Endocrine disrupting chemicals and male fertility: from physiological to molecular effects

Abstract

The deleterious effects of chemical or non-chemical endocrine disruptors (EDs) on male fertility potential is well documented but still not fully elucidated. For example, the detection of industrial chemicals' metabolites in seminal plasma and follicular fluid can affect efficiency of the gametogenesis, the maturation and competency of gametes and has guided scientists to hypothesize that endocrine disrupting chemicals (EDCs) may disrupt hormonal homoeostasis by leading to a wide range of hormonal control impairments. The effects of EDCs exposure on reproductive health are highly dependent on factors including the type of EDCs, the duration of exposure, individual susceptibility, and the presence of other co-factors. Research and scientists continue to study these complex interactions. The aim of this review is to summarize the literature to better understand the potential reproductive health risks of EDCs in France.

Keywords: endocrine disrupting chemicals; epigenetics modification; hormonal disorders; pesticides; sperm characteristics; spermatogenesis.

Figure 1

BPA’s effect on androgen signaling pathway in Leydig cells. BPA as an endocrine disruptor has an androgenic property to interact with androgen receptors in cells, with lower affinity than natural androgens. BPA can bind to androgen receptors and militate or inhibit certain androgenic responses, potentially leading to disruptions in hormone signaling including testosterone synthesis as described in figure: Upon binding to LH, the LH receptor undergoes a conformational change that activates a G protein, usually a Gαs protein. The activated G protein (Gαs) increases cAMP levels and activates PKA, which then phosphorylates various proteins within the Leydig cell. This includes the cholesterol side-chain cleavage enzyme (P450scc), resulting in the conversion of cholesterol to pregnenolone. Pregnenolone is then converted through a series of enzymatic reactions to produce testosterone.

Figure 2

The GRP78-PERK pathway leading to testicular cell apoptosis as a response of BPA’s oxidative stress. The interaction between BPA exposure, ROS generation, UPR activation, stress transducers and apoptosis in testicular cells highlights the complicated cellular responses to environmental toxins and endocrine disruptors. As a response to ER stress caused by ROS, the chaperone protein GRP78 is recruited to bind to unfolded/misfolded proteins allowing PERK to become activated. PERK activation leads to the phosphorylation of eIF2α (eukaryotic translation initiation factor 2α). The phosphorylation of eIF2α leads to a global reduction in protein synthesis ATF4 transcriptionally upregulates genes involved in apoptotic pathways, including CHOP (C/EBP homologous protein, also known as GADD153).

Figure 3

Schematic representation of possible mechanism actions of EDCs on DNA integrity and epigenetic changes. The EDCs (agonist or antagonist) disrupt the normal hormonal balance by mimicking, blocking, or altering the action of hormones in the body. These substances can bind to hormone receptors, interfere with hormone synthesis, metabolism, or transport, and disrupt the signaling pathways involved in hormone regulation such as the hypothalamo-pituitary-gonadal axis. Germ cells are the specialized cells in the gonads, responsible for transmitting genetic information from one generation to the next. The link between germ cells, epigenetic aspects, and DNA integrity is intertwined. DNA integrity is vital for the transmission of accurate genetic information. Various mechanisms work together to safeguard DNA integrity in germ cells. DNA repair pathways are active in germ cells to correct DNA damage and prevent the propagation of mutations to future generations. Epigenetic modifications (DNA methylation, histone modifications, and non-coding RNA molecules) is a heritable change in gene expression that does not involve alterations in the DNA sequence itself. This process helps establish and maintain the specific gene expression patterns required for proper germ cell differentiation and function. Additionally, the epigenetic landscape of germ cells can influence DNA integrity by regulating chromatin structure and accessibility, thereby protecting the genetic material from potential DNA damage.