Effects of Developmental Exposure to Mixtures of Environmental Contaminants on the Hepatic Metabolism of Estradiol-17β in Immature Female Sprague Dawley Rats

Abstract

Exposure to environmental contaminants induces the activation of cytochrome P450s (CYP) which lead to the hydroxylation of contaminants and endogenous hormones such as estrogens. The hydroxylation of estrogens forms catecholestrogens (CEs), one of them being the mutagenic 4-hydroxyestradiol-17β (4-OH-E2). Catecholestrogens are transformed by catechol-o-methyltransferases (COMTs) into nonreactive methoxyestrogens. To investigate the hepatic metabolism of estradiol-17β in female offspring at postnatal day (PND) 21, pregnant rats were dosed daily from gestation day 1 until PND 21 with 2 dose levels of organochlorine pesticides (OCPs; 0.019 or 1.9 mg/kg per d), methylmercury (MeHg; 0.02 or 2 mg/kg per d), polychlorinated biphenyls (PCBs; 0.011 or 1.1 mg/kg per d), or a mixture (M; 0.05 or 5 mg/kg per d) including all 3 groups of chemicals. Concentrations of organochlorines in the mixture M were based on their proportions in serum of the Canadian Arctic population. The messenger RNA (mRNA) expressions of CYP and COMT were analyzed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). High-performance thin layer chromatography and phosphor imaging were used to measure the transformation of (14)C substrates into estrogen metabolites. The low-dose treatments or the MeHg groups had no effect. The high-dose OCP, PCB, and M group increased the production of 2-OH-E2 and 6α-OH-E2, while only the PCB and M groups increased the 2-OH-CE/methoxyestrogen ratio. In all groups, the cytosolic COMT activity exceeded the microsomal production rate of 4-OH-E2. Although the M treatment included the PCB and OCP mixtures, it did not modify the estrogen metabolism more than did the PCB mixture alone. This endocrine disruption information contributes to our understanding of chemical interactions in the toxicology of chemical mixtures.

Endosulfan and Cypermethrin Pesticide Mixture Induces Synergistic or Antagonistic Effects on Developmental Exposed Rats Depending on the Analyzed Behavioral or Neurochemical End Points

“…A similar antagonistic interaction was reported for a mixture of PCBs and methylmercury. Developmental exposure to methylmercury or PCBs 126 or 153 impairs learning ability and motor coordination, while the mixture of any PCB with methylmercury did not affect these functions. , …”

“…Developmental exposure to methylmercury or PCBs 126 or 153 impairs learning ability and motor coordination, while the mixture of any PCB with methylmercury did not affect these functions. 46,47 Interaction between Cypermethrin and Endosulfan in the Effects of Developmental Exposure on Spontaneous Motor Activity. We also assessed the effect of the mixture of CYP + END on motor activity during 1 h. Ambulatory activity also was significantly altered by pesticides in a sex-dependent way: F 166,3 = 8.98, p ≤ 0.0001 for the effect of pesticide and F 166,1 = 1.49, p ≤ 0.0001 for the effect of sex.…”

Effects of cross-fostering and developmental exposure to mixtures of environmental contaminants on hepatic gene expression in prepubertal 21 days old and adult male Sprague-Dawley rats

“…These enzymes alter steroid metabolism. It is of interest that developmental exposure to a different preparation of the same mixture favored the production of catechol estrogens (Desaulniers et al 2012). Finally, the occurrence of altered lipid and retinoid metabolism is wellestablished.…”