The Effects of Perinatal/Juvenile Methoxychlor Exposure on Adult Rat Nervous, Immune, and Reproductive System Function,

Abstract

In order to address data gaps identified by the NAS report Pesticides in the Diets of Infants and Children, a study was performed using methoxychlor (MXC). Female rats were gavaged with MXC at 0, 5, 50, or 150 mg/kg/day for the week before and the week after birth, whereupon the pups were directly dosed with MXC from postnatal day (pnd) 7. Some dams were killed pnd7 and milk and plasma were assayed for MXC and metabolites. For one cohort of juveniles, treatment stopped at pnd21; a modified functional observational battery was used to assess neurobehavioral changes. Other cohorts of juveniles were dosed until pnd42 and evaluated for changes to the immune system and for reproductive toxicity. Dose-dependent amounts of MXC and metabolites were present in milk and plasma of dams and pups. The high dose of MXC reduced litter size by approximately 17%. Ano-genital distance was unchanged, although vaginal opening was accelerated in all treated groups, and male prepuce separation was delayed at the middle and high doses by 8 and 34 days, respectively. In the neurobehavioral evaluation, high-dose males were more excitable, but other changes were inconsistent and insubstantial. A decrease in the antibody plaque-forming cell response was seen in males only. Adult estrous cyclicity was disrupted at 50 and 150 MXC, doses which also showed reduced rates of pregnancy and delivery. Uterine weights (corrected for pregnancy) were reduced in all treated pregnant females. High-dose males impregnated fewer untreated females; epididymal sperm count and testis weight were reduced at the high, or top two, doses, respectively. All groups of treated females showed uterine dysplasias and less mammary alveolar development; estrous levels of follicle stimulating hormone were lower in all treated groups, and estrus progesterone levels were lower at 50 and 150 MXC, attributed to fewer corpora lutea secondary to ovulation defects. These data collectively show that the primary adult effects of early exposure to MXC are reproductive, show that 5 mg/kg/day is not a NO(A)EL in rats with this exposure paradigm (based on changes in day of vaginal opening, pubertal ovary weights, adult uterine and seminal vesicle weights, and female hormone data) and imply that the sites of action are both central and peripheral.

Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor

“…Methoxychlor is an environmental contaminant, which is widely used as a pesticide in several countries (Chapin et al 1997). This pesticide is considered to be a proestrogen that is metabolized to mono-and bis-hydroxymetabolites, which have been shown to have more estrogenic properties than the parent compound (Bulger et al 1978).…”

Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes

“…Vinclozolin (VCZ), a fungicide possessing an anti-androgenic activity affected spermatogenesis inducing decreases in sperm number and motility and an increase in apoptosis in the seminiferous tubules germ cells (Shimamura et al 2002, Anway et al 2005, Buckley et al 2006, Elzeinova et al 2008. MXC, administered perinatally or during gestation, was also found to affect spermatogenesis in the adult or in the offspring respectively (Chapin et al 1997, Anway et al 2005). An intriguing observation of these studies is that the effects on male genital tract and spermatogenesis were found to be transgenerational, extending from F1 to F4 for VCZ (Anway et al 2005(Anway et al , 2006(Anway et al , 2008 and from F1 to F2 for MXC (Anway et al 2005).…”

Effects of Endocrine-disrupting Chemicals on Female Reproductive Health

“…These included acceleration of the vaginal opening (sign of puberty), acceleration of the onset of the first estrus, irregular cycles with persistent vaginal estrus, reduced pregnancy rate and litter size despite apparent mating, and early reproductive senescence [157 -159]. Serum estradiol and progesterone levels were altered with increased FSH levels [158]. The effects on the ovary were dramatic, with both folliculogenesis and ovulation being inhibited.…”