METHOXYCHLOR EXPOSURE DURING THE FETAL/NEONATAL PERIOD OF DEVELOPMENT IMPAIRS ADULT OVARIAN FUNCTION AND LEADS TO REDUCED FERTILITY IN RATS

Abstract

Methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl)ethane; MXC] is a non-steroidal chlorinated hydrocarbon pesticide that is an environmental endocrine disruptor used as a replacement for DDT. MXC is a low affinity estrogen receptor agonist; however, it is known to possess estrogenic, anti-estrogenic, or anti-androgenic activities when metabolized. The objective of this investigation was to determine the effects of exposure to MXC during fetal and neonatal periods on ovarian function and fertility. Fischerinbred CDF rats were exposed to vehicle (DMSO:oil; 1:2; control), 20 μg/kg/day MXC or 100 mg/kg/day MXC at time periods 19 – 22 days post coitum (dpc), postnatal day (PND) 4 – 7, and 19 dpc - PND 7. Adult ovarian functions and reproductive parameters, such as the age of puberty, age of first estrous cycle, irregular cyclicity, litter size, and fertility was determined. In addition, the ovary was evaluated for the protein levels of lutenizing hormone receptor (LHR), steroidogenic acute regulatory protein (StAR), and anti-Mullerian hormone (AMH). The results demonstrated that the age of puberty was reduced by 100 mg/kg/day MXC (P < 0.01) for treatment period 19 dpc-PND 7. Age of first estrous cycle was reduced by 100 mg/kg/day MXC (P < 0.05) for treatment periods 19–22 dpc and 19 dpc-PND 7 and (P < 0.01) for treatment period PND 4–7. Litter size was reduced by 100 mg/kg/day MXC (P < 0.05) for treatment period 19 – 22 dpc and (P < 0.01) for treatment period 19 dpc – PND 7. Fertility (percent pregnancy) was reduced by 100 mg/kg/day MXC for treatment period 19 dpc – PND 7. Estrous cyclicity was altered by 100 mg/kg/day MXC for treatment period 19 dpc – PND 7, in which 40% of animals showed persistent estrus and 60% of animals showed a prolonged cycle as early as PND 110. Exposure to MXC during the late fetal and early neonatal period of development decreases the age of puberty, the age of first estrous cycle and causes irregular cyclicity, along with decreasing the litter size and fertility. Furthermore, LHR was increased by 20 μg/kg/day MXC and 100 mg/kg/day MXC (P < 0.05) for treatment periods PND 4 – 7 and (P < 0.01) for treatment period 19 dpc – PND 7; whereas StAR was decreased by 100 mg/kg/day MXC (P < 0.05) for treatment period 19 – 22 dpc. However, 100 mg/kg/day MXC caused an increased trend in MIS for treatment periods PND 4 – 7 and 19 dpc – PND7. In conclusion, MXC is a model endocrine disruptor that alters the function of the ovary by effecting the age of puberty, age of first estrous cycle, estrous cyclicity, fertility and protein level of LHR, StAR, and MIS. Supported by funds from NIEHS/NIH to MU. (poster)