Our results indicate that follicular fluid PFAS exposure was associated with increased odds of low probability of fertilization, clinical pregnancy and live birth among POR women. These findings are consistent with prior literature that has evaluated the relationship between PFASs and female fecundity[7, 8, 9]. The majority of studies have suggested that PFASs affect human fecundity through a longer time to pregnancy (TTP)[7, 8, 9].
Unlike prior studies that followed a self-selected set of individuals who succeeded in conceiving, the research design in the present study focused on the impact of maternal PFAS exposure on ART outcomes. Our results provide evidence that elevated PFAS exposure reduced the probability of fertilization, pregnancy and live birth, which is partially in line with prior studies[16, 17]. For example, Governi L observed a significant negative correlation (R = 0.75; p < 0.001) between FF PFAS levels and the fertilization rate, and McCoy identified a negative relationship between FF PFDA and PFUnDA and blastocyst conversion rates[16, 17]. However, the researchers did not observe associations between PFAS exposure and pregnancy probability after IVF[16, 17, 18]. This was largely due to sample size constraints given the relative infrequency with which such outcomes occurred (the maximum sample size was 38). It is also possible that women with poor ovarian response are sensitive to reproductive toxic substances.
The underlying mechanisms of PFAS-induced reproductive toxicity in humans remain largely unknown, although some in vitro studies have reported that PFAS can directly interact with oocytes and granulosa cells and influence oocyte quality and survival[11, 12, 20]. For example, a recent study reported that 10 µg mL− 1 PFNA for 22 h had a severe negative effect on blastocyst formation in bovine oocytes in vitro, which could be attributed to the disturbance in lipid droplet distribution. Peroxisome proliferator-activated receptors (PPARs) are crucial for successful oocyte development and lipid metabolism [21, 22]. Previous experiments have shown that PFASs can bind and activate PPAR [23, 24], and the activity of human PPAR-alpha increased with increasing carbon backbone chain length . It is plausible that PFASs may interfere with ovarian cell function and oocyte maturation by interacting with PPARs.
Furthermore, PFAS exposure could affect oocyte survival by altering cell–cell communication within a follicle. When treated with PFDA during porcine oocyte maturation in vitro, gap junction intercellular communication (GJIC) among cumulus cells and oocytes was disrupted, and the number of live oocytes and the percentage of matured oocytes decreased. Similarly, Domínguez A’s study found that PFOS interfered with GJIC in cumulus-oocyte complexes during the first hours of oocyte maturation.
On the other hand, our results highlighted the declining trend of a well-known long-chain PFAS compound (PFOS) in FF. More specifically, the concentration of PFOS in our study was more than four times lower than that in previous studies that recruited patients in the period of 2006–2011 and in 2015[26, 27]. This finding confirms the decline in contamination with PFOS in China, which can be mainly attributed to the phasing out of PFOS-based products and the restriction of PFOS in industrial and consumer products by international organizations since 2009[28, 29]. In contrast to the PFOS ban, PFOA is classified as a highly concerning substance but has not yet been completely phased out worldwide. This may be an explanation as to why our PFOA follicular concentrations were quite comparable with previous studies[16, 26, 27].
To our knowledge, we are the first to report that PFBA was the PFAS found at the highest concentration in FF [16, 26, 27]. The PFAS contamination pattern in FF is very similar to that in Chinese drinking water : PFBA is detected at the highest concentration, followed by PFHpA, PFOA, and PFOS. There are two reasons for this phenomenon. First, the increase in PFASs in the surrounding environment would lead to an increase in PFASs in the human body. Drinking and dietary intake have been considered the main routes by which PFASs enter the human body . Currently, short-chain PFASs, especially PFBA, have become the major PFAS contaminants in Chinese drinking water, wheat and vegetables [31, 33, 34, 35]. Evidence has also shown that ongoing exposure to even relatively low concentrations of PFASs in drinking water increases human serum levels . Second, the blood-follicle transfer efficiencies for PFASs decrease with increasing chain length . Although PFBA was the most abundant PFAS in FF, the present study failed to confirm any association between PFBA and ART outcomes. The possible reasons include the following: First, PFBA serum half-lives are much shorter than those of PFOA (48–96 h vs 1273 days) . Second, short-chain PFBA showed less cytotoxicity, inhibition of aromatase activity and alteration of cellular lipids than long-chain homologs . Since environmental long-chain PFASs have gradually decreased and been replaced by short-chain PFASs in China [31, 35], the risks posed by short-chain PFASs require further investigation.
The present study has several limitations. First, our study focused on women with POR, and it may not be possible to generalize our findings to couples from the overall population of couples attempting conception. Second, we did not consider male partner exposure. Further studies are needed to explore whether maternal or paternal plasma PFASs had effects on IVF outcomes. The small sample size limited the interpretation of this study.
In conclusion, our study supports the association of higher FF PFAS contamination being associated with a lower chance of successful pregnancy and live birth, mainly due to a reduced fertilization rate. Additionally, this study confirmed that the levels of long-chain PFAS contamination are declining in the FF. The risks posed by short-chain PFASs require further investigation.