Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

Abstract

-A two-generation reproduction toxicity study in rats adding extra endpoints to detect endocrine disrupting activity was conducted using lindane by dietary administration at 0, 10, 60, and 300 ppm, for investigation of its utility. The extra endpoints included anogenital distance (AGD), nipple development, sexual maturation (vaginal opening and preputial separation), estrous cycle, spermatogenesis, sex organ weights, and blood hormone concentrations (thyroid and sex hormones). F1 offspring were examined for emotionality (open field test), motor coordination (rotarod test), as well as learning and memory (pole-climbing test). Hepatic drug-metabolizing enzyme activities were also measured. The results revealed general toxicological effects on parental animals, influence on reproductive function, and altered development of offspring; however, they did not demonstrate any distinct changes in the extra endpoints for detection of endocrine disrupting activity. Adult toxicity was observed in both F0 and F1 animals, including suppressed body weight gain and reduced food consumption in both sexes, and deaths of females at 300 ppm. Convulsions and irritability were observed during the perinatal period in pregnant F1 females given 300 ppm. Pathological examination revealed increased liver weights and centrilobular hepatocellular hypertrophy in both sexes and generations at 10 or 60 ppm and above; in addition, increased kidney weights and increased hyaline droplets in the proximal tubule epithelium, and basophilic renal tubules in males were noted at 10 ppm and above. Pituitary weights were decreased in F0 females and in F1 males and females and adrenal weights were increased in F1 males and females at 300 ppm; however, no histological changes were observed, and manifestations suggesting endocrine disrupting activity related to these changes were lacking. Hypertrophy of the thyroid follicular epithelium in F0 females at 300 ppm and in F1 males at 60 and 300 ppm, and decreases in T3 and/or T4 in both sexes and generations at 300 ppm were presumed to be secondary changes associated with the induction of hepatic drug-metabolizing enzymes. Blood hormone analysis revealed no changes in sex hormones attributable to lindane in males or females. Hepatic drug-metabolizing enzyme activities were increased dose-dependently from 10 ppm in both sexes and generations, with the rise in BROD activity being the most prominent. There were also increases in MROD, EROD, T-6β-OH, and T4-UDP-GT activities (BROD >> EROD > MROD, T-6β-OH, T4-UDP-GT). This suggests that while lindane most strongly induces CYP2B, it also upregulates a number of other drug metabolizing enzymes, such as CYP1A, CYP3A, and UDP-GT. As for effects on reproductive function, lack of maternal behavior, including lactation and retrieval behavior, and consequent total litter loss were observed in F1 dams at 300 ppm. There were no effects of lindane on the estrous cycle, spermatogenesis, mating, fertility, pregnancy, or parturition. Neonatal toxicity was observed in bot...

Canadian Arctic Contaminants and Their Effects on the Maternal Brain and Behaviour: A Scoping Review of the Animal Literature

“…The 60 ppm group consumed 3.389 ± 0.167 and 8.941 ± 0.677, while the 300 ppm lindane group consumed 16.55 ± 0.95 and 45.21 ± 3.54 mg/kg body weight per day during the gestational and lactational periods, respectively. Lack of retrieval behaviour and consequential litter loss were observed in one 300 ppm lindane-exposed dam [90]. Other than the one case, lindane exposure did not affect any maternal behaviours, including lactation, nest building, and cannibalism [90].…”

“…Lack of retrieval behaviour and consequential litter loss were observed in one 300 ppm lindane-exposed dam [90]. Other than the one case, lindane exposure did not affect any maternal behaviours, including lactation, nest building, and cannibalism [90].…”

Effect of lindane on CYP‐mediated steroid hormone metabolism in male mice following in utero exposure

“…The eff ect may be relevant, persisting up to the sexual maturation. Although with substantially diff erent study designs, previous results also suggested eff ects of LIN on CYP ontogeny (Matsuura et al, 2005;Johri et al, 2008).…”

Wildlife Toxicity Assessment for Hexachlorocyclohexane (HCH)

“…General toxicological effects (i.e., reduced gains in body weight, decreased food consumption, and deaths of females from the 15 mg/kg/day group) were seen in parental animals [44]. In the two-generation study, Crj:CD(SD)IGS rats (SPF) received 0, 10, 60, or 300 ppm of 99.5% pure g-HCH (corresponding to a dose of 0, 0.5, 3.0, and 15 mg/kg/day, respectively).…”