Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data

Abstract

Background: Because only 25% of cases of premature ovarian insufficiency (POI) have a known etiology, the aim of this review was to summarize the associations and mechanisms of the impact of the environment on this pathology. Eligible studies were selected from an electronic literature search from the PUBMED database from January 2000 to February 2016 and associated references in published studies. Search terms included ovary, follicle, oocyte, endocrine disruptor, environmental exposure, occupational exposure, environmental contaminant, pesticide, polyaromatic hydrocarbon, polychlorinated biphenyl PCB, phenol, bisphenol, flame retardant, phthalate, dioxin, phytoestrogen, tobacco, smoke, cigarette, cosmetic, xenobiotic. The literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We have included the human and animal studies corresponding to the terms and published in English. We have excluded articles that included results that did not concern ovarian pathology and those focused on ovarian cancer, polycystic ovary syndrome, endometriosis or precocious puberty. We have also excluded genetic, auto-immune or iatrogenic causes from our analysis. Finally, we have excluded animal data that does not concern mammals and studies based on results from in vitro culture. Data have been grouped according to the studied pollutants in order to synthetize their impact on follicular development and follicular atresia and the molecular pathways involved. Ninety-seven studies appeared to be eligible and were included in the present study, even though few directly address POI. Phthalates, bisphenol A, pesticides and tobacco were the most reported substances having a negative impact on ovarian function with an increased follicular depletion leading to an earlier age of menopause onset. These effects were found when exposure occured at different times throughout the lifetime from the prenatal to the adult period, possibly due to different mechanisms. The main mechanism seemed to be an increase in atresia of pre-antral follicles.

Conclusion: Environmental pollutants are probably a cause of POI. Health officials and the general public must be aware of this environmental effect in order to implement individual and global preventive actions.

Keywords: Environment; Fertility; Ovarian reserve; Pollutants; Premature ovarian insufficiency.

Fig. 1

The different mechanisms inducing POI. Folliculogenesis (❶) begins after assembly (black arrows) of primordial follicles during second trimester of pregnancy. Activation of primordial follicles (green color) to enter the growth phase of folliculogenesis is continuous from third trimester of fetal life to menopause. This activation is driven by local factors and is independent of gonadotropins. Basal follicular growth (pink color) is driven by paracrine factors. From the early antral follicle stage, their growth depends on gonadotrophins to enter the final phase (orange color) up to ovulation. From the beginning, follicles undergo physiological atresia (blue lines around arrows), that participate to the decrease of the pool with years. Mechanisms leading to POI (symbolized by a final pale preovulatory follicle,): • decrease of the pool of primordial follicles (❺) either due to massive atresia (❺a) or default in assembly (❺b). • increase in follicular apoptosis concerning any other follicular stage (❷ and ❸). • increase of the activation (large green arrow) of the resting pool of primordial follicles (❹) resulting in its exhaustion. It is generally followed by increased atresia at following follicular stages (large blue arrow). • default in basal follicular growth leading to its arrest before the antral stages preventing ovulation while the pool of primordial follicles is normal (❻)

Fig. 2

Flow chart of the selection of articles

Fig. 3

The major ways used by environmental pollutants to induce defaults in folliculogenesis leading to POI. Environmental pollutants can act through several mechanisms. • actions as endocrine disruptors as ligands to nuclear estrogen receptors (ER, salmon arrows) and aryl hydrocarbon receptors (AhR, blue arrows). Once linked to AhR, they can bind to AhR nuclear translocator (ARNT) to interfere with xenobiotoc responsive elements (XRE) from promotors and affect gene expression, notably promoting pro-apoptotic genes and inhibiting anti-apopototic genes. • creation of an imbalance between oxydative defenses and oxydative stress favoring apoptosis at different follicular stages (green arrows). • Modification of epigenetic marks such as DNA methylation (●) or histones post-traductional modifications (▸, , ●) affecting the transcriptional state of chromatin and therefore gene expression. • binding to several membrane receptors suchs as membrane bound ER (mER) or receptor protein tyrosine kinases (RPTK) activating the PI3 Kinase pathway are suspected (grey dotted arrows)