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Effects of perinatal exposure to phthalate/adipate esters on hypothalamic gene expression and sexual behavior in rats
Hwi-Cheul Lee1, Keitaro Yamanouchi, Masugi Nishihara
1Department of Veterinary Physiology, Veterinary Medical Science, The University of Tokyo, Japan.
Insights
Perinatal exposure to endocrine disruptors like DBP, DINP, and DEHA altered granulin (grn) and p130 gene expression in neonatal rat brains, impacting sexual behaviors later in life.
Area of Science:
- Neuroendocrinology
- Developmental Toxicology
- Molecular Biology
Background:
- Granulin (grn) and p130 genes are sex steroid-regulated in the neonatal rat hypothalamus and may influence brain sexual differentiation.
- Environmental endocrine disruptors, including phthalate/adipate esters, can possess estrogenic or antiandrogenic properties, potentially affecting brain sexual development.
Purpose of the Study:
- To assess the effects of perinatal exposure to di-n-butyl phthalate (DBP), diisononyl phthalate (DINP), and di-2-ethylhexyl adipate (DEHA) on grn and p130 mRNA expression in the hypothalamus.
- To evaluate the impact of this exposure on sexual behaviors in adult rats.
Main Methods:
- Maternal rats received diets containing varying doses of DBP, DINP, or DEHA from gestational day 15 to postnatal day 21.
- Hypothalamic grn and p130 mRNA levels were measured on postnatal day 7.
- Copulatory behavior in males and lordosis quotient in females were assessed after maturation.
Main Results:
- DBP and DINP increased hypothalamic grn and p130 mRNA in females and males, respectively.
- DEHA decreased grn mRNA in males and p130 mRNA in females, without a clear dose-dependent effect.
- Perinatal exposure to DBP, DINP, and DEHA reduced copulatory behavior in males and the lordosis quotient in females post-maturation.
Conclusions:
- Perinatal exposure to DBP, DINP, and DEHA can lead to altered grn and p130 gene expression in the neonatal rat hypothalamus.
- These gene expression changes may cause permanent effects, resulting in decreased sexual behavior in adulthood.
- Hormone levels (LH, FSH) and estrous cycles were not significantly affected by the exposures.
Abstract:
Our previous research has identified the granulin (grn) and p130 genes as sex steroid-regulated genes in the neonatal rat hypothalamus that might be involved in sexual differentiation of the brain. Since phthalate/adipate esters such as di-n-butyl phthalate (DBP), diisononyl phthalate (DINP), and di-2-ethylhexyl adipate (DEHA) are suspected to interfere with the endocrine system as environmental endocrine disruptors having estrogenic or antiandrogenic properties, these chemicals may affect sexual differentiation of the brain. The present study assessed the effects of perinatal exposure to DBP, DINP, and DEHA on grn and p130 mRNA expressions in the hypothalamus on postnatal day (PND) 7 and sexual behaviors after maturation in rats. Maternal rats were given a phytoestrogen-free diet containing different doses of DBP (20, 200, 2,000, and 10,000 ppm), DINP (40, 400, 4,000, and 20,000 ppm) and DEHA (480, 2,400, and 12,000 ppm) from gestational day 15 to the day of weaning (PND 21). DBP and DINP exposure during the perinatal period resulted in an increase in hypothalamic grn and p130 mRNA levels in females and males, respectively, but DEHA exposure decreased expression levels of grn in males and p130 in females, although the effects were not dose-dependent. After maturation, male rats that were exposed to several doses of DBP, DINP, and DEHA displayed decreased copulatory behavior. The lordosis quotient was decreased in females perinatally exposed to DBP, DINP, and DEHA at all the doses used. On the other hand, serum levels of LH and FSH in both sexes and the estrous cycles in females were not affected by the treatments. These results suggest that inappropriate expression of grn and/or p130 genes in the brains of male and female neonatal rats by perinatal exposure to these chemicals may exert permanent effects on the hypothalamus, thereby decreasing sexual behavior after maturation.
