Antifertility Actions of a-Chlorohydrin in the Male

Abstract

Non-steroidal chemicals that affect male fertility have been known for over 25 years but only one compound, alpha-chlorohydrin, possesses most of the attributes of an ideal male contraceptive. In the male rat, for example, continuous daily oral administration of low doses produces an almost immediate and continuous antifertility response that ceases when treatment is withdrawn. Such a dose regime does not interfere with libido, is apparently not toxic and the action is specific towards mature sperm. Furthermore, the action of the compound is species-specific: it is effective in the rat, ram, boar, guinea pig, hamster, rhesus monkey and upon ejaculated human sperm but it is ineffective in the mouse and the rabbit. High doses of alpha-chlorohydrin can be neurotoxic, nephrotoxic and, in rats, lead to prolonged or permanent infertility. However, the antifertility response and the toxicity of racemic alpha-chlorohydrin may be due, respectively, to the separate enantiomers. No other antifertility chemical has been investigated to such an extent as alpha-chlorohydrin; this article reviews the progress that has been achieved with alpha-chlorohydrin during the past six years.

Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate toxicity in rat testis

“…In addition, data analysis suggests alterations relevant to the onset of testicular cancer. This is in good agreement with the results from previous animals studies which have convincingly shown that testis is a main target organ of 3-MCPD, especially with regard to the induction of male infertility and Leydig cell tumorigenesis (Cho et al, 2008;Jones, 1983;Kirton et al, 1970).…”

“…These inhibitory effects of 3-MCPD are reversible (Ericsson and Youngdale, 1970). At higher doses of 3-MCPD of >10e20 mg/kg body weight per day, alterations in sperm morphology and epididymal lesions are additionally observed in rats (Jones, 1983). Moreover, spermatotoxic effects of 3-MCPD are suggested to be mediated by reduced H1-ATPase expression and effects on protein kinase A signaling, leading to a disruption of sperm maturation and reduced sperm motility (Kwack et al, 2004;Zhang et al, 2012).…”

“…It has been suggested that metabolites of 3-MCPD inhibit enzymes involved in spermatozoan glycolysis and reduce the motility of the spermatozoa already at low doses of about 1 mg/kg body weight per day (Jones, 1983;Jones and Porter, 1995;Lynch et al, 1998). Especially the activities of the enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and triosephosphate isomerase are inhibited by the 3-MCPD metabolite b-chlorolactaldehyde (JECFA, 2002;Jones and Porter, 1995;Mohri et al, 1975).…”

“…While not being highly toxic in acute toxicity studies (Liu et al, 2012), severe effects have been reported in response to long-term administration of the compound. In vivo investigations indicate that the reproductive system of males is, besides well-documented effects on the kidney (Jones et al, 1979;Lynch et al, 1998), one of the primary targets for the toxic effects of 3-MCPD, since 3-MCPD has been shown to induce male infertility in rodents and primates in reproductive toxicity studies (Jones, 1983;Kirton et al, 1970). In a more recent 90-day toxicological study using Wistar rats, 3-MCPD and its dipalmitate were compared at an equimolar dosage, demonstrating qualitatively similar, but somewhat milder effects after 3-MCPD diester treatment.…”

Experimental immunological infertility effect of anti-GAPDH-2 antibodies on the fertility of female mice

“…Approximately 10 enzymes in this pathway have spermatogenic cell-specific isozymes (9)(10)(11)(12), including GAPDH-2 or GAPDS, a spermatogenic isoform of somatic GAPDH (12,13). This enzyme is expressed only in spermatids among the male germ cells (12)(13)(14)(15) and is a key regulator of glycolysis in spermatogenic cells concerned with male fertility (16)(17)(18). Sperm-specific antigens are potential candidates in the development of immunocontraceptives.…”