Bisphenol A promotes autophagy in ovarian granulosa cells by inducing AMPK/mTOR/ULK1 signalling pathway
A study of normogonadotrophic infertile patients (mostly normal hormone levels) was carried out to better understand the link between BPA and infertility among women, and how it might effect granulosa cells in the ovaries.
Initially 106 infertile normogonadotrophic women, between 20-40 years of age, were recruited to undergo their very first IVF/ICSI cycle using fresh embryos (no donor eggs). Urine samples for analysis of BPA levels was collected twice, during ovarian stimulation and on day of oocyte retrieval.
Only the standard long gonadotropin-releasing hormone agonist protocol was used, with either long or short agonists, to minimize potential test differences between the women and effect on results. Following fertilization and cleavage, a maximum of 3 embryos was then transferred back into the uterus on day 3. Implantation rate was defined as the number of gestational sacs divided by number of embryos transferred.
For the next part of the study, 24 female Kunming mice were procured for the in vivo experiments and randomized into 4 groups; Control, 1 μg/kg BPA, 10 μg/kg, 100 μg/kg BPA, which was administered once daily for a total 2 weeks. At the end of this period ovary samples were then collected for histopathological analysis and western blot assays.
Initial analysis of urine samples, from the 106 women, showed that BPA concentration varied from 0 to 11.62 μg/L, with a median (majority) BPA level of 0.743 μg/L. General patient characteristics did not differ between low and high BPA exposure, however total antral follicle count was moderately lower in the high BPA exposure group (16.8 ±9.0 vs 13.7 ±6.7). On the other hand oocyte retrieval rate (89.7% vs 65.1%), maturation rate (90.0% vs 85.0%) and implantation rate (50.6% vs 34.3%) was significantly lower in the same high BPA exposed group. This resulted in a moderate decrease of the clinical pregnancy rate per cycle (67.5% vs 53.1%).
Next in vivo experiments, featuring the 24 mice, showed that as BPA levels increased, serum levels of estradiol, progesterone and AMH significantly decreased, while follicles dilated and the number of granulosa cells decreased. In vitro experiments also confirmed a significant decrease in levels of estradiol and progesterone with an increase in lactate acid (dehydrogenase) and cell apoptosis, which were all BPA dose dependent. Immunofluorescence staining demonstrated an increase in autophagy induced by BPA while western blot analysis confirmed BPA interference with the AMPK/mTOR biological pathway.
The authors noted that peak oestradiol levels in the high BPA exposed women was slightly reduced (3095.5 ±2142.5 vs 3316.2 ±2044.0) as seen in the mice results, although in this particular study, statistical significance could not be confirmed due to the small number of participants.
SUMMARY: BISPHENOL (BPA) AND FEMALE FERTILITY
According to this study, elevated BPA levels impairs fertility in females. Specifically, through significantly reduced oocyte retrieval rates (89.7% vs 65.1%) and implantation rates (50.6% vs 34.3%) leading to a moderate decrease in clinical pregnancy rate per IVF/ICSI cycle (67.5% vs 53.1%).
- Larger number of women required to confirm statistically insignificant trends
Zhou W, et al. (2016). Bisphenol a and ovarian reserve among infertile women with polycystic ovarian syndrome. https://doi.org/10.3390/ijerph14010018
Ehrlich S, et al. (2012). Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF. https://doi.org/10.1093/humrep/des328
Grasselli F, et al. (2010). Bisphenol A disrupts granulosa cell function. https://doi.org/10.1016/j.domaniend.2010.01.004
Xu J, et al. (2002). Bisphenol A Induces Apoptosis and G2-to-M Arrest of Ovarian Granulosa Cells. https://doi.org/10.1006/bbrc.2002.6644
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