Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes

Abstract

Endocrine-disrupting chemicals (EDCs), among which methoxychlor (MXC), have been reported to affect the male reproductive system. This study evaluates the possible deleterious effects of MXC on imprinted genes. After administration of the chemical in adult male mice or in pregnant mice we analyzed by pyrosequencing possible methylation defects in two paternally imprinted (H19 and Meg3 (Gtl2)) and three maternally imprinted (Mest (Peg1), Snrpn, and Peg3) genes in the sperm and in the tail, liver, and skeletal muscle DNAs of the adult male mice and of the male offspring. MXC treatment of adult mice decreased the percentages of methylated CpGs of Meg3 and increased those of Mest, Snrpn, and Peg3 in the sperm DNA. MXC treatment of pregnant mice decreased the mean sperm concentrations by 30% and altered the methylation pattern of all the imprinted genes tested in the F1 offspring. In the latter case, MXC effects were transgenerational but disappeared gradually from F1 to F3. MXC did not affect imprinting in the somatic cells, suggesting that it exerts its damaging effects via the process of reprogramming that is unique to gamete development. A systematic analysis at the CpG level showed a heterogeneity in the CpG sensitivity to MXC. This observation suggests that not only DNA methylation but also other epigenetic modifications can explain the transgenerational effects of MXC. The reported effects of EDCs on human male spermatogenesis might be mediated by complex imprinting alterations analogous to those described in this study.

Smoking induces differential miRNA expression in human spermatozoa: A potential transgenerational epigenetic concern?

“…Four of these miRNAs (hsa-miR-146b-5p, hsamiR-509-5p, hsa-miR-519d and hsa-miR-652) have already been shown to be altered in the testes, seminal plasma and/or semen environmental toxins and factors) can induce harmful phenotypes in the descendants of exposed individuals. [6][7][8][9][10][11][12][13][14] Although the mechanisms underlying transmission of environmentallyinduced phenotypes through generations are not well understood, epigenetic changes within the germ line appear to play a central role. The association of DNA methylation with environmental exposures and heritable phenotypes has been widely established.…”

“…6,7 Such multigenerational toxicity has been observed following exposure to other environmental chemicals and environmental factors such as nutrition and stress. [8][9][10][11][12][13][14] Epidemiological studies suggest that this phenomenon may also occur in human populations. [15][16][17][18][19] recent work has suggested that environmental chemicals, including those contained in cigarette smoke, can have adverse effects on the exposed individuals as well as their future progeny.…”

Effects of Aroclor 1254 on the Dna Methylation of Imprinted Genes in the Adult Mouse Sperm

“…Poplinski et al determined that low sperm counts were clearly associated with Igf2 ⁄ H19 ICR1 hypomethylation and, even stronger, with Mest hypermethylation and idiopathic male infertility is strongly associated with imprinting defects at Igf2 ⁄ H19 ICR1 and Mest, with aberrant Mest methylation being a strong indicator for sperm quality (Poplinski et al, 2010). Stouder and Paoloni-Giacobino's studies using the xenoestrogen vinclozolin (Stouder and Paoloni-Giacobino, 2010) and methoxychlor (Stouder and Paoloni-Giacobino, 2011) have also shown changes in sperm imprinted genes that can be maintained up to the F2 generation. Indeed, methylation defects in the maternally http://www.…”

Antiandrogenic and Estrogenic Compounds: Effect on Development and Function of Male Reproductive System

“…Several studies revealed that endocrine disrupting chemicals are implicated in epigenetic programming and DNA methylation (McLachlan, 2001;Skinner & Anway, 2005). Indeed, hypermethylation found in several genes in the sperm DNA (i. a. Mest, Snrpn, Peg1 and Peg3) was accompanied by the reduction of semen quality (Stouder & Paoloni-Giacobino, 2010). These changes may be heritable, if they occur during certain stages of development (Crews & McLachlan, 2006).…”