TY - JOUR AB - In Europe, the male to female ratio at birth (secondary sex ratio: SSR; sex odds: SO) is 1.04-1.06, is influenced by many factors and is declining in industrialized countries. This study was carried out to identify possible impacts of fallout by atomic bomb tests or by the Chernobyl event on SSR in Italy. Italy is a country without commercial nuclear power generation for the last four decades and thus nearly free of radiological confounders. Counts of annual male and female live births in Italy are provided by the World Health Organization (WHO) and by the Italian Istituto Nazionale di Statistica (ISTAT). This study included 57.7 million live births (1940-2019) with overall SSR 1.05829. The Italian SSR trend was modelled with linear and non-linear logistic regression. Trend changes, i.e., periods with level shifts were estimated with Markov Chain Monte Carlo (MCMC). Two distinct idealized level shifts were identified superimposed on a uniform secular downward trend. The first one is seen towards the end of the 1960s with a jump sex odds ratio (SOR) 1.00681, p < 0.0001. The second one occurred in 1987 with SOR 1.00474, p < 0.0001. In each of the 3 periods separated by the two jumps, SSR uniformly decreased with trend SOR per 100 years of 0.98549, p < 0.0001. In conclusion, the secular trend in the Italian SSR showed two marked level shifts, at the end of the 1960s and from 1987 onward. These follow the release of radioactivity by atmospheric atomic bomb tests during the 1960s and by Chernobyl in 1986 and corroborate the hypothesis that ionizing radiation increases SSR. AU - Scherb, H. AU - Grech, V.* C1 - 61179 C2 - 50072 CY - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, England SP - 137-142 TI - The secondary sex ratio in Italy over the past eighty years (1940 to 2019) and potential impact of radiological contamination after atmospheric nuclear testing and after Chernobyl: Temporal change-point analysis using Markov Chain Monte Carlo. JO - Reprod. Toxicol. VL - 100 PB - Pergamon-elsevier Science Ltd PY - 2021 SN - 0890-6238 ER - TY - JOUR AB - Increases in childhood cancer near nuclear facilities in France and in Germany as well as elevated human birth sex ratios after the atmospheric atomic bomb tests and after Chernobyl motivated the inspection of the secondary sex ratio and the corresponding gender-specific birth counts in the vicinity of nuclear facilities. Focus is on which changes in the birth counts go along with significant changes in the sex ratios. Official municipality-specific annual birth counts by sex for all of France and for whole Germany are updated until 2016 and 2017, respectively. Using logistic regression, we determine significant change-points (jumps) after distinct radiological events in sex ratio time-trends in circular areas around pertinent nuclear facilities. With Poisson regression, we quantify the corresponding change-points in the trends of absolute annual birth counts for boys and girls. In the 35-km vicinity of the 'Centre de l'Aube Nuclear Disposal Facility (CSA)' in France in the year 2000, we observe a jump in the sex odds (SO) with sex odds ratio (SOR) 1.101; 95% CI: (1.033, 1.175), p-value 0.0033. This jump in the sex odds can be associated with a drop in boys of 3.44% ( - 4.02, 10.37), p-value 0.3561, and a drop in girls of 8.44% (1.33, 15.04), p-value 0.0208. In the highly populated area around the nuclear power plant Philippsburg in Germany from 2001 onward, we see a similar effect: SOR 1.027 (1.008, 1.046), p-value 0.0045; drop in boys 5.56% (2.24, 8.76), p-value 0.0012; drop in girls 6.92% (3.62, 10.10), p-value < 0.0001. The presented findings corroborate and specify earlier observations and call for intensifying bio-physical research in exposure mechanisms and exposure pathways of natural or artificial ionizing radiation including neutron radiation and neutron activation. Reinforced biological and epidemiological research should aim at clarifying the associated genetic and carcinogenic consequences at the population level. AU - Scherb, H. AU - Kusmierz, R.* AU - Voigt, K.* C1 - 56661 C2 - 47216 CY - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, England SP - 159-167 TI - Secondary sex ratio and trends in the associated gender-specific births near nuclear facilities in France and Germany: Update of birth counts. JO - Reprod. Toxicol. VL - 89 PB - Pergamon-elsevier Science Ltd PY - 2019 SN - 0890-6238 ER - TY - JOUR AB - The possible detrimental genetic impact on humans living in the vicinity of nuclear facilities has been previously studied. We found evidence for an increase in the human secondary sex ratio (sex odds) within distances of up to 35km from nuclear facilities in Germany and Switzerland. Here, we extend our pilot investigations using new comprehensive data from France. The French data (1968-2011) account for 36,565 municipalities with 16,968,701 male and 16,145,925 female births. The overall sex ratio was 1.0510. Using linear and nonlinear logistic regression models with dummy variables coding for appropriately grouped municipalities, operation time periods, and corresponding spatiotemporal interactions, we consider the association between annual municipality-level birth sex ratios and minimum distances of municipalities from nuclear facilities. Within 35km from 28 nuclear sites in France, the sex ratio is increased relative to the rest of France with a sex odds ratio (SOR) of 1.0028, (95% CI: 1.0007, 1.0049). The detected association between municipalities' minimum distances from nuclear facilities and the sex ratio in France corroborates our findings for Germany and Switzerland. AU - Scherb, H. AU - Kusmierz, R. AU - Voigt, K. C1 - 47912 C2 - 39751 CY - Oxford SP - 104-111 TI - Human sex ratio at birth and residential proximity to nuclear facilities in France. JO - Reprod. Toxicol. VL - 60 PB - Pergamon-elsevier Science Ltd PY - 2016 SN - 0890-6238 ER - TY - JOUR AB - Boron treatment of rats, mice, and dogs has been associated with testicular toxicity, characterized by inhibited spermiation at lower dose levels and a reduction in epididymal sperm count at higher dose levels. The no-adverse-effect level for reproductive effects in male rats is 17.5mg B/kg bw/day. Earlier studies in human workers and populations have not identified adverse effects of boron exposure on fertility, but outcome measures in these studies were relatively insensitive, based mainly on family size and did not include an evaluation of semen end points. A recent study of nearly 1000 men working in boron (B) mining or processing in Liaoning province in northeast China has been published in several Chinese and a few English language papers. This study included individual assessment of boron exposure, interview data on reproductive experience and semen analysis. Employed men living in the same community and in a remote community were used as controls. Boron workers (n=75) had a mean daily boron intake of 31.3mg B/day, and a subset of 16 of these men, employed at a plant where there was heavy boron contamination of the water supply, had an estimated mean daily boron intake of 125 mg B/day. Estimates of mean daily boron intake in local community and remote background controls were 4.25mg B/day and 1.40 mg/day, respectively. Reproductive outcomes in the wives of 945 boron workers were not significantly different from outcomes in the wives of 249 background control men after adjustment for potential confounders. There were no statistically significant differences in semen characteristics between exposure groups, including in the highly exposed subset, except that sperm Y:X ratio was reduced in boron workers. Within exposure groups the Y:X ratio did not correlate with the boron concentration in blood, semen and urine. In conclusion, while boron has been shown to adversely affect male reproduction in laboratory animals, there is no clear evidence of male reproductive effects attributable to boron in studies of highly exposed workers. AU - Scialli, A.R.* AU - Bonde, J.P.* AU - Brüske, I. AU - Culver, B.D.* AU - Li, Y.H.* AU - Sullivan, F.M.* C1 - 1476 C2 - 27542 SP - 10-24 TI - An overview of male reproductive studies of boron with an emphasis on studies of highly exposed Chinese workers. JO - Reprod. Toxicol. VL - 29 IS - 1 PB - Elsevier PY - 2010 SN - 0890-6238 ER - TY - JOUR AB - We aimed to describe if polymorphisms in xenobiotics-metabolizing genes modify the effect of maternal exposure to fine particulate matter (PM(2.5)) on offspring birth weight. Among newborns from LISA cohort, we tested if polymorphisms of GSTT1, GSTP1, GSTM1, and CYP2D6 genes modified the effect measure of PM(2.5) on term birth weight. Subsequently, we tested if polymorphisms modified the effect of other exposure factors with possibly similar pathways of action (active or passive smoking). PM (2.5) exposure above the median value (reference, below) was associated with birth weight changes by 76 g in the homozygous wild type genotype (n=161), -90 g in the heterozygous genotype (n=154) and -168 g in children with GSTP1 *1B/*1B mutant genotype (n=39, interaction test, p=0.05). No effect measure modification with PM(2.5) was detected for GSTT1, GSTM1 or CYP2D6 polymorphisms (p≥ 0.12). No effect measure modification with GSTP1 polymorphism was detected for active (p=0.71) nor for passive smoking effects on birth weight (p=0.13). AU - Slama, R.* AU - Gräbsch, C.* AU - Lepeule, J.* AU - Siroux, V.* AU - Cyrys, J. AU - Sausenthaler, S. AU - Herbarth, O.* AU - Bauer, M.* AU - Borte, M.* AU - Wichmann, H.-E. AU - Heinrich, J. C1 - 5829 C2 - 28171 SP - 600-612 TI - Maternal fine particulate matter exposure, polymorphism in xenobiotic-metabolizing genes and offspring birth weight. JO - Reprod. Toxicol. VL - 30 IS - 4 PB - Elsevier PY - 2010 SN - 0890-6238 ER - TY - JOUR AB - To investigate trends in the sex odds before and after the Chernobyl accident, gender-specific annual birth statistics were obtained from the Czech Republic, Denmark, Finland, Germany, Hungary, Norway, Poland, and Sweden between 1982 and 1992. For parts of Germany, annual birth statistics and fallout measurements after Chernobyl are available at the district level. Trend models allowing for discontinuities of the male birth proportions are suggested. Superimposed on a downward trend in male proportions there was a jump in 1987 with a sex odds ratio of 1.0047 (95%-confidence interval: 1.0013–1.0081, p = 0.0061). A positive association of the male proportion in Germany between 1986 and 1991 with radioactive exposure at the district level is reflected by a sex odds ratio of 1.0145 per mSv/a (1.0021–1.0271, p = 0.0218). These findings suggest a possible long-term chronic influence of the Chernobyl Nuclear Power Plant accident on the human sex odds at birth in several European countries. AU - Scherb, H. AU - Voigt, K. C1 - 5333 C2 - 24409 SP - 593-599 TI - Trends in the human sex odds at birth in Europe and the Chernobyl Nuclear Power Plant accident. JO - Reprod. Toxicol. VL - 23 IS - 4 PB - Elsevier PY - 2007 SN - 0890-6238 ER - TY - JOUR AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a reproductive toxicant and endocrine disrupter that is known to block ovulation. This study was designed to investigate alterations in relevant ovarian genes that may be involved in the blockage of ovulation by TCDD in immature intact rats primed with equine chorionic gonadotropin (eCG). In this ovulation model, rats were given either 32 microg/kg TCDD or corn oil by gavage on 25 days of age. The next day, eCG (5 IU) was injected subcutaneously (s.c.) to stimulate follicular development. Ovulation occurs 72 h after administration of eCG in controls of this model. TCDD blocked ovulation at the expected time and also reduced both ovarian and body weights. At 72 h after eCG (the morning after expected ovulation), TCDD did not alter significantly serum concentrations of progesterone (P4) and androstenedione (A4). However, estradiol (E2) was significantly higher at 72 h after eCG in TCDD-treated rats when compared with controls. Western blots revealed that ovarian CYP1A1 was induced by TCDD. In addition, the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) were down- and up-regulated by TCDD, respectively, indicating that AhR-mediated signal transduction was altered in the ovary. Ovarian estrogen receptor (ER)alpha, ER beta and progesterone receptor (PR) were not altered significantly by TCDD, but ovarian glucocorticoid receptor (GR) was increased at 24h after TCDD and decreased at 72 h after eCG when compared with controls. TCDD induced the early appearance of ovarian plasminogen activator inhibitor type-1 (PAI-1), plasminogen activator inhibitor type-2 (PAI-2), urokinase plasminogen activator (uPA), and tissue plasminogen activator (tPA) at 24h after dosing when compared with controls. On the morning after ovulation (72 h after eCG), no significant differences between control and TCDD-treated rats were observed except that TCDD had still increased tPA and decreased PAI-2 when compared with controls. Interestingly, ovarian COX-2 was induced on the morning after ovulation (72 h after eCG) in controls, but was greatly inhibited in TCDD-treated rats at that time. On the other hand, COX-1 was constitutively expressed throughout the ovulatory period and remained unaffected by TCDD. Immunolocalization of COX-2 in the ovary revealed that TCDD inhibited COX-2 expression in the granulosa cell layer when assessed in the morning of expected ovulation. In conclusion, AhR signaling is activated in the ovary by TCDD and inhibition of COX-2 appeared to be a critical step in the TCDD blockage of ovulation because blockage or reduction of COX-2 expression is well known to be associated with failure of ovulation. AU - Mizuyachi, K.* AU - Son, D.S.* AU - Rozman, K.K. AU - Terranova, P.F.* C1 - 23885 C2 - 31380 SP - 299-307 TI - Alteration in ovarian gene expression in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin: reduction of cyclooxygenase-2 in the blockage of ovulation. JO - Reprod. Toxicol. VL - 16 IS - 3 PB - Elsevier PY - 2002 SN - 0890-6238 ER - TY - JOUR AB - Intact and hypophysectomized immature rats were pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 0 or 32 mug/kg p.o.) and sacrificed throughout synchronized follicular development (0, 12, 24, 48, and 72 It after equine chorionic gonadotropin, eCG). TCDD administration to intact rats resulted in a premature elevation of serum FSH and LH by 12 h post-eCG. In intact rats pretreated with TCDD, the intensity of ovarian immunoreactivity for inhibin and the number of ovarian follicles staining for inhibin in midsaggital ovarian sections were decreased at the time of eCG administration (24 It post-TCDD) in comparison to controls. However, this decreased ovarian staining for inhibin was not associated with alterations in serum inhibin concentrations. Serum inhibin was suppressed in TCDD-treated rats when compared to intact controls only at 24 h post-eCG. Hypophysectomized animals exhibited no effect of TCDD on serum inhibin at any timepoint but did have decreased estradiol concentrations during follicular development. In summary, TCDD reduced serum concentrations of inhibin after the premature increases in FSH and LH suggesting that inhibin is not important in the initial elevation of FSH following exposure to TCDD. AU - Petroff, B.K.* AU - Gao, X.* AU - Ohshima, K.-I.* AU - Son, D.-S.* AU - Roby, K.F.* AU - Rozman, K.K. AU - Watanabe, G.* AU - Taya, K.* AU - Terranova, P.F.* C1 - 9874 C2 - 20315 SP - 97-105 TI - Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on serum inhibin concentrations and inhibin immunostaining during follicular development in female Spraque-Dawley rats. JO - Reprod. Toxicol. VL - 16 PB - Pergamon Press PY - 2002 SN - 0890-6238 ER - TY - JOUR AU - Petroff, B.K.* AU - Gao, X.* AU - Rozman, K.K. AU - Terranova, P.F.* C1 - 21918 C2 - 20235 SP - 269-274 TI - The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on weight gain and hepatic ethoxyresorufin-o-deethylase (EROD) induction vary with ovarian hormonal status in the immature gonadotropin-primed rat model. JO - Reprod. Toxicol. VL - 15 PY - 2001 SN - 0890-6238 ER - TY - JOUR AB - Several studies have established that 2,3,7,8 tetrachloro-p-dioxin (TCDD) blocks ovulation. The main purpose of this study was to determine if induced ovulation was delayed temporarily by TCDD. The ovulation model used was that of the gonadotropin-primed intact or hypophysectomized rat. Immature intact female Sprague-Dawley rats (IIR) were given 32 microg TCDD/kg by gavage on day 24 of age. The next day equine chorionic gonadotropin (eCG) (5 IU) was injected sc to stimulate follicular development. The number of ova in the oviducts, the ovulation rate, and steroid concentrations were determined at 72, 96, 120, and 144 h after eCG. Immature female Sprague-Dawley rats (IHR) were hypophysectomized on day 23 of age. On day 26, the IHR were given 20 microg TCDD/kg by gavage. The next day eCG (10 IU) was injected sc to stimulate follicle development and at 52 h after eCG, 10 IU human chorionic gonadotropin (hCG) was given to induce ovulation. The same parameters as in IIR were determined in IHR at 72, 96, and 120 h after eCG. TCDD decreased body and ovarian weight gains in both IIR and IHR. In IIR, TCDD delayed ovulation by 24 to 48 h reducing the number of ova shed as well as the number of animals ovulating at 72 and 96 h after eCG. In IHR, however, TCDD reduced only the number of ova shed but caused no delay in ovulation. The IIR treated with TCDD had low levels of progesterone (P4) at 72 and 96 h after eCG but high levels of estradiol (E2) at the same time points. This sustained high level of E2 production coincided with a transient decrease in serum concentrations of androstenedione (A4). The alteration of steroid hormones by TCDD was restored to normal by 48 h after ovulation in IIR. Serum P4 concentration was not altered by TCDD in IHR at 72 h after eCG but was decreased thereafter. The delay in ovulation induced by TCDD in IIR indicates the disruption of the hypothalamus-pituitary-ovary axis during proestrus. The decrease in number of ova shed in IHR induced by exogenous gonadotropins indicates an additional direct ovarian effect of TCDD in blocking ovulation. AU - Ushinohama, K.* AU - Son, D.* AU - Roby, K.F.* AU - Rozman, K.K. AU - Terranova, P.F.* C1 - 23914 C2 - 31389 SP - 275-280 TI - Impaired ovulation by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) in immature rats treated with equine chorionic gonadotropin. JO - Reprod. Toxicol. VL - 15 IS - 3 PB - Elsevier PY - 2001 SN - 0890-6238 ER - TY - JOUR AU - Petroff, B.K.* AU - Gao, X.* AU - Rozman, K.K. AU - Terranova, P.F.* C1 - 21867 C2 - 20089 SP - 247-255 TI - Interaction of estradiol and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in an ovulation model : Evidence for systemic potentiation and local ovarian effects. JO - Reprod. Toxicol. VL - 14 PY - 2000 SN - 0890-6238 ER - TY - JOUR AB - The main purpose of this study was to investigate the direct effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on ovarian function including ovulation and steroidogenesis. In vivo effects of TCDD were investigated on ovulation and alteration of circulating and ovarian steroid hormones in immature hypophysectomized rats (IHR) primed with equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG). In addition, in vitro effects of TCDD on the steroidogenesis of granulosa cells (GC), theca-interstitial cells (TIC), and whole ovarian dispersates derived from the ovary of IHR were investigated. In the ovulation model, rats were hypophysectomized on Day 23 of age. On Day 26, the IHR were given 20 microg TCDD/kg by gavage. The next day eCG (10 IU) was injected sc to stimulate follicular development. Fifty-two hours after eCG, 10 IU hCG was given to induce ovulation. TCDD (20 microg/kg) blocked ovulation and reduced ovarian weight in IHR. Concentrations of progesterone (P4), androstenedione (A4), and estradiol (E2) in sera and ovaries were not altered by TCDD at 12, 24, 48, and 72 h after eCG. except for a two-fold increase in ovarian concentration of A4 at 48 h after TCDD. However, this higher concentration of A4 at 48 h after TCDD did not reflect that of A4 in sera and did not correlate with E2 in either sera or ovaries. In isolated GC from untreated IHR, TCDD (0.1 to 100 nM) had no significant effect on P4 and E2 after stimulation by LH or FSH. In TIC and whole ovarian dispersates containing GC, TIC, and other ovarian cells, TCDD (0.1 to 800 nM) had no effect on A4 and P4 secretion stimulated by LH. Using RT-PCR, AhR mRNA was shown to be expressed constitutively in the whole ovary of IHR with maximum down-regulation at 6 h after TCDD (20 microg/kg). Ovarian CYP1A1 was induced maximally at 6 h after TCDD, whereas CYP1B1 could not be detected. The induction of AhR related genes by TCDD in the ovary implies the existence of AhR-mediated signal transduction pathways. In summary, these results indicate that TCDD does not affect ovulation in IHR by altering ovarian steroidogenesis. It seems that inhibition of ovulation by TCDD is due to processes related to follicular rupture. AU - Son, D.S.* AU - Ushinohama, K.* AU - Gao, X.* AU - Taylor, C.C.* AU - Roby, K.F.* AU - Rozman, K.K. AU - Terranova, P.F.* C1 - 24100 C2 - 31441 SP - 521-530 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) blocks ovulation by a direct action on the ovary without alteration of ovarian steroidogenesis: Lack of a direct effect on ovarian granulosa and thecal-interstitial cell steroidogenesis in vitro. JO - Reprod. Toxicol. VL - 13 IS - 6 PB - Elsevier PY - 1999 SN - 0890-6238 ER -