Environmental influences on ovarian dysgenesis — developmental windows sensitive to chemical exposures

Key Points

  • Humans are continuously exposed to numerous chemicals, including endocrine-disrupting chemicals (EDCs), throughout life

  • The ovarian dysgenesis syndrome hypothesis proposes that exposure to certain chemicals, including EDCs, during fetal life can lead to reproductive disorders later in life

  • Female fetuses are particularly sensitive to chemical exposure during four developmental windows: early gonadal development, meiotic division of germ cells, follicular assembly and early follicle recruitment

  • Some human epidemiological data suggest that the incidence of female reproductive disorders has increased since the mid-1950s and that EDCs are potential contributors

Abstract

A woman's reproductive health and ability to have children directly affect numerous aspects of her life, from personal well-being and socioeconomic standing, to morbidity and lifespan. In turn, reproductive health depends on the development of correctly functioning ovaries, a process that starts early during fetal life. Early disruption to ovarian programming can have long-lasting consequences, potentially manifesting as disease much later in adulthood. A growing body of evidence suggests that exposure to chemicals early in life, including endocrine-disrupting chemicals, can cause a range of disorders later in life, such as those described in the ovarian dysgenesis syndrome hypothesis. In this Review, we discuss four specific time windows during which the ovary is particularly sensitive to disruption by exogenous insults: gonadal sex determination, meiotic division, follicle assembly and the first wave of follicle recruitment. To date, most evidence points towards the germ cell lineage being the most vulnerable to chemical exposure, particularly meiotic division and follicle assembly. Environmental chemicals and pharmaceuticals, such as bisphenols or mild analgesics (including paracetamol), can also affect the somatic cell lineages. This Review summarizes our current knowledge pertaining to environmental chemicals and pharmaceuticals, and their potential contributions to the development of ovarian dysgenesis syndrome. We also highlight knowledge gaps that need addressing to safeguard female reproductive health.

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Figure 1: Ovarian dysgenesis syndrome hypothesis.
Figure 2: Germ cell development and chemical exposure in mice.
Figure 3: Temporal comparison between human and mouse germ cell development.

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Acknowledgements

The authors thank the Ministry of Food and Environment of Denmark, who funded their work from 2011 to 2016.

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H.K.L.J., T.S. and J.B. researched data for the article, provided substantial contribution to discussion of content, wrote the article and reviewed and/or edited the manuscript before submission. P.A.F. and A.M.V. provided substantial contribution to discussion of content, and reviewed and/or edited the manuscript before submission.

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Correspondence to Julie Boberg.

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The authors declare no competing financial interests.

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Glossary

Endocrine-disrupting chemicals

The WHO defines an endocrine disruptor as “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)population”.

Testicular dysgenesis syndrome

A collective term for male reproductive disorders (testicular germ cell cancer, cryptorchidism and some cases of poor sperm quality and hypospadias) that are hypothesized to share a common fetal origin; that is, disruptions of signalling pathways controlling early development of the male reproductive system.

Cohesin complex

A multisubunit protein complex responsible for cohesion between sister chromatids during both mitosis and meiosis. It is also central to DNA double-strand break repair, especially in meiotic cells.

Synaptonemal complex

A meiosis specific structure composed of multiple proteins that connect homologous chromosomes during prophase I.

Nests

Clusters of germ cells connected by intercellular bridges.

Disorders of sex development

Congenital conditions in which chromosomal, gonadal or anatomical sex is atypical.

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Johansson, H., Svingen, T., Fowler, P. et al. Environmental influences on ovarian dysgenesis — developmental windows sensitive to chemical exposures. Nat Rev Endocrinol 13, 400–414 (2017). https://doi.org/10.1038/nrendo.2017.36

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