaluate the impact of breast milk contaminants, including well-known PFAS (perfluorooctanoic acid or PFOA; perfluorooctane sulfonic acid or PFOS), on the thyroid system. The thesis is divided in two distinct parts: Chapter Two and Chapter Three focusing on sex steroid disruption, and Chapter Four and Chapter Five covering thyroid system interferences, respectively. In Chapter Two, the method developed to extract EDCs from breast milk samples, used throughout the thesis, is described. In this chapter, estrogenic, anti-estrogenic, androgenic, and anti-androgenic activities derived from ten human milk extracts were analyzed on the (anti-)ERα and (anti-)AR CALUX bioassays. To rule out the impact of endogenous hormones in the measured activity, a pooled breast milk sample presenting anti-androgenic activity was fractionated and screened for natural hormones and metabolites by means of non-target screening using time-of-flight mass spectrometry UHPLC-Q-TOF-MS/MS. Chapter Three describes a larger-scale study involving 199 participants and presents results of anti-androgenic EDC activity in breast milk samples. In this chapter, we investigated the potential association between anti-androgenic activity in mothers’ milk and the occurrence of cryptorchidism, an androgen-dependent deformity, in the offspring. Moreover, we estimated the overall extent of exposure of a nursing child to anti-androgenic EDCs via breastfeeding. In Chapter Four, the TRβ CALUX bioassay, allowing screening of TRβ disrupting activity, and the TTR-TRβ CALUX assay, designed to detect competing properties towards T4 for TTR binding, were evaluated using well-known reference compounds. The performance of the TTR-TRβ CALUX assay was also evaluated during a short pilot study involving water samples. In Chapter Five the newly validated TRβ and TTR-TRβ CALUX bioassays were further used to assess a set of thirteen PFAS, known to affect the TH system (Chang et al. 2008; Thibodeaux et al. 2003) for thyroid-disrupting activities. Subsequently, ten breast milk extracts, with known PFOS and PFOA concentrations, were analyzed on the same assays. In this chapter, the impact of PFOS and PFOA levels was weighed in respect to thyroid-disrupting activity in breast milk. Furthermore, the average exposure to thyroid-disrupting EDCs during the first year of life of a nursing infant through breastfeeding was estimated. Finally, Chapter Six reviews and discusses the most important outcomes of the studies regarding hormonal-disruption derived from the presence of EDCs in Norwegian breast milk samples. General conclusions and an outlook on future perspective are presented.
Original languageEnglish
QualificationPhD
Awarding Institution
  • Vrije Universiteit Amsterdam
Supervisors/Advisors
  • Brouwer, A., Supervisor
  • van der Burg, B., Co-supervisor, External person
  • van Gestel, Kees, Co-supervisor
Award date3 Mar 2021
Place of Publications.l.
Publisher
Print ISBNs9789464212396
Electronic ISBNs9789464212396
Publication statusPublished - 3 Mar 2021

Keywords

  • CALUX
  • Endocrine disruptors
  • androgens
  • bioassays
  • breast milk
  • endogenous hormones
  • estrogens
  • human milk
  • in vitro

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