Effect of lindane on CYP-mediated steroid hormone metabolism in male mice following in utero exposure.
A wide number of pesticides, including highly persistent organochlorinated compounds, such as lindane (LIN), may induce reproductive and developmental alterations by directly binding to the estrogen/androgen receptors or altering steroid hormone metabolism. In the present work, we have investigated whether LIN in utero exposure of CD1 mice affects the reproductive system in male offspring by causing an impairment of the CYP-dependent steroid hormone metabolism. Dam exposure to 25 mg kg(-1) b.w. LIN occurred during critical developmental periods, from gestational days 9 to 16. Effects on hepatic CYP-mediated testosterone (TST) hydroxylase, aromatase activities and testicular parameters were tested at postnatal days (PND 50, 65-69, 100) that are critical for sexual maturation in CD1 mice. In the adult F1 mice significant changes of male reproductive endpoints (testis weight, spermatid number) as well as dramatic effects on CYP-mediated TST metabolism were observed on PND 65-69, in the absence of any of systemic toxicity. The levels of TST 6beta- and 2alpha-hydroxylation and dehydrogenation showed the highest level of reduction, suggesting CYP 3A and 2C families as the major target of LIN induced effects. All changes were almost recovered on PND 100. No effects on aromatase activity were evidenced. Overall, these findings provide useful information for a better characterization of the LIN mode of action. They suggest that LIN-induced toxicity in males is linked to an impairment of steroid hormone homeostasis, due to CYP-mediated TST catabolism modulation and differs from LIN receptor-mediated mechanism previously reported in females.
Di Consiglio
Emma
E
Environment and Primary Prevention Department, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy. emma.diconsiglio@iss.it
De Angelis
Giovanna
G
Traina
Maria Elsa
ME
Urbani
Elisabetta
E
Testai
Emanuela
E
D000375:Aging; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D007306:Insecticides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D055101:Semen Analysis; D013737:Testis / Q000187:drug effects / Q000473:pathology; D013739:Testosterone / Q000378:metabolism
D012739:Gonadal Steroid Hormones; D007306:Insecticides; D013739:Testosterone; D001556:Hexachlorocyclohexane; D003577:Cytochrome P-450 Enzyme System; D001141:Aromatase