Phthalate-Induced Fetal Leydig Cell Dysfunction Mediates Male Reproductive Tract Anomalies

Abstract

Male fetal Leydig cells in the testis secrete androgen and insulin-like 3, determining the sexual differentiation. The abnormal development of fetal Leydig cells could lead to the reduction of androgen and insulin-like 3, thus causing the male reproductive tract anomalies in male neonates, including cryptorchidism and hypospadias. Environmental pollutants, such as phthalic acid esters (phthalates), can perturb the development and differentiated function of Leydig cells, thereby contributing to the reproductive toxicity in the male. Here, we review the epidemiological studies in humans and experimental investigations in rodents of various phthalates. Most of phthalates disturb the expression of various genes encoded for steroidogenesis-related proteins and insulin-like 3 in fetal Leydig cells and the dose-additive effects are exerted after exposure in a mixture.

Toxicological Effects of Cadmium on Mammalian Testis

“…As mentioned above, FLCs secrete two important hormones, T and INSL3, to stimulate the development of the male reproductive tract and the descent of the testis. Perinatal exposure to environmental toxicants can cause TDS (Wang et al, 2019). Cd affects the development and function of FLCs ( Table 1).…”

Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

“…In adult rats, prenatal exposure before mating and during pregnancy to a mixture of brominated flame retardants downregulated Insl3 and Cyp17a1 expression in the ovary, but increased circulating androgen levels and caused increased number of (pre)antral follicles and antral follicle size in the dams (Lefèvre et al 2016 ). There are numerous studies reporting disrupted INSL3 expression in testes following exposure to industrial chemicals such as phthalates leading to male reproductive tract anomalies (Anand-Ivell et al 2018 ; Wang et al 2019 ). It can be speculated that effects in the ovaries would be similar to effects seen in testes; however, direct evidence in the human female is lacking.…”

Bisphenols and Leydig Cell Development and Function

“…In fetuses, T and metabolically activated dihydrotestosterone (DHT) from T by 5α-reductase is essential for the development of the male reproductive tract (3). Failure to synthesize T may cause abnormalities in the male reproductive tract, such as hypospadias and small penis [see review (4)]. Androgens are also essential for testis descent (4).…”

“…Failure to synthesize T may cause abnormalities in the male reproductive tract, such as hypospadias and small penis [see review (4)]. Androgens are also essential for testis descent (4). INSL3 binds to its receptor in the gubernaculum and pulls the testis from the kidney position to the lower part of abdomen (5).…”

“…Although the exact cause is unclear, the high incidence of male reproductive tract defects in male neonates has brought significant attention to children's health (10,11). In adults, T is essential for the onset of puberty, the maintenance of secondary sexual characteristics, the promotion of spermatogenesis, and the promotion of muscle health (4). INSL3 is essential for regulating bone metabolism in adult males (12) and acts as an anti-apoptotic factor against germ cell apoptosis (13).…”