Polycyclic aromatic hydrocarbons (PAH) are ubiquitous and recalcitrant pollutants produced by incomplete combustion of organic substances (Alegbeleye et al., 2017). Polluted air, occupational exposure, cigarette smoke and charbroiled or contaminated food are exposing millions of humans to PAH (Zhang et al., 2008; Liu et al., 2012). Sixteen PAH are designated priority pollutants for monitoring by the European and US environmental protection agencies for their carcinogenic and mutagenic properties (European Parliament, Council on Environmental Quality Standards in the Field of Water Policy, 2008; US Environmental Protection Agency, 2014).
Data on the effect of PAH exposure on human reproduction are scarce. The results of several studies have suggested that the exposure of men to PAH is associated with DNA damage in spermatozoa without interfering with semen parameters. In men, exposure to PAH might therefore be related to infertility and might not be diagnosed by a common semen analysis (Zenzes et al., 1999a; Gaspari et al., 2003; Han et al., 2011; Perrin et al., 2011; Jeng et al., 2013; Yang et al., 2017). In-vivo studies in mice have identified several mechanisms that explain how exposure to PAH could damage spermatozoa DNA (Revel et al., 2001; Inyang et al., 2003; Ramesh et al., 2004; 2008). The transformation of PAH into epoxide metabolites that bind covalently to DNA and induces a stable primary lesion (termed a DNA adduct) is the most unanimously accepted mechanism (Zenzes et al., 1999a; Revel et al., 2001; Baird and Ralston, 2004; Perrin et al., 2011). In addition, PAH epoxide metabolites are formed via a microsomal cytochrome P450-dependent monooxygenase system that is known to increase the production of reactive oxygen species and potentially damage DNA (Park et al., 1996; Lopes et al., 1998).
Data on the effect of PAH exposure on female fertility are even more scarce. In-vivo animal studies have suggested that the PAH affect the ovarian follicles and oocyte and cumulus cell DNA through similar mechanisms than for spermatozoa (Bengtsson et al., 1983; Neal et al., 2007; Ramesh et al., 2010; Sobinoff et al., 2012; Einaudi et al., 2014). Because of obvious difficulties obtaining human ovarian cells, to date, only one study has investigated the effect of PAH on female fertility. In 1998, Zenzes et al. (1998) revealed the formation of BPDE-DNA adducts in the granulosa cells of 32 women undergoing IVF treatment who were exposed to cigarette smoke (Zenzes et al., 1998). The same team found more BPDE-DNA adducts in the embryos of smoking couples than in those of non-smoking couples, suggesting that DNA damage caused by PAH exposure could be transmitted to the embryos. The reproductive outcomes of IVF, however, were not reported in that study (Zenzes et al., 1999a).
Over recent decades, increasing research has been conducted to identify the best practices to increase the chances of pregnancy with IVF treatment (Kushnir et al., 2017). The influence of lifestyle and environmental exposure on the outcomes of IVF have increasingly been researched (Hornstein, 2016; Vizcaíno et al., 2016; Choe et al., 2018). Despite the presumption of impairment of human gametes owing to PAH exposure, however, to the best of our knowledge, nothing is known on its influence on the success of assisted reproductive technology (ART) treatments.
The aim of this small-scale prospective, monocentric, cohort study was to determine whether PAH exposure among women and men was associated with the outcomes of IVF treatment.
A small-scale prospective, monocentric, cohort study was conducted in our ART unit at La Conception University Hospital in Marseille, France. Data were prospectively and anonymously collected. The study was approved (20 June 2018) by the Ouest II Committee for the Protection of Research Subjects (RCB: 2018-A00364-51). Women and men from each couple provided written informed consent. The trial is registered with ClincalTrials.gov (reference: NCT03914859).
Couples who underwent IVF treatments in
During the study period, 22 couples undergoing IVF treatment at our ART unit were included in the study. Four couples did not have embryo transfer on day 2 after oocyte retrieval (three for ovarian hyperstimulation syndrome and one for failure to obtain embryos of sufficient quality) and were excluded from the final analysis. Among the 18 remaining couples, six (33%) had positive HCG, and 12 (67%) had negative HCG on day 14 after embryo transfer. Characteristics of women and embryological
To the best of our knowledge, this small-scale study is the first study to investigate the association between PAH exposure and the reproductive outcomes of IVF treatment. The urinary 1-OHP levels in women were positively correlated with fragmentation of the highest- grade embryo transferred and were significantly higher in women with a negative HCG test result 14 days after embryo transfer compared with women with a positive result. This finding suggests an association between PAH exposure in
The authors would like to thank Dr Claire Sunyach and all the people involved in the Couple Reproduction Environnement et Risque (CREER) platform for their contribution to the organization of the present study. This work was financially supported by the French Biomedecine Agency (Agence de la biomédecine).
Dr Antoine Netter is currently pursuing a fellowship in advanced gynaecologic surgery at Aix-Marseille University in France. His research mainly focuses on endometriosis and human reproduction. Key message Urinary 1-hydroxypyrene concentrations the day before oocyte retrieval were lower in women with a positive HCG test 14 days after embryo transfer versus those with a negative result. This exploratory research should encourage further studies to determine the effect of women's
Moreover, several studies have demonstrated that BaP affects the ovarian follicles and oocyte DNA (Einaudi et al., 2014; Neal et al., 2007; Ramesh et al., 2010). Finally, urine PAH concentration, as a biomarker of BaP exposure, is inversely related to fertilization rate in assisted reproduction (Jeng et al., 2013; Netter et al., 2020). Despite the extensive research on BaP toxicity at the peripheral gonadal level, very little is known about the effect of BaP exposure at the central level on the GnRH regulatory network.
These changes occurred in association with increased ovarian expression of PPARα and PPARγ and suggest that BaP-induced ovotoxicity may be attributed, in part, to PPAR-mediated signaling (Xu et al., 2010). While there is limited evidence on the effects of PAC exposure and reproduction in humans, there is more data reporting adverse effects on male fertility and damage to spermatozoa (Reviewed in: (Madeen & Williams, 2017)) compared to data on female fertility and ovarian function (Netter et al., 2020). Perturbations in the vital processes that support ovarian function can lead to ovarian disorders including polycystic ovary syndrome (PCOS), anovulation, premature ovarian insufficiency (POI), and infertility (Barontini et al., 2001; Mikhael et al., 2019; Molina et al., 2018; Petraglia et al., 2008).
Dr Antoine Netter is currently pursuing a fellowship in advanced gynaecologic surgery at Aix-Marseille University in France. His research mainly focuses on endometriosis and human reproduction. Key message Urinary 1-hydroxypyrene concentrations the day before oocyte retrieval were lower in women with a positive HCG test 14 days after embryo transfer versus those with a negative result. This exploratory research should encourage further studies to determine the effect of women's exposure to PAH on reproductive outcomes of IVF treatment.
