Effect of endosulfan on male reproductive development - Children's Health

Environmental Health Perspectives, Dec, 2003 by Habibullah Saiyed, Aruna Dewan, Vijay Bhatnagar, Udyavar Shenoy, Rathika Shenoy, Hirehall Rajmohan, Kumud Patel, Rekha Kashyap, Pradip Kulkarni, Bagalur Rajan, Bhadabhai Lakkad

There is experimental evidence of adverse effects of endosulfan on the male reproductive system, but there are no human data. Therefore, we undertook a study to examine the relationship between environmental endosulfan exposure and reproductive development in male children and adolescents. The study population was composed of 117 male schoolchildren (10-19 years of age) of a village situated at the foothills of cashew plantations, where endosulfan had been aerially sprayed for more than 20 years, and 90 comparable controls with no such exposure history. The study parameters included recording of clinical history, physical examination, sexual maturity rating (SMR) according to Tanner stages, and estimation of serum levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone, and endosulfan residues (70 study and 47 control subjects). Mean [ or -] SE serum endosulfan levels in the study group (7.47 [ or -] 1.19 ppb) were significantly higher (p < 0.001) than in controls (1.37 [ or -] 0.40 ppb). Multiple regression analysis showed that SMR scoring for development of pubic hair, testes, penis, and serum testosterone level was positively related to age and negatively related to aerial exposure to endosulfan (AEE; p < 0.01). Serum LH levels were significantly positively related to AEE after controlling for age (p < 0.01). The prevalence of congenital abnormalities related to testicular descent (congenital hydrocele, undescended testis, and congenital inguinal hernia) among study and controls subjects was 5.1% and 1.1%, respectively, but the differences were statistically nonsignificant. Our study results suggest that endosulfan exposure in male children may delay sexual maturity and interfere with sex hormone synthesis. Our study is limited by small sample size and nonparticipation. Key words: endocrine disruptor, endosulfan, luteinizing hormone, male reproductive development, sexual maturity rating, testosterone. Environ Health Perspect 111:1958-1962 (2003). doi:10.1289/ehp.6271 available via http://dx.doi.org/[Online 22 September 2003]

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Endosulfan (6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2, 4,3-benzodioxathiepin-3-oxide) is a broad-spectrum insecticide and acaricide first registered for use in the United States in 1954 to control agricultural insect and mite pests on a variety of field, fruit, and vegetable crops. Technical-grade endosulfan is composed of two stereochemical isomers, [alpha]-endosulfan and [beta]-endosulfan, in concentrations of approximately 70% and 30%, respectively. Use data from 1987 to 1997 indicate an average domestic use of approximately 1.38 million pounds of active ingredient per year [U.S. Environmental Protection Agency (U.S. EPA) 2002]. It has been found in at least 162 of the 1,569 current National Priorities List sites by the U.S. EPA (HazDat 2000). In India, it is widely used against a variety of agricultural pests. During 1999-2000, about 81,000 metric tons of endosulfan was manufactured in India, and in terms of tonnage its production was next only to mancozeb (103,000 metric tons) and monocrotophos (95,000 metric tons) (Anonymous 2001).

Oral LD50 (lethal dose sufficient to kill 50% of population) endosulfan in rats is 80 mg/kg, and it has been classified as a moderately hazardous (class II) pesticide [World Health Organization (WHO) 2002]. Neurotoxicity is the major end point of concern in acute endosulfan exposure in human beings and experimental animals. No data are available for subacute or chronic exposure to endosulfan in human subjects; however, the subacute and chronic toxicity studies of endosulfan in animals suggest that the liver, kidneys, immune system, and testes are the main target organs [Agency for Toxic Substances and Disease Registry (ATSDR) 2000].

In recent years, there has been growing concern about toxicity of a number of chemicals, including pesticides, on the male reproductive system (Murray et al. 2001; Sharpe 2001). Reported effects of endosulfan on the male reproductive system in experimental animals have been variable, depending on species, age at exposure, dose, duration of exposure, and study end points. Routine gross and histopathologic examination of the reproductive organs of male mice that consumed doses of 7.3 mg/kg/day for 13 weeks (Hoechst. Unpublished data) or 2.5-5.0 mg/kg/day for 2 years [Hack et al. 1995; Hoechst. Unpublished data; National Cancer Institute (NCI) 1978] revealed no toxic effects. Later on, more detailed studies in adult rats exposed to 2.5, 5, and 10 mg/kg/day endosulfan for 5 days per week for 10 weeks showed reduced intratesticular spermatid counts, sperm abnormalities, and changes in the marker enzymes of testicular activities, such as lactate dehydrogenase, sorbitol dehydrogenase, [gamma]-glutamyl transpeptidase, and glucose-6-phosphate dehydrogenase, providing further evidence of effects on spermatogenesis (Khan and Sinha 1996; Sinha et al. 1995). Exposure of younger animals (3 weeks old) showed marked depletion of spermatid count as well as decreased daily sperm production at a dose of 2.5 mg/kg/day (Sinha et al. 1997), which was earlier seen only at 5 mg/kg/day in adult rats by the same investigators (Sinha et al. 1995). More recent studies have shown that exposure of pregnant rats to endosulfan at 1 mg/kg/day from day 12 through parturition leads to decreased spermatogenesis in offspring (Sinha et al. 2001). Dalsenter et al. (1999) reported similar observations at 3 mg/kg/day but not at 1.5 mg/kg/day, and they attributed this to strain variation (Dalsenter et al. 2003). Thus, experimental studies suggest that endosulfan can affect the male reproductive system and also that these effects are likely to be greater if exposure occurs during the developmental phase.