Estrogen Sensitivity of Target Genes and Expression of Nuclear Receptor Co-Regulators in Rat Prostate after Pre- and Postnatal Exposure to the Ultraviolet Filter 4-Methylbenzylidene Camphor

Abstract

Background and objectivesIn previous studies, we found that the ultraviolet filter 4-methyl-benzylidene camphor (4-MBC) exhibits estrogenic activity, is a preferential estrogen receptor (ER)-β ligand, and interferes with development of female reproductive organs and brain of both sexes in rats. Here, we report effects on male development.Methods4-MBC (0.7, 7, 24, 47 mg/kg/day) was administered in chow to the parent generation before mating, during gestation and lactation, and to offspring until adulthood. mRNA was determined in prostate lobes by real-time reverse transcription–polymerase chain reaction and protein was determined by Western blot analysis.Results4-MBC delayed male puberty, decreased adult prostate weight, and slightly increased testis weight. Androgen receptor (AR), insulin-like growth factor-1 (IGF-1), ER-α, and ER-β expression in prostate were altered at mRNA and protein levels, with stronger effects in dorsolateral than ventral prostate. To assess sensitivity of target genes to estrogens, offspring were castrated on postnatal day 70, injected with 17β-estradiol (E2; 10 or 50 μg/kg, sc) or vehicle on postnatal day 84, and sacrificed 6 hr later. Acute repression of AR and IGF-1 mRNAs by E2, studied in ventral prostate, was reduced by 4-MBC exposure. This was accompanied by reduced co-repressor N-CoR (nuclear receptor co-repressor) protein in ventral and dorsolateral prostate, whereas steroid receptor coactivator-1 (SRC-1) protein levels were unaffected.ConclusionsOur data indicate that 4-MBC affects development of male reproductive functions and organs, with a lowest observed adverse effect level of 0.7 mg/kg. Nuclear receptor coregulators were revealed as targets for endocrine disruptors, as shown for N-CoR in prostate and SRC-1 in uterus. This may have widespread effects on gene regulation.

17β-estradiol protects male mice from cuprizone-induced demyelination and oligodendrocyte loss

“…We were not able to assess IGF-1 protein levels from the corpus callosum of mice with available antibodies for ELISA assay or Western blots. In the literature, the effects of E2 on the expression of IGF-1 appear mixed, with a few reports that it results in increased IGF-1 expression in various tissues (Michels et al 1993; Murphy et al 1987; Shingo and Kito 2003) and others reporting a reduction (Borski et al 1996; Durrer et al 2007). We and others have previously showed IGF-1 is primarily produced by microglia and astrocytes (Mason et al 2000; Komoly et al 1992).…”

Male pubertal development: are endocrine-disrupting compounds shifting the norms?

“…This resulted in increased testosterone production and therefore no change in the weights of androgen-responsive male reproductive structures. Other compounds such as lead, methoxychlor, styrene, and IPRO have also been associated with delayed onset of male puberty (Gray et al 1989, Rasier et al 2006, Dickerson & Gore 2007, Durrer et al 2007. Observations of reproductive toxicity in wildlife as well as insights from these and other animal exposure models confirm that pubertal-timing endpoints are sensitive to disruption by hormonally active compounds.…”

Gender and Age Related Modulation of Xenoestrogen-Induced Tumorigenesis

“…In newborns the skin barrier is not fully developed and compounds from personal care products can be transdermally absorbed more than in adults. Many personal care products still contain as additives or ingredients xenobiotics that can act as xenoestrogens, like parabens (especially butyl-and propyl-) used as preservants [67,68] and the UV-filtering agent methyl benzylidene camphor [69]. Products for newborns also may contain extracts from plants containing phytoestrogens such as the phytosterol-rich Aloe vera [70].…”