The toxic effect of BPA on the male reproductive functions is well defined in animals model and demonstrated by physiological changes throughout foetal, pubertal and adult life of male rats (Table 1) [15, 24, 25]. In addition several in vitro studies were performed to elucidate the mechanisms through which BPA is able to modify the endocrine response, the effect of steroid hormones as well as spermatogenesis.

Table 1 Bisphenol-A and Male Reproduction in Animal Models Full size table

It is proven that developing embryos are more vulnerable to environmental contaminants than the adult animals [26]. The extensive evidence, reported above, that BPA exerts estrogenic activity and the possibility that even a low exposure during foetal life could have a toxic effect at several physiological levels is under debate [15].

Several studies confirm that mice treated with BPA, even at low dosage, during the foetal life show persistent effects on tissues of male reproductive organs, structural and neurological changes as well as alteration of androgens functions that play a fundamental role in male sex differentiation and development of the male phenotype [27,28,29].

In particular, male mice exposed to BPA during the preimplantation period (days 1–5 of gestation), showed a reduction of serum and testicular testosterone levels when euthanized at 24 postnatal days and an increase of GnRH mRNA at 35 and 50 postnatal days [30]. In addition, retardation of testicular development with a reduction of seminiferous tubules’ diameter and epithelium height in BPA-exposed mice (35 postnatal days) and a scanty spermatogenesis in terms of numbers of spermatogenic cells (50 postnatal days) was detected. Finally, a decrease in expression of testicular StAR (responsible for cholesterol transport to the inner mitochondrial membrane), and a reduction of histone acetylation of the StAR gene promoter, was observed in BPA-exposed mice at 35 and 50 postnatal days [30].

Recently, an in vivo study in pregnant mice exposed to BPA on embryonic days 7 to 14 showed testis morphological alteration with a reduction in the number of stage VIII seminiferous epithelial cells and a decrease of sperm count, motility parameters, and intracellular ATP levels in offspring mice analysed at postnatal day 120 [31]. In addition, this study showed a decrease of protein kinase A (PKA) activity and tyrosine phosphorylation in spermatozoa (essential proteins for ATP generation and oxidative stress response).

Contrary, female rats treated with Bisphenol AF (1,1,1,3,3,3-hexafluoro-2,2-bis(4-hydroxyphenyl) propane, BPAF), an analogue of BPA, during gestational and lactation period showed a significant increase of testosterone levels and significant decrease of inhibin B (INHB) levels in offspring’s testis [28]. Moreover, using RNA-seq analysis, BPAF was shown to alter the expression of 279 genes in the testis of pups exposed to BPA both in prenatal and postnatal stages. Especially, expression alteration was detected for those genes involved in G2/M checkpoint, cell differentiation, cell cycle, G2/M transition, and DNA recombination [28]. Specifically, in disaccord with previously mentioned study, these experiments showed that BPAF was able to increase the transcription of StAR, and mRNA levels of ERa and AR. In addition, testes of male rats exposed to BPAF exhibited increased protein levels of genes involved in steroidogenesis (P450scc and StAR) compared to those in the control group [28].

Studies in pubertal male rats showed that exposure to BPA determines an increase of plasma LH after LHRH injection and a reduction of plasma testosterone levels, with a consequent decrease of epididymal sperm count. In addition, an enlarged ventral prostate gland and an increase of plasma IGF-I were observed in BPA-treated rats [29]. The toxic effect of BPA on spermatogenesis is probably due to its ability to perturb the integrity of the blood-testis barrier; in vitro studies on Sertoli cells showed an association between exposure to BPA, ERK pathway activation, a decline in the levels of specific tight junctions proteins, basal ectoplasmic specialization and blood-testis barrier gap junctions [29].

BPA chemical toxic effects are confirmed in adult rats, showing reduced testes and prostate gland weights, decreased serum testosterone levels, reduced diameter and thickness of seminiferous tubules, significantly thinner seminiferous epithelium and subsequent abnormal spermatogenesis in term of decreased sperm count and motility [25]. The authors postulate that in rats exposed to BPA there is a loss of structural integration in the gonadal compartment with the formation of gaps between germinal cells, as demonstrated previously in in vitro studies [32, 33].

Studies focused on the effect of BPA on spermatogenesis revealed a reduction of type A spermatogonia, spermatocytes and spermatids and an inhibition of spermiation, characterized by an increase in stage VII and a decrease in stage VIII of the seminiferous epithelium cycle [34, 35]. In an in vivo study by Jin and colleagues, low dosages of BPA were given to rats via oral administration; results show an impairment of spermatogenesis caused by the reduction of reproductive hormones serum level (FSH, LH, GnRH) and stopping germ cells meiosis process, thus activating the apoptosis pathway in germ cells [35]. In details, BPA administration reduces testosterone biosynthesis and secretion, thus inhibiting the activity of GnRH neurons, and lowering the expression of steroidogenic enzymes. Consequently, a decline of testosterone levels and a reduction in spermatozoa concentration was seen.

Another study, male chicks treated with oral administration of BPA in low doses for more than 23 weeks resulted in developmental arrest and reduced weight of the testes, which showed smaller seminiferous tubules defective spermatogenesis [36].

Additionally, levels of malondialdehyde and superoxide dismutase and decreased levels of glutathione peroxidase were found increased in the liver of BPA-treated rats compared to the control group. This observation leads to the hypothesis that BPA also induces antioxidants depletion and oxidative stress in epididymal sperm [25]. As a result, BPA disrupts the rapid movement of sperm through the epididymis, ultimately compromising its function. Moreover, the oxidative stress caused by BPA alters cellular metabolism, depleting ATP metabolism, affecting the intermediate piece functions and ultimately decreasing spermatozoa motility and velocity [37]. BPA administration in animals was also found associated to significant DNA fragmentation in sperm cells [37]. Additionally, a recent study by D’Cruz et al. suggests that BPA ability of inducing oxidative stress and estrogenic activity may also perturb glucose homeostasis in testes [38].