Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) promotes the transgenerational inheritance of adult-onset reproductive dysfunctions through the female germline in mice

Endocrine disruptors (EDS) are compounds known to promote transgenerational inheritance of adult-onset disease in subsequent generations after maternal exposure during fetal gonadal development. This study was designed to establish whether gestational and lactational exposure to the plasticizer di(2-ethylhexyl)phthalate (DEHP) at environmental doses promotes transgenerational effects on reproductive health in female offspring, as adults, over three generations in the mouse. Gestating F0 mouse dams were exposed to 0, 0.05, 5 mg/kg/day DEHP in the diet from gestational day 0.5 until the end of lactation. The incidence of adult-onset disease in reproductive function was recorded in F1, F2 and F3 female offspring. In adult Fl females, DEHP exposure induced reproductive adverse effects with: i) altered ovarian follicular dynamics with reduced primordial follicular reserve and a larger growing pre-antral follicle population, suggesting accelerated follicular recruitment; ii) reduced oocyte quality and embryonic developmental competence; iii) dysregulation of the expression profile of a panel of selected ovarian and pre-implantation embryonic genes. F2 and F3 female offspring displayed the same altered reproductive morphological phenotype and gene expression profiles as Fl, thus showing transgenerational transmission of reproductive adverse effects along the female lineage. These findings indicate that in mice exposure to DEHP at doses relevant to human exposure during gonadal sex determination significantly perturbs the reproductive indices of female adult offspring and subsequent generations. Evidence of transgenerational transmission has important implications for the reproductive health and fertility of animals and humans, significantly increasing the potential biohazards of this toxicant

Exposure to di(2-ethyl-hexyl) phthalate (DEHP) in utero and during lactation causes long-term pituitary-gonadal axis disruption in male and female mouse offspring

The present study examined the effects in mice of exposure to di(2-ethyl-hexyl) phthalate (DEHP) throughout pregnancy and lactation on the development and function of the pituitary-gonadal axis in male and female offspring once they have attained adulthood. Groups of two to three dams were exposed with the diet from gestational d 0.5 until the end of lactation, at 0, 0.05, 5, and 500 mg DEHP/kg \ub7 d. The experiment was repeated three times (total: seven to 10 dams per treatment). The 500-mg dose caused complete pregnancy failure, whereas exposure to doses of 0.05 and 5 mg did not affect pregnancy and litter size. In total, about 30 male and 30 female offspring per group were analyzed. Offspring of the DEHP-treated groups, compared with controls, at sexual maturity showed: 1) lower body weight (decrease 20-25%, P < 0.001); 2) altered gonad weight (testes were 3c13% lighter and ovaries 3c40% heavier; P < 0.001); 3) poor germ cell quality (semen was 3c50% less concentrated and 20% less viable, and 3c10% fewer oocytes reached MII stage, P < 0.001); 4) significant lower expression of steroidogenesis and gonadotropin-receptor genes in the gonads; and 5) up-regulated gonadotropin subunit gene expression in the pituitary. In conclusion, our findings suggest that, in maternally exposed male and female mice, DEHP acts on multiple pathways involved in maintaining steroid homeostasis. Specifically, in utero and lactational DEHP exposure may alter estrogen synthesis in both sexes. This, in turn, induces dysregulation of pituitary-gonadal feedback and alters the reproductive performance of exposed animals

Effects of polychlorinated biphenyls in Cd-1 mice : reproductive toxicity and intergenerational transmission

Several studies indicate that in-utero and peri-natal exposure to polychlorinated biphenyls (PCBs) induces adverse reproductive effects but it remains unclear whether such effects may be transmitted to subsequent generations. We therefore investigated the association between maternal exposure to PCBs and reproductive health in male and female offspring over three generations.Mouse dams were fed 0, 1, 10, 100 \u3bcg/kg/day of a PCB mixture (101+118) during pregnancy and lactation. PCB levels were measured in the tissues of both dams and offspring.PCB concentrations at all doses investigated were greater in the offspring than in the dams (P 640.0001) confirming that the progeny were exposed as a result of maternal exposure. In F1 offspring, exposure to PCBs resulted in reductions in: i) testis weight (P 640.05) and seminiferous tubule diameter (P 640.05); ii) sperm viability (P 640.0001) and developmental capacity (P 640.05); iii) ovary weight (P 640.05); iv) oocyte developmental capacity (P 640.05), and in v) increased follicular atresia (P 640.0001).In females, adverse effects were observed only in the F1 animals. In contrast, male offspring exhibited reduced sperm viability and altered seminiferous tubule distribution up to the third generation, showing intergenerational transmission.In summary, our data indicate that exposure to PCBs at the time of gonadal sex determination perturbed, significantly, the reproductive physiology of male and female offspring in adulthood. Furthermore, male reproductive deficiencies may be observed in at least two further generations. These findings have significant implications for reproductive health and fertility of animals and humans

A direct access to a potential LTB4-antagonist, SM-9064, via disilyl derivatives

The synthesis of SM-9064, a potential LTB4 antagonist, which is effective in some types of inflammation, has been easily achieved in a few steps by electrophilic substitution reactions between (1E,3E,5E)-1,6-bis(trimethylsilyl)-1,3,5-hexatriene and acyl chlorides in the presence of aluminum trichloride, followed by reduction reaction and formation of pyrrolidine derivative

An easy access to 4-(1,2,3-triazolylalkyl)-1,2,3-triazole-fused dihydroisoquinolines and dihydroisoindoles

A convenient synthesis of 4-(1,2,3-triazolylalkyl)-1,2,3-triazole fused dihydroisoquinolines and dihydroisoindoles is reported, starting from easily available (2-iodoaryl)alkyl azides and terminal alkynols. The procedure is based upon transition-metal catalyzed coupling reactions followed by iterative cycloaddition reactions

An easy approach to 1-silylated ketones and asymmetrical 1,6- and 1,8-dicarbonyl compounds

A variety of 1-silylated ketones and asymmetrical 1,6- and 1,8-dicarbonyl compounds are synthesized with 70-85% yields by means of Pd-catalysed selective hydrogenation reactions of the corresponding unsaturated conjugated products, readily available by a previously reported procedure