Arsenic Toxicity in Male Reproduction and Development

Abstract

Arsenic is a toxic metalloid that exists ubiquitously in the environment, and affects global health problems due to its carcinogenicity. In most populations, the main source of arsenic exposure is the drinking water. In drinking water, chronic exposure to arsenic is associated with increased risks of various cancers including those of skin, lung, bladder, and liver, as well as numerous other non-cancer diseases including gastrointestinal and cardiovascular diseases, diabetes, and neurologic and cognitive problems. Recent emerging evidences suggest that arsenic exposure affects the reproductive and developmental toxicity. Prenatal exposure to inorganic arsenic causes adverse pregnancy outcomes and children's health problems. Some epidemiological studies have reported that arsenic exposure induces premature delivery, spontaneous abortion, and stillbirth. In animal studies, inorganic arsenic also causes fetal malformation, growth retardation, and fetal death. These toxic effects depend on dose, route and gestation periods of arsenic exposure. In males, inorganic arsenic causes reproductive dysfunctions including reductions of the testis weights, accessory sex organs weights, and epididymal sperm counts. In addition, inorganic arsenic exposure also induces alterations of spermatogenesis, reductions of testosterone and gonadotrophins, and disruptions of steroidogenesis. However, the reproductive and developmental problems following arsenic exposure are poorly understood, and the molecular mechanism of arsenic-induced reproductive toxicity remains unclear. Thus, we further investigated several possible mechanisms underlying arsenic-induced reproductive toxicity.

Keywords: Arsenic; Development; Male; Reproduction; Steroidogenesis.

Fig. 1.. Metabolic pathway of inorganic arsenic.

Arsenate (As⁵⁺) is reduced by As⁵⁺ reductase with glutathione (GSH) to yield arsenite (As³⁺) and glutathione disulfide (GSSG). As³⁺ is converted to pentavalent monomethylarsonic acid (MMA⁵⁺), a reaction catalyzed by arsenic-3-methyltransferase (AS3MT), with Sadenosylmethione (SAM) serving as the methyl donor; in the process, SAM is hydrolyzed to Sadenosyl homocysteine (SAH). After the reduction of MMA⁵⁺ to MMA³⁺, a second methylation step result in the synthesis of dimethylarsinic acid (DMA⁵⁺), and then it is reduced to DMA³⁺.

Fig. 2.. Hormonal controls of spermatogenesis in the hypothalamic-pituitary-testicular axis.

Luteinizing hormone (LH) acts directly upon the Leydig cells to stimulate testosterone (T) production. T and folliclestimulating hormone (FSH) act upon the Sertoli cells within seminiferous epithelium to support development and maturation of germ cells.

Fig. 3.. Possible mechanisms involved in arsenic-induced male reproductive toxicity.

Arsenic may inhibit spermatogenesis and sperm maturation following certain key molecular mechanisms including reductions of testosterone and gonadotrophins LH and FSH, disruptions of steroidogenic enzymes 3β-HSD and 17β-HSD, negative regulations of LH and FSH by increased corticosterone, decreases of sperm motility and viability following the direct binding of arsenic (As) to sperm, and direct damages or apoptosis of testicular component germ cells or Sertoli cells. The dotted lines represent negative regulations of the general spermatogenesis following arsenic exposure. LH, luteinizing hormone; FSH, follicle-stimulating hormones; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 17β-HSD, 3β-hydroxysteroid dehydrogenase.