To our knowledge, this is the first study to examine the relationships between urinary BPA concentrations and markers of reproductive function (semen quality and hormone levels) in fertile men. We saw a significant association with FAI/LH (but not T/LH or FT/LH) and FAI after controlling for covariates.
Our results are divergent from those reported previously by Takeuchi and Tsutsumi (2002)
and Hanaoka et al. (2002)
. Takeuchi and Tsutsumi (2002)
used an enzyme-linked immunosorbent assay (ELISA) to measure BPA in the serum of men and women, showing statistically significant positive correlations between BPA concentrations and total T and FT levels in all subjects. However, these differences may be related to differences both in population size and the different methodological approaches to measuring BPA (i.e., ELISA versus online SPE-HPLC-MS/MS; human serum versus urine). ELISA is known to be a very sensitive method but is not as specific as MS/MS. It is possible that with ELISA, substances other than BPA and its conjugates—including other bisphenols—can be detected (Vandenberg et al. 2010
). Hanaoka et al. (2002)
examined men occupationally exposed to BPA and reported that urinary concentrations of BPA, measured by HPLC with electrochemical detection, were significantly higher in exposed workers than in controls; the authors also found a significant inverse association between urinary BPA concentrations and serum FSH levels. Nevertheless, FT levels (measured by radio immunosolvent assay) did not differ between the two groups.
In the present study we did not observe any relationship between serum FSH levels and urinary BPA concentrations, but we did observe an inverse association between FAI and urinary BPA concentrations. Hanaoka et al. (2002)
speculated that BPA binds to estrogen receptor (ER) in the pituitary gland, resulting in direct suppression of FSH secretion; this is based on studies that have found ERs in the pituitary gland (Pelletier 2000
) and that E2
directly inhibits gonadotropin secretion at the pituitary level in men (Finkelstein et al. 1991
). Recently, Meeker et al. (2010)
evaluated men referred for fertility work-up; in a subset who collected at least two urine samples (n
= 75), the authors observed inverse associations between urinary BPA and FAI, E2
, and thyroid-stimulating hormone levels. However, when they analyzed the entire cohort of men (n =
167), all of whom collected a single urine sample, urinary BPA concentrations were inversely associated only with serum inhibin B levels and positively associated with serum FSH levels.
There is a large and consistent body of literature showing BPA to be estrogenic (Richter et al. 2007
; Wetherill et al. 2007
), and it is considered by some researchers to be one of the most potent reproductive toxicants among EDCs (Maffini et al. 2006
). Animal and in vitro
studies have shown that BPA is associated with the induction of testicular toxicity in neonatal, pubertal, and adult rodents (Richter et al. 2007
; Wetherill et al. 2007
). Akingbemi et al. (2004)
described an inhibitory effect of BPA on testicular steroidogenesis at low exposure levels in pubertal rats, which they ascribed to an ER-mediated effect. In addition to its antiandrogenic effects through ER-mediated down-regulation of steroidogenesis (and thereby T production), BPA might also act as an androgen receptor antagonist, preventing endogenous androgens from regulating androgen-dependent transcription (Wetherill et al. 2007
). The disruption of the androgen receptor–androgen interaction has been speculated to be significant in eliciting adverse effects on the male reproductive system, including sexual dysfunctions (Li et al. 2010
Our results suggest that FAI levels—one of the markers of the biologically active T—may be somewhat decreased by BPA exposure. Nonetheless, the magnitude of the effect of BPA in the present cross-sectional study on FAI was small compared with, for example, the diurnal variation in this parameter in healthy young men (Bremner et al. 1983
; Diver et al. 2003
). However, the effects of long-term exposure to BPA in adult men are unknown, and we cannot rule out that such exposure may exert an effect on their hormone production. It is also important to point out that we are certainly exposed to a mixture of EDCs, and the cumulative effects that these chemicals may exert in combination are only now being studied (Kortenkamp 2008
In the present study, we observed an inverse association between BPA exposure and FAI levels in vivo with no apparent compensatory increase in serum gonadotropins, as shown by the lack of significant associations with LH and FSH. However, we cannot rule out a possible compensatory increase in serum gonadotropins in a larger study or another kind of study population. The fact that FAI and SHBG are statistically associated with urinary BPA concentrations while T individually is not suggests that the small associations observed between these hormones and BPA could have resulted from an increase in SHBG. The regulation of SHBG is not completely understood, but androgen action lowers serum SHBG, whereas estrogen action increases it. The increase in SHBG levels we report here could be a direct result of the estrogenic action of BPA. Alternatively, it is possible that BPA acts by decreasing androgen action through ER-mediated decrease in steroid production. However, there might be noncausal explanations for the association with SHBG as well.
We speculate that BPA in vivo may act at several levels. In addition to the alteration of markers of androgenic action, the endocrine feedback loop (mainly the hypothalamic– pituitary–target organ axis) could also be affected by BPA, showing no compensatory mechanisms of increased LH or FSH. Alternatively, because there is no change in T with BPA (adjusted β = 0.01; 95% CI, −0.04 to 0.06), this suggests that the signal is insufficient to trigger the feedback mechanism to the hypothalamus and pituitary.
We observed no significant associations between semen parameters and BPA exposures in our population of fertile men. It is important to remember that spermatogenesis takes 70–80 days, and a clear association between semen parameters and relatively low and chronic urinary BPA concentrations may be difficult to assess. It is also possible that in men with compromised semen quality (such as those attending an infertility clinic) or men exposed occupationally to higher concentrations of BPA, some associations may be seen that are absent in our fertile population.
Urinary concentrations of BPA in our subjects were only about half as high as those reported in a national sample of U.S. men (CDC 2008
). For example, the 25th, median, and 75th percentile values for BPA in adult males (range, 18–65 years of age) from NHANES 2003–2004 were 1.5, 3.1, and 6.1 μg/L, respectively, compared with 0.80, 1.7, and 3.0 μg/L in the present study. Whether the lower BPA urinary concentrations in the men in our study compared with men in NHANES was related to their fertility is not a question we could examine in this data set. Recently, in an analysis of NHANES data, Stahlhut et al. (2009)
showed that BPA was detectable in urine up to 24 hr after the last meal, suggesting substantial nonfood exposure, accumulation in body tissues such as fat, or both. In addition, we cannot rule out some level of occupational exposure to BPA in our study population, but it is not likely because of the relatively low levels mentioned above.
Our study was limited because we selected only fertile men; therefore, our results should be applied only to that type of population. Also, we used a single urine sample to assess BPA exposure and a single serum sample to describe hormone function. However, Mahalingaiah et al. (2008)
maintained that, despite within-person variability in urinary BPA concentrations, a single sample is predictive of long-term exposure (over weeks to months) and provides good sensitivity to classify individuals in epidemiologic studies. Exposure measurement error is likely in the present study; if this measurement error was nondifferential, we could expect that, on average, the effect estimates might be biased toward the null. Similarly, a single sample can be used to classify men’s reproductive hormones (Bjornerem et al. 2006
). As with all studies of semen quality, small participation rates, potential selection bias, and uncontrolled confounding are of concern. In a previous study (Swan et al. 2003
), we examined selection bias by comparing questionnaire data on time to pregnancy and history of infertility, as well as demographics, of study subjects and nonparticipants and of men who did and did not give semen samples. Reassuringly, we found little evidence that those populations differed.