Other indications of ovarian dysfunction may first become apparent in adulthood, when women wish to conceive. These include infertility and POI. A woman is considered to have POI if she is under 40 years of age, has had amenorrhea (absence of menstrual bleeding) for more than 4 months and two elevated serum follicle-stimulating hormone (FSH) measurements within the menopausal range occurring at least 1 month apart (Nelson 2009). There are multiple established etiologies, but over 90% of POI cases are idiopathic without any obvious cause (Nelson 2009; Torrealday et al. 2017). Women with POI may experience symptoms similar to menopause as a result of low estrogen levels. Unlike postmenopausal women, however, they may still become pregnant, albeit with a reduced chance of conceiving (Fraison et al. 2019). The prevalence of POI is generally estimated to be 1%, but a study using Swedish Patient Registry data from 1973 to 1993, including just over 1 million women, reported a prevalence of 1.9% (Lagergren et al. 2018). Furthermore, based on a recent meta-analysis of 31 studies, a pooled prevalence of 3.7% was found (Golezar et al. 2019). A few studies report on associations between chemical exposure levels and POI. Exposure to perfluorinated alkyl substances was associated with a higher risk for POI in Chinese women (Zhang et al. 2018), whereas a cross-sectional study on women from the USA looking at over 100 EDCs found associations between early menopause and numerous compounds, including phthalates, polychlorinated biphenyls and organochlorine pesticides (Grindler et al. 2015). Finally, tobacco smoke has been shown by several studies to correlate negatively with both POI and early menopause, as reviewed by others (Vabre et al. 2017).
This pAOP network proposes that increased ERα and AHR (Aryl hydrocarbon receptor) signaling following EDC exposure results in accelerated primordial follicle formation and germ cell death, by dysregulating primordial follicle formation and intraovarian signaling. Ultimately, this leads to impaired adult fertility via compromised ovarian reserve. AHR is a ligand-activated transcription factor that is expressed in mouse and human ovaries and well-known for its role in xenobiotic metabolism. This pAOP is based on the weight of evidence for fetal ovarian development in the human, including disruption following exposure to maternal smoking in utero (Fowler et al. 2014) and underpinned by data from studies of model species considered more similar to the human than rat or mouse in terms of ovarian development, including baboon and hamster. The validity of the pAOP is supported by population-level evidence for the adverse effects of in utero exposure to maternal smoking on subsequent adult fertility of female human offspring (Ye et al. 2010).
The sequence from maternal smoking to fetal AHR activation, disturbed primordial follicle formation and reduced germ cell proliferation are well established (Anderson et al. 2015; Jurisicova et al. 2007; Matikainen et al. 2001; Tuttle et al. 2009). The increased AHR signaling in smoke-exposed fetuses is likely due to increased estrogen and estrogenic polycyclic aromatic hydrocarbon metabolites (Fowler et al. 2014), which leads to increased AHR signaling, (Tarnow et al. 2019). In addition, maternal smoking is associated with disturbed or reduced number of germ and gonadal somatic cells in the offspring (Lutterodt et al. 2009; Mamsen et al. 2010). The consequence of early estradiol and AHR activation would thus be early onset of primordial follicle formation (premature increase in germ cell VASA protein (gene DDX4: DEAD-box helicase 4) when germ cell OCT4 protein predominates in control (gene POU5F1: POU class 5, homeobox 1) and, given imbalanced proportions of germ and somatic cells, subsequently reduced primordial follicle pool establishment, leading to shorter reproductive lifespan and, ultimately, reduced fertility.
Exposure to di-ethylhexyl phthalate and its metabolite mono-ethylhexyl phthalate has been shown to accelerate growth of isolated mouse ovarian follicles in vitro, as well as in mice in vivo with concurrent activation of PI3K in follicles measured as pAkt (Hannon et al. 2014, 2015). In mice, this results in premature ovarian insufficiency (Hannon et al. 2016). 2b1af7f3a8